METHOD FOR TREATING TUMOR BY USING RECOMBINANT INTERFERON WITH CHANGED SPATIAL CONFIGURATION
The present invention provides methods for treating tumors in subjects by using a recombinant interferon (rSIFN-co), and optionally, methods for treating solid tumors, such as lung cancer, among others, with or without prior surgery, and as a first line or second line monotherapy or in combination with one or more other anti-tumor therapies. The present invention further provides non-surgical methods for eliminating tumors or reducing tumor sizes in subjects, and/or preventing postoperative tumor recurrence and/or metastases in subjects by using the recombinant interferon (rSIFN-co) which comprises a unique spatial configuration, alone or in conjunction with radiotherapy, chemotherapy, and/or one or more anti-tumor drugs such as biological agents, targeted drugs, small molecules, Traditional Chinese Medicine (TCM) and the like.
The present invention relates to methods for treating tumors in subjects by using recombinant interferon, and to methods for treating solid tumors, including lung cancers in subjects. The present invention further relates to non-surgical methods for eliminating tumors or reducing the sizes of tumors in subjects, or preventing postoperative tumor recurrence and/or metastases and/or prolonging tumor free survival in subjects by using a recombinant interferon (rSIFN-co) with changed spatial configuration, either alone, or in conjunction with radiotherapy, chemotherapy, and/or anti-tumor drugs such as biological agents, targeted drugs and the like.
BACKGROUND OF THE INVENTIONCancer is one of the major causes of death in people around the world. The total number of cases worldwide continues to increase. According to the statistics of the world health organization (WHO), it is estimated that the global cancer deaths will be increased by 45% (from U.S. Pat. No. 7,900,000 to Ser. No. 11/500,000) from 2007 to 2030, and the new cases of cancer will zoom from 11,300,000 in 2007 to 15,500,000 in 2030 in the same period, wherein the incidence rate and the death rate of the lung cancer ranks first in the global malignant tumors. According to the statistical data, the amount of the worldwide new cases of lung cancer every year is more than 3,000,000 and increases continuously (see Gray, J. et al. Chest, 2007, 132, 56S-68S). The number of deaths caused by lung cancer is more than 1,300,000 around the world every year, which is more than the sum of the number of cancer-related deaths caused by other three common cancers (breast cancer, prostate cancer and colorectal cancer).
The classic methods for treating cancer include surgical therapy, radiotherapy and chemotherapy. However, the surgical therapy is not suitable for all types of solid tumors. The surgical therapy may not eliminate cancer cells thoroughly due to metastatic lesions and the like, so as not to achieve the purpose of cure. Radiotherapy is only suitable for the tumors situated at positions that are sensitive to rays, take muscles as tumor beds and have better blood circulation, and the radiotherapy may accidentally injure normal cells to cause various side effects, so as to affect the quality of life of the patients. The effect of the chemotherapy as the systemic treatment means is determined by the types and the states of cancers. Chemotherapy can suppress the growth and the spread of the cancers more especially, and same with the radiotherapy, the chemotherapy can also accidentally injure normal cells to affect the quality of life of the patients.
Surgical therapy can be performed to eliminate tumors, improve the quality of life and provide time for follow-up treatment for some early or medium-term solid tumor patients; but for some advanced patients with metastasized solid tumors, the treatment methods in the prior art are only chemotherapy, radiotherapy or combining the chemotherapy, radiotherapy and other treatment methods when the quality of life is obviously affected and life is even threatened, these treatment methods are not ideal in effects and cannot achieve the purpose of eliminating the tumors and completely alleviating the condition of the patients.
According to the mass data, the existing methods for treating cancer, in particular, chemotherapy, cannot obtain the satisfied treatment effect for advanced lung cancer patients, and the number of complete remission (CR) cases is few and is even zero. For example, in the clinical trial of 78 cases which employed cis-platinum for combining Navelbine, Gemzar and Taxotere, respectively, to treat advanced non-small cell lung cancers, no complete remission appeared in any case (see Song, Y. et al, Journal of Modern Oncology, 2005, 13(4), 494-496); however, in the clinical observation of 1155 cases which employed four chemotherapy protocols (Cisplatin+Paclitaxel, Cisplatin+Gemcitabine, Cisplatin+Docetaxel, and Carboplatin+Paclitaxel) for treating the advanced non-small cell lung cancers, complete response was observed, but the complete response (CR) rate was less than 1% (see Schiller, J. H. et al. N Engl J Med, 2002, 346(2), 92-98); and in a random, double-blind, control and multicenter III-stage clinical research which employed recombinant human endostatin for combining NP to treat the advanced non-small cell lung cancers, the 486 evaluable cases in the test group and the control group yielded no cases of complete remission (see Wang, J. W. et al, Chinese Journal of Lung Cancer, 2005, 8(4), 283-290).
In the recent 20 years, due to the in depth research on the cell biology, molecular biology, tumor immunology and the like and the development of the bio-engineering technology, the biotherapy has become the important treatment means for cancer treatment after surgical therapy, radiotherapy and chemotherapy has been performed.
Since Isaacs and Lindenmann discovered interferon (IFN), interferon has been widely researched. Interferon (IFN) is a kind of soluble protein produced by a variety of cells which has many important biological functions, including anti-viral, anti-tumor, and immunoregulatory functions. Interferons can be divided into type I, type II, and type III interferons according to the differences in the types of producing cells, receptors and biological activities, etc. Type I IFNs, which are mostly induced by viruses and synthetic double-stranded RNA, are also known as anti-viral interferons. There are three forms of type I interferons: interferon-alpha or alpha-interferon (IFNα), interferon-beta (INFβ) and interferon omega (IFNω).
In recent years, many companies in the world have engaged in the research of interferon. For example, U.S. Pat. Nos. 4,695,623 and 4,897,471 disclosed new types of human interferon polypeptides which possessed amino acid sequences containing the common or predominant amino acids found in naturally occurring α-interferon polypeptides. One new type of interferon was named IFN-con (consensus interferon α). Compared with leukocyte interferon or other type I interferons, studies have shown that recombinant IFN-con has higher anti-viral, anti-proliferative and natural killer cell activities in vitro. By the end of 1997, the FDA had approved the use of human IFN-con, which was produced by US Amgen and sold under the brand name INFERGEN® (interferon alfacon-1), for clinical treatment of hepatitis C.
It is generally known that the amino acid sequence of a protein can determine the three-dimensional structure of the protein and further determine the functionality thereof. However, in recent years, evidence shows that synonymous mutation(s) of the nucleotide sequence encoding the protein (that is, codon mutation(s) with no change in the amino acid sequence of the encoded protein) can affect the spatial structure and the function of the encoded protein, namely, the nucleotide sequence with synonymous mutation(s) can express and generate proteins with different final spatial structure and different function compared with the wild type protein (see Sarfaty, C. K. et al. Science, 2007, 315:525-528).
A recombinant interferon (rSIFN-co) which has enhanced therapeutic effects, smaller side effects and can be used in a larger doses was disclosed in U.S. Pat. No. 7,364,724, U.S. Pat. No. 7,585,647, U.S. Pat. No. 8,114,395, CN 1740197 A, CN 101001644 A, US 2009/0123417, US 2011/0158941 and WO 2011072487A1. This recombinant interferon, rSIFN-co, has the same amino acid sequence as that of INFERGEN®, but the encoding nucleotide sequences of this recombinant interferon, rSIFN-co, and that of INFERGEN® are different (i.e. synonymous mutations exists in the nucleotide sequence encoding the recombinant interferon, rSIFN-co), resulting in changes in spatial configuration of the recombinant interferon, rSIFN-co, and qualitative changes in its biological efficacy.
SUMMARY OF THE INVENTIONOne of the objects of the present invention is to provide new methods for treating tumors in subjects by using the recombinant interferon, rSIFN-co encoded by the nucleotide sequence of SEQ ID NO: 2. Another one of the objects of the present invention is to provide new methods for treating lung cancers in subjects by using the recombinant interferon encoded by the nucleotide sequence of SEQ ID NO: 2 (hereafter also be referred to as recombinant super-compound interferon or rSIFN-co).
The present invention is illustrated by the various embodiments described below. However, the present invention is not limited by these illustrative embodiments and should be interpreted to include those embodiments taught by the description herein and as understood by persons skilled in the art. Illustrative examples of the various embodiments of the present invention include:
In one aspect, the present invention provides:
(1) A method for treating a tumor in a subject, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2.
(2) The method of (1), wherein the tumor in the subject comprises a metastasized tumor.
(3) The method of (1) or (2), wherein the subject is an early, medium-term, or advanced cancer patient, optionally, the subject is a medium-term, or advanced cancer patient, further optionally, the subject is an advanced cancer patient.
(4) The method of (1) or (2), wherein the subject is a stage 0, I, II, III, or IV cancer patient, optionally, the subject is a stage III or stage IV cancer patient.
(5) The method of any one of (1)-(4), wherein the tumor is a cancer or a solid tumor that is indicated or appropriate for surgery.
(6) The method of any one of (1)-(4), wherein the tumor is a cancer or a solid tumor that is not indicated nor appropriate for surgery.
(7) The method of any one of (1)-(5), wherein the tumor is a tumor that is capable of being resected.
(8) The method of any one of (1)-(4) and (6), wherein the tumor is a tumor that is not capable of being resected.
(9) The method of (7) or (8), wherein the tumor is resected by a surgical resection.
(10) The method of any one of (1)-(9), wherein the tumor is a solid tumor.
(11) The method of (10), wherein the solid tumor comprises one or more of: lung cancer, liver cancer, hepatocellular carcinoma (HCC), esophageal cancer, cholangiocarcinoma, gallbladder carcinoma, stomach cancer, abdominal cancer, gastrointestinal cancer, gastric cancer, pancreatic cancer, renal cell carcinoma, renal cancer, bone cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, endometrial cancer, colorectal cancer, colon cancer, rectal cancer, bladder cancer, superficial bladder cancer, prostate cancer, adrenal tumors, squamous cell carcinoma, neuroma, malignant neuroma, myoepithelial carcinoma, synovial sarcoma, rhabdomyosarcoma, gastrointestinal interstitial cell tumor, skin cancer, basal cell carcinoma, malignant melanoma, thyroid cancer, nasopharyngeal carcinoma, hemangioma, epidermoid carcinoma, head and neck cancer, glioma, or Kaposi's sarcoma.
(12) The method of (11), wherein the solid tumor comprises lung cancer, optionally, the lung cancer comprises small cell lung cancer (SCLC), non small cell lung cancer (NSCLC), or both.
(13) The method of any one of (1)-(4), wherein the tumor is a non-solid tumor.
(14) The method of (13), wherein the non-solid tumor comprises one or more of: leukemia, acute leukemia, chronic leukemia, chronic myelocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell leukemia, hairy cell leukemia, polycythemia, myelodysplastic syndrome, multiple myeloma, lymphadenoma, Hodgkin's lymphoma, and Non-Hodgkin's lymphoma.
(15) The method of any one of (1)-(14), wherein the recombinant interferon is administered to the subject by at least one of: systemic administration, local administration, and topical administration.
(16) The method of any one of (1)-(15), wherein the recombinant interferon is administered to the subject by an administration route, the administration route comprises one or more of: oral, rectal, sublingual, intravenous, intra-arterial, intramuscular, subcutaneous, intra-bone, intracutaneous, intra-articular, intraperitoneal, intrathecal, intracerebral, vaginal, percutaneous, transdermal, epidermal, transmucosal, transocular, pulmonary, nasal, abdominal, intrapleural, intraventricular, pericardial, inhalation, intratumoral, uterine, infiltration, and intravesical administration.
(17) The method of any one of (1)-(16), wherein an effective amount of recombinant interferon encoded by the nucleotide sequence of SEQ ID NO: 2 is administered to the subject, optionally, the effective amount is a therapeutically effective amount.
(18) The method of any one of (1)-(17), wherein the recombinant interferon is administered to the subject in a single dose in a range of about 2 μg to about 2000 μg, optionally, the recombinant interferon is administered to the subject in a single dose in a range of about 4 μg to about 1500 μg, further optionally, the recombinant interferon is administered to the subject in a single dose in a range of about 9 μg to about 1000 μg.
(19) The method of any one of (1)-(18), wherein the recombinant interferon is administered in one or more treatment cycles, optionally, the more treatment cycles comprises 2, 3, 4, 5, 6, 7, 8, 9, 10 treatment cycles, further optionally, the number of treatment cycles comprises more than 10 treatment cycles.
(20) The method of (19), wherein the duration of the treatment cycle is at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years and the like, or optionally, the recombinant interferon can be administered for a long time, including over the life time of the subject; or the duration of recombinant interferon treatment can also be about 1 day to about 6 years, about 1 week to about 4 years, about 2 weeks to about 3 years, about 1 month to about 1 year, or about 2 months to about 9 months and the like.
(21) The method of (19) or (20), wherein the time interval between any two adjacent treatment cycles of the more treatment cycles is at least about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years and the like; or optionally the time interval can be about 2 days to about 6 years, about 4 days to about 3 years, about 1 week to about 1 year, about 2 months to about 9 months, or about 3 months to about 6 months and the like.
(22) The method of any one of (1)-(21), wherein the recombinant interferon is administered to the subject as monotherapy.
(23) The method of any one of (1)-(21), further comprising at least one other anti-cancer therapy administered to the subject, optionally, the at least one other anti-cancer therapy is administered to the subject before, simultaneously, and/or after administration of the recombinant interferon.
(24) The method of (23), wherein the at least one other anti-cancer therapy comprises at least one of: chemotherapy, radiotherapy, surgical therapy, interventional therapy, biotherapy, gene therapy, ablation therapy, immunotherapy, targeted therapy, and traditional Chinese medicine therapy.
(25) The method of (24), wherein the at least one other anti-cancer therapy comprises at least one of: chemotherapy, radiotherapy, surgical therapy, targeted therapy, and biotherapy.
(26) The method of (25), wherein the at least one other anti-cancer therapy comprises at least one of: chemotherapy and radiotherapy.
(27) The method of any one of (24)-(26), wherein the chemotherapy is administered as first-line chemotherapy, optionally, one or more chemotherapeutic drugs used in the first-line chemotherapy comprise platinum compounds, such as Cisplatin.
(28) The method of any one of (24)-(27), wherein the targeted therapy comprises at least one of: Gefitinib, Erlotinib, and recombinant human endostatin.
(29) The method of any one of (1)-(28), wherein the therapies eliminate the tumor or reduce the size of the tumor as compared to the tumor before treatment.
(30) The method of (29), wherein the reduced size of the tumor converts the tumor to a resectable tumor.
(31) The method of (30), wherein the tumor is indicated for a surgical resection.
(32) The method of any one of (1)-(28), wherein the tumor, such as cancer or solid tumor, that is not earlier indicated nor appropriate for surgery becomes one that is indicated or appropriate for surgery.
(33) The method of (32), further comprising surgery to resect the tumor.
(34) The method of any one of (30)-(31) and (33), further comprising administering to the subject the recombinant interferon after resecting the tumor, to prevent tumor recurrence and/or metastasis, or to prolong or maintain a tumor-free status, optionally, a prophylactically effective amount of the recombinant interferon is administered to the subject to prevent tumor recurrence and/or metastasis, and/or to prolong or maintain a tumor-free status.
(35) A method for treating tumor in a subject, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2, and at least one other anti-cancer therapy, wherein the at least one other anti-cancer therapy is administered to the subject before, simultaneously, and/or after administration of the recombinant interferon, and wherein the tumor is a cancer or solid tumor that is not indicated nor appropriate for surgery, or the tumor is a solid tumor that cannot be resected, and the combination of the recombinant interferon and the at least one other anti-cancer therapy eliminate the tumor or reduce the size of the tumor compared to the tumor before treatment.
(36) The method of embodiment 35, wherein the subject is a medium-term, advanced cancer patient, or stage III or stage IV cancer patient, optionally, the subject is an advanced, or stage III or stage IV cancer patient.
(37) The method of any one of (1)-(29) and (35)-(36), wherein the therapies are the non-surgical therapies.
In another aspect, another embodiment of the present invention provides:
(1) A method for preventing tumor recurrence and/or metastasis or prolonging or maintaining a tumor-free status in a subject with a tumor after at least one anti-cancer therapy, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2.
(2) The method of (1), wherein the tumor in the subject comprises a metastasized tumor.
(3) The method of (1) or (2), wherein the subject is an early, medium-term, or advanced cancer patient.
(4) The method of (1) or (2), wherein the subject is a stage 0, I, II, III, or IV cancer patient.
(5) The method of any one of (1)-(4), wherein the tumor is a cancer or solid tumor that is indicated or appropriate for surgery.
(6) The method of any one of (1)-(4), wherein the tumor is a cancer or solid tumor that is not indicated nor appropriate for surgery.
(7) The method of any one of (1)-(4), wherein the tumor is a tumor that is capable of being resected.
(8) The method of any one of (1)-(4), wherein the tumor is a tumor that is not capable of being resected.
(9) The method of (7) or (8), wherein the tumor is resected by a surgical resection.
(10) The method of any one of (1)-(9), wherein the tumor is a solid tumor.
(11) The method of (10), wherein the solid tumor comprises one or more of: lung cancer, liver cancer, hepatocellular carcinoma (HCC), esophageal cancer, cholangiocarcinoma, gallbladder carcinoma, stomach cancer, abdominal cancer, gastrointestinal cancer, gastric cancer, pancreatic cancer, renal cell carcinoma, renal cancer, bone cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, endometrial cancer, colorectal cancer, colon cancer, rectal cancer, bladder cancer, superficial bladder cancer, prostate cancer, adrenal tumors, squamous cell carcinoma, neuroma, malignant neuroma, myoepithelial carcinoma, synovial sarcoma, rhabdomyosarcoma, gastrointestinal interstitial cell tumor, skin cancer, basal cell carcinoma, malignant melanoma, thyroid cancer, nasopharyngeal carcinoma, hemangioma, epidermoid carcinoma, head and neck cancer, glioma, or Kaposi's sarcoma.
(12) The method of (11), wherein the solid tumor comprises lung cancer, optionally, the lung cancer comprises small cell lung cancer (SCLC), non small cell lung cancer (NSCLC), or both.
(13) The method of any one of (1)-(4), wherein the tumor comprises a non-solid tumor.
(14) The method of (13), wherein the non-solid tumor comprises one or more of: leukemia, acute leukemia, chronic leukemia, chronic myelocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell leukemia, hairy cell leukemia, polycythemia, myelodysplastic syndrome, multiple myeloma, lymphadenoma, Hodgkin's lymphoma, and Non-Hodgkin's lymphoma.
(15) The method of any one of (1)-(14), wherein the recombinant interferon is administered to the subject by at least one of: systemic administration, local administration, and topical administration.
(16) The method of any one of (1)-(15), wherein the recombinant interferon is administered to the subject by an administration route, the administration route comprises one or more of: oral, rectal, sublingual, intravenous, intra-arterial, intramuscular, subcutaneous, intra-bone, intracutaneous, intra-articular, intraperitoneal, intrathecal, intracerebral, vaginal, percutaneous, transdermal, epidermal, transmucosal, transocular, pulmonary, nasal, abdominal, intrapleural, intraventricular, pericardial, inhalation, intratumoral, uterine, infiltration, and intravesical administration.
(17) The method of any one of (1)-(16), wherein an effective amount of recombinant interferon encoded by the nucleotide sequence of SEQ ID NO: 2 is administered to the subject, optionally, the effective amount is a prophylactically effective amount.
(18) The method of any one of (1)-(17), wherein the recombinant interferon is administered to the subject in a single dose in the range of about 2 μg to about 2000 μg, optionally, the recombinant interferon is administered to the subject in a single dose in the range of about 4 μg to about 1500 μg, more optionally, the recombinant interferon is administered to the subject in a single dose in the range of about 9 μg to about 1000 μg.
(19) The method of any one of (1)-(18), wherein the recombinant interferon is administered in one or more prevention cycles, optionally, the more prevention cycles comprises 2, 3, 4, 5, 6, 7, 8, 9, or 10 prevention cycles, or optionally, more than 10 prevention cycles.
(20) The method of (19), wherein the duration of each prevention cycle is at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years and the like, or the recombinant interferon can be administered for a long time, including over the life time of the subject; or the duration can also be about 1 day to about 6 years, about 1 week to about 4 years, about 2 weeks to about 3 years, about 1 month to about 1 year, or about 2 months to about 9 months and the like.
(21) The method of (19) or (20), wherein the time interval between any two adjacent prevention cycles of the more prevention cycles is at least about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years and the like; or the time interval can also be about 2 days to about 6 years, about 4 days to about 3 years, about 1 week to about 1 year, about 2 months to about 9 months, or about 3 months to about 6 months and the like.
(22) The method of any one of (1)-(21), wherein the at least one anti-cancer therapy comprises at least one of: chemotherapy, radiotherapy, surgical therapy, interventional therapy, biotherapy, gene therapy, ablation therapy, immunotherapy, targeted therapy, and traditional Chinese medicine therapy, optionally, the at least one anti-cancer therapy comprises at least one of: chemotherapy, radiotherapy, surgical therapy, and biotherapy.
(23) The method of (22), wherein the at least one anti-cancer therapy comprises surgical therapy.
(24) The method of (23), wherein the recombinant interferon is administered to the operative site of the surgical therapy.
(25) The method of (24), wherein the recombinant interferon is administered to the operative site by topical or local administration.
(26) The method of (24) or (25), wherein the recombinant interferon is administered to the operative site by an administration route, the administration route comprises one or more of: infiltration administration, intrapleural administration, abdominal administration, pericardial administration, uterine administration, intravesical administration, intratumoral administration, pulmonary administration, nasal administration, percutaneous administration, transdermal administration, epidermal administration, and transmucosal administration.
(27) The method of (26), wherein the intrapleural administration, abdominal administration, pericardial administration, uterine administration, or intravesical administration comprises intrapleural perfusion administration, abdominal perfusion administration, pericardial perfusion administration, uterine perfusion administration, or intravesical perfusion administration, respectively.
(28) The method of (26), wherein the intratumoral administration comprises intratumoral injection.
(29) The method of (26), wherein the pulmonary administration or nasal administration comprises pulmonary inhalation administration or nasal inhalation administration, respectively.
(30) The method of (26), wherein the percutaneous administration, transdermal administration, epidermal administration, or transmucosal administration comprises percutaneous spray administration, transdermal spray administration, epidermal spray administration, or transmucosal spray administration, respectively.
(31) The method of any one of (25)-(30), wherein the recombinant interferon is further administered to the subject by systemic administration before, simultaneously, and/or after the topical or local administration of the recombinant interferon.
(32) The method of (31), wherein the systemic administration comprises at least one of: subcutaneous and intramuscular administration, optionally, the protocols in (24)-(32) also apply to the above-specified method for treatment of tumor in a subject.
(33) The method of any one of (1)-(32), wherein the recombinant interferon is administered to the subject as monotherapy.
In another aspect, another embodiment of the present invention provides:
(1) A non-surgical method for eliminating a tumor in a subject or reducing the size of a tumor in a subject, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2.
(2) The method of (1), wherein the tumor is a cancer or a solid tumor that is indicated or appropriate for surgery.
(3) The method of (1), wherein the tumor is a cancer or a solid tumor that is not indicated nor appropriate for surgery.
(4) The method of (1), wherein the tumor is a tumor that is capable of being resected.
(5) The method of (1), wherein the tumor is a tumor that is not capable of being resected.
(6) The method of (4) or (5), wherein the tumor is resected by a surgical resection.
(7) The method of any one of (1)-(6), wherein the subject is an early, medium-term, or advanced cancer patient, optionally, the subject is a medium-term, or advanced cancer patient, or further optionally, the subject is an advanced cancer patient.
(8) The method of any one of (1)-(6), wherein the subject is a stage 0, I, II, III, or IV cancer patient, optionally, the subject is a stage III or IV cancer patient.
(9) The method of any one of (1)-(8), wherein the subject is a medium-term, or advanced cancer patient, or a stage III or stage IV cancer patient, optionally, the subject is an advanced, or stage III or stage IV cancer patient.
(10) The method of any one of (1)-(9), wherein the tumor is a solid tumor.
(11) The method of (10), wherein the solid tumor comprises one or more of: lung cancer, liver cancer, hepatocellular carcinoma (HCC), esophageal cancer, cholangiocarcinoma, gallbladder carcinoma, stomach cancer, abdominal cancer, gastrointestinal cancer, gastric cancer, pancreatic cancer, renal cell carcinoma, renal cancer, bone cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, endometrial cancer, colorectal cancer, colon cancer, rectal cancer, bladder cancer, superficial bladder cancer, prostate cancer, adrenal tumors, squamous cell carcinoma, neuroma, malignant neuroma, myoepithelial carcinoma, synovial sarcoma, rhabdomyosarcoma, gastrointestinal interstitial cell tumor, skin cancer, basal cell carcinoma, malignant melanoma, thyroid cancer, nasopharyngeal carcinoma, hemangioma, epidermoid carcinoma, head and neck cancer, glioma, or Kaposi's sarcoma.
(12) The method of (11), wherein the solid tumor comprises lung cancer, optionally, the lung cancer comprises small cell lung cancer (SCLC), non small cell lung cancer (NSCLC), or both.
(13) The method of any one of (1)-(12), wherein the recombinant interferon is administered to the subject by at least one of: systemic administration, local administration, and topical administration, optionally, the recombinant interferon is administered to the subject by topical or local administration, further optionally, the recombinant interferon is administered to the subject by local administration.
(14) The method of any one of (1)-(13), wherein the recombinant interferon is administered to the subject by an administration route, the administration route comprises one or more of: infiltration administration, intrapleural administration, abdominal administration, pericardial administration, uterine administration, intravesical administration, intratumoral administration, pulmonary administration, nasal administration, percutaneous administration, transdermal administration, epidermal administration, and transmucosal administration.
(15) The method of (14), wherein the intratumoral administration comprises intratumoral injection.
(16) The method of (15), wherein the recombinant interferon is administered in an amount in a range of: about 60 μg to about 600 μg, optionally about 60 μg to about 500 μg, further optionally, about 80 μg to about 400 μg, still optionally about 100 μg to about 250 μg, by one intratumoral injection.
(17) The method of (15) or (16), wherein the recombinant interferon is administered by intratumoral injection once every about 1 day to about 10 days, optionally, every about 1 day to about 7 days, such as every about 1, 2, 3, 4, 5, 6, or 7 days.
(18) The method of any one of (14)-(17), wherein the protocol of intratumoral administration is as follows: the recombinant interferon is administered by intratumoral injection once every about 1 day for about 4 to about 8 times, and then the recombinant interferon is administered by intratumoral injection once every about 3 days to about 5 days for about 4 to about 8 times, and then the recombinant interferon is administered by intratumoral injection once every about 7 days, the intratumoral administration is stopped when the tumor disappears or becomes too small to conduct the intratumoral injection.
(19) The method of (14), wherein the intrapleural administration, abdominal administration, pericardial administration, uterine administration, or intravesical administration comprises intrapleural perfusion administration, abdominal perfusion administration, pericardial perfusion administration, uterine perfusion administration, or intravesical perfusion administration, respectively.
(20) The method of (14), wherein the pulmonary administration, or nasal administration comprises pulmonary inhalation administration, or nasal inhalation administration, respectively.
(21) The method of (14), wherein the percutaneous administration, transdermal administration, epidermal administration, or transmucosal administration comprises percutaneous spray administration, transdermal spray administration, epidermal spray administration, or transmucosal spray administration, respectively.
(22) The method of any one of (13)-(21), wherein the recombinant interferon is further administered to the subject by systemic administration, and/or at least one other therapeutic drug is administered to the subject by topical, local and/or systemic administration before, simultaneously, and/or after the topical or local administration of the recombinant interferon.
(23) The method of (22), wherein the recombinant interferon is further administered to the subject by systemic administration, and/or at least one other therapeutic drug is administered to the subject by topical, local and/or systemic administration simultaneously and/or after the topical or local administration of the recombinant interferon.
(24) The method of (22) or (23), wherein the at least one other therapeutic drug comprises at least one antitumor drug.
(25) The method of (24), wherein the at least one antitumor drug comprises one or more chemotherapeutic drugs, targeted drugs, and/or biological drugs.
(26) The method of (25), wherein the one or more chemotherapeutic drugs comprise platinum compounds, such as Cisplatin.
(27) The method of (25), wherein one or more targeted drugs comprise Gefitinib, Erlotinib, and/or recombinant human endostatin.
In another aspect, another embodiment of the present invention provides:
(1) A method for eliminating or reducing the pleural effusion, ascites, and/or pericardial effusion in a subject with tumor, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2.
(2) The method of (1), wherein the tumor is a cancer or a solid tumor that is indicated or is appropriate for surgery.
(3) The method of (1), wherein the tumor is a cancer or a solid tumor that is not indicated nor appropriate for surgery.
(4) The method of (1), wherein the tumor is a tumor that is capable of being resected.
(5) The method of (1), wherein the tumor is a tumor that is not capable of being resected.
(6) The method of (4) or (5), wherein the tumor is resected by a surgical resection.
(7) The method of any one of (1)-(6), wherein the subject is an early, medium-term, or advanced cancer patient, optionally, the subject is a medium-term, or advanced cancer patient, or further optionally, the subject is an advanced cancer patient.
(8) The method of any one of (1)-(6), wherein the subject is a stage 0, I, II, III, or IV cancer patient, optionally, the subject is a stage III or stage IV cancer patient.
(9) The method of any one of (1)-(8), wherein the subject is a medium-term, or advanced cancer patient, or stage III or stage IV cancer patient, optionally, the subject is an advanced, or stage III or stage IV cancer patient.
(10) The method of any one of (1)-(9), wherein the tumor is a solid tumor.
(11) The method of (10), wherein the solid tumor comprises one or more of: lung cancer, liver cancer, hepatocellular carcinoma (HCC), esophageal cancer, cholangiocarcinoma, gallbladder carcinoma, stomach cancer, abdominal cancer, gastrointestinal cancer, gastric cancer, pancreatic cancer, renal cell carcinoma, renal cancer, bone cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, endometrial cancer, colorectal cancer, colon cancer, rectal cancer, bladder cancer, superficial bladder cancer, prostate cancer, adrenal tumors, squamous cell carcinoma, neuroma, malignant neuroma, myoepithelial carcinoma, synovial sarcoma, rhabdomyosarcoma, gastrointestinal interstitial cell tumor, skin cancer, basal cell carcinoma, malignant melanoma, thyroid cancer, nasopharyngeal carcinoma, hemangioma, epidermoid carcinoma, head and neck cancer, glioma, or Kaposi's sarcoma.
(12) The method of (11), wherein the solid tumor comprises lung cancer, optionally, the lung cancer comprises small cell lung cancer (SCLC), non small cell lung cancer (NSCLC), or both.
(13) The method of any one of (1)-(12), wherein the pleural effusion is a malignant pleural effusion, the ascites is a malignant ascites, and/or the pericardial effusion is a malignant pericardial effusion.
(14) The method of any one of (1)-(13), wherein the recombinant interferon is administered to the subject by at least one of: systemic administration, local administration, and topical administration, optionally, by topical and local administration, further optionally, by local administration.
(15) The method of any one of (1)-(14), wherein the recombinant interferon is administered to the subject by an administration route, the administration route comprises one or more of: infiltration administration, intrapleural administration, abdominal administration, and pericardial administration.
(16) The method of any one of (1)-(15), wherein the administration is conducted by perfusion.
(17) The method of any one of (14)-(16), wherein the recombinant interferon is administered in an amount in a range of about 30 μg to about 2000 μg, optionally, about 100 μg to about 1500 μg, further optionally, about 150 μg to about 1000 μg, still further optionally, about 200 μg to about 800 μg, still optionally, about 200 μg to about 400 μg by one topical or local administration.
(18) The method of any one of (14)-(17), wherein the recombinant interferon is administered by topical or local administration once every about 1 to about 10 days, optionally every about 1 to about 7 days, such as every about 1, 2, 3, 4, 5, 6, or 7 days.
(19) The method of any one of (14)-(18), wherein the recombinant interferon is further administered to the subject by systemic administration, and at least one other therapeutic drug is administered to the subject by topical, local and/or systemic administration before, simultaneously, and/or after the topical or local administration of the recombinant interferon.
(20) The method of (19), wherein the recombinant interferon is further administered to the subject by systemic administration, and at least one other therapeutic drug is administered to the subject by topical, local and/or systemic administration simultaneously and/or after the topical or local administration of the recombinant interferon.
(21) The method of (19) or (20), wherein the at least one other therapeutic drug comprises an antitumor drug.
(22) The method of (21), wherein the antitumor drug comprises at least one of: chemotherapeutic drug, targeted drug, and biological drug.
(23) The method of (22), wherein the at least one chemotherapeutic drug comprises at least one platinum compounds, such as Cisplatin.
(24) The method of (22), wherein at least one targeted drug comprises at least one of: Gefitinib, Erlotinib, and recombinant human endostatin.
(25) The method of any one of (1)-(24), wherein the therapies eliminate the tumor or reduce the size of the tumor compared to the tumor before treatment.
(26) The method of any one of (1)-(25), wherein the therapies are the non-surgical therapies.
In another aspect, another embodiment of the present invention provides:
(1) A method for treating tumor in a subject, comprising topically or locally administering to the tumor lesions of the subject a recombinant interferon encoded by SEQ ID NO: 2.
(2) The method of (1), wherein the tumor lesions comprise metastatic tumor lesions.
(3) A method for eliminating or reducing metastatic tumor lesions in a subject, comprising topically or locally administering to the metastatic tumor lesions of the subject a recombinant interferon encoded by SEQ ID NO: 2.
(4) The method of any one of (1)-(3), wherein the tumor lesions comprise at least one of: bone lesions, muscular lesions, subcutaneous tissue lesions, prostatic lesions and lymph node lesions, and the tumor metastatic lesions comprise at least one of: bone metastatic lesions, muscular metastatic lesions, subcutaneous tissue metastatic lesions, prostatic metastatic lesions, and lymph node metastatic lesions, optionally, the tumor metastatic lesions comprise bone metastatic lesions.
(5) The method of any one of (1)-(4), wherein the subject is a medium-term, advanced, or stage III or stage IV cancer patient, optionally, the subject is an advanced, or stage III or stage IV cancer patient.
(6) The method of any one of (1)-(4), wherein the tumor or the metastatic tumor lesions comprise a cancer or a solid tumor that is not indicated nor appropriate for surgery.
(7) The method of any one of (1)-(6), wherein the topical or local administration comprises at least one of: infiltration administration, percutaneous administration, transdermal administration, epidermal administration and transmucosal administration, optionally, the topical and local administration comprises transdermal administration, or infiltration administration.
(8) The method of (7), wherein the infiltration administration comprises one or more of: percutaneous infiltration administration, epidermal infiltration administration, transdermal infiltration administration, and transmucosal infiltration administration.
(9) The method of (7), wherein the percutaneous administration, transdermal administration, epidermal administration, or transmucosal administration comprises percutaneous spray administration, transdermal spray administration, epidermal spray administration, or transmucosal spray administration, respectively.
(10) The method of any one of (1)-(9), wherein the recombinant interferon is administered in an amount in a range of about 2 μg to about 2000 μg, optionally about 4 μg to about 1500 μg, further optionally about 9 μg to about 1000 μg by one topical or local administration.
(11) The method of any one of (1)-(10), wherein the recombinant interferon is administered to the subject by topical or local administration about 1, 2, 3, 4, 5, 6, 7, 8, or more times per day, or the recombinant interferon is administered to the subject by topical or local administration once at the time interval of every about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days, every month, every 2 months, or a longer time.
(12) The method of any one of (7)-(11), wherein the recombinant interferon is administered in an amount in a range of about 6 μg to about 100 μg, optionally about 10 μg to about 40 μg, further optionally about 20 μg to about 40 μg by one spray administration when the topical or local administration is conducted by spray administration.
(13) The method of (12), wherein the recombinant interferon is administered by spray administration about 1 to about 6 times, such as about 1, 2, 3, 4, 5, or 6 times, per day.
(14) The method of any one of (1)-(13), wherein the recombinant interferon and/or one or more other therapeutic drugs are administered to the subject by systemic administration before, simultaneously, and/or after the topical or local administration of the recombinant interferon.
(15) The method of (14), wherein the systemic administration comprises subcutaneous and/or intramuscular administration.
(16) The method of (15), wherein the subcutaneous administration comprises subcutaneous injection.
(17) The method of (15), wherein the intramuscular administration comprises intramuscular injection.
(18) The method of any one of (15)-(17), wherein the recombinant interferon is administered one or more times by subcutaneous administration and/or intramuscular administration at an induction dose in the range of about 2 μg to about 10 μg each time, optionally, about 4 μg to about 10 μg each time, more optionally about 4.5 μg to about 9 μg each time, such as about 4.5 μg each time or about 9 μg each time, and then the recombinant interferon is administered more times by subcutaneous administration and/or intramuscular administration at a therapeutic dose of about 10 μg to about 70 μg each time, optionally about 12 μg to about 50 μg each time, more optionally about 12 μg to about 30 μg each time.
(19) The method of (18), wherein the time interval between administration of induction dose and administration of therapeutic dose is about 1 day to about 1 month, optionally about 1 day to about 1 week, further optionally about 1 day to about 3 days, comprising such as about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, or about 1 month.
(20) The method of (18) or (19), wherein the recombinant interferon is administered once every about 1 day to about 10 days, optionally every about 1 day to about 7 days, further optionally every about 1 to about 2 days, comprising such as every about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days when the recombinant interferon is administered more times at an induction dose.
(21) The method of any one of (18)-(20), wherein the recombinant interferon is administered at a therapeutic dose once every about 1 day to about 10 days, optionally every about 1 day to about 7 days, further optionally every about 1 to about 2 days, comprising such as every about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days.
(22) The method of any one of (18)-(21), wherein the duration of administration of induction dose and therapeutic dose is at least: about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years and the like, or the recombinant interferon can be administered for a long time, including over the life time of the subject.
(23) The method of any one of (1)-(22), wherein the recombinant interferon is administered to the subject as monotherapy.
(24) The method of any one of (1)-(22), further comprising at least one other anti-cancer therapy administered to the subject, optionally, the at least one other anti-cancer therapy is administered to the subject before, simultaneously, and/or after administration of the recombinant interferon.
(25) The method of (24), wherein the at least one other anti-cancer therapy comprises one or more of: chemotherapy, radiotherapy, surgical therapy, interventional therapy, biotherapy, gene therapy, ablation therapy, immunotherapy, targeted therapy, and traditional Chinese medicine therapy.
(26) The method of any one of (1)-(25), wherein the recombinant interferon therapy and/or at least one other anti-cancer therapy eliminate the tumor or tumor metastatic lesions or reduce the size of the tumor or tumor metastatic lesions compared to the tumor or tumor metastatic lesions before treatment.
(27) A method for eliminating or reducing the bone metastatic lesions of tumor in a subject, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2 by topical or local administration, wherein the topical or local administration comprises transdermal administration and/or infiltration administration, optionally, the recombinant interferon is administered to the bone metastatic lesions of tumor of the subject.
(28) A method for eliminating or reducing the bone lesions of tumor such as bone metastatic lesions of tumor, muscular lesions of tumor such as muscular metastatic lesions of tumor, subcutaneous tissue lesions of tumor such as subcutaneous tissue metastatic lesions of tumor, prostatic lesions of tumor such as prostatic metastatic lesions of tumor, and/or lymph node lesions of tumor such as lymph node metastatic lesions of tumor in a subject, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2 by any administration route through the skin, so that eliminating or reducing the bone lesions of tumor such as bone metastatic lesions of tumor, muscular lesions of tumor such as muscular metastatic lesions of tumor, subcutaneous tissue lesions of tumor such as subcutaneous tissue metastatic lesions of tumor, prostatic lesions of tumor such as prostatic metastatic lesions of tumor, and/or lymph node lesions of tumor such as lymph node metastatic lesions of tumor, optionally, the recombinant interferon is administered to the metastatic lesions of tumor of the subject.
(29) The method of any one of (1)-(28), wherein the therapies are non-surgical therapies.
In another aspect, another embodiment of the present invention provides:
(1) A method for treating lung cancer in a subject, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2.
(2) The method of (1), wherein the lung cancer comprises small cell lung cancer (SCLC), non small cell lung cancer (NSCLC), or both.
(3) The method of (1) or (2), wherein the lung cancer in the subject comprises a metastasized tumor.
(4) The method of any one of (1)-(3), wherein the subject is an early, medium-term, or advanced cancer patient, optionally, the subject is a medium-term, or advanced cancer patient, further optionally, the subject is an advanced cancer patient.
(5) The method of any one of (1)-(3), wherein the subject is a stage 0, I, II, III, or IV cancer patient, optionally, the subject is an stage III or stage IV cancer patient.
(6) The method of any one of (1)-(5), wherein the lung cancer comprises a lung cancer that is indicated or appropriate for surgery.
(7) The method of any one of (1)-(5), wherein the lung cancer comprises a lung cancer that is not indicated nor appropriate for surgery.
(8) The method of any one of (1)-(5), wherein the lung cancer comprises a lung cancer that is capable of being resected.
(9) The method of any one of (1)-(5), wherein the lung cancer comprises a lung cancer that is not capable of being resected.
(10) The method of (8) or (9), wherein the lung cancer is resected by a surgical resection.
(11) The method of any one of (1)-(10), wherein an effective amount of recombinant interferon encoded by the nucleotide sequence of SEQ ID NO: 2 is administered to the subject, optionally, the effective amount is a therapeutically effective amount.
(12) The method of any one of (1)-(11), wherein the recombinant interferon is administered to the subject by at least one of: systemic administration, topical administration, and local administration.
(13) The method of any one of (1)-(12), wherein the recombinant interferon is administered to the subject by an administration route, the administration route comprises one or more of: oral, rectal, sublingual, intravenous, intra-arterial, intramuscular, subcutaneous, intra-bone, intracutaneous, intra-articular, intraperitoneal, intrathecal, intracerebral, vaginal, percutaneous, transdermal, epidermal, transmucosal, transocular, pulmonary, nasal, abdominal, intrapleural, intraventricular, pericardial, inhalation, intratumoral, uterine, infiltration, and intravesical administration.
(14) The method of any one of (1)-(13), wherein the recombinant interferon is administered to the subject by subcutaneous administration and/or intramuscular administration.
(15) The method of (14), wherein the subcutaneous administration comprises subcutaneous injection.
(16) The method of (14), wherein the intramuscular administration comprises intramuscular injection.
(17) The method of any one of (14)-(16), wherein the recombinant interferon is administered in an amount in a range of about 2 μg to about 70 μg by one subcutaneous and/or intramuscular administration.
(18) The method of (17), wherein the recombinant interferon is administered in an amount in a range of about 4 μg to about 50 μg by one subcutaneous and/or intramuscular administration.
(19) The method of (18), wherein the recombinant interferon is administered in an amount in a range of about 4 μg to about 30 μg by one subcutaneous and/or intramuscular administration.
(20) The method of any one of (14)-(19), wherein the recombinant interferon is administered by subcutaneous and/or intramuscular administration once every about 1 to about 7 days.
(21) The method of (20), wherein the recombinant interferon is administered by subcutaneous and/or intramuscular administration once every about 1 to about 2 days.
(22) The method of any one of (1)-(21), wherein the recombinant interferon is administered to the subject by inhalation administration.
(23) The method of (22), wherein the recombinant interferon is administered by pulmonary and/or nasal inhalation.
(24) The method of (22) or (23), wherein the inhalation administration comprises dry powder inhalation and/or aerosol inhalation.
(25) The method of any one of (22)-(24), wherein the recombinant interferon is administered in an amount in a range of about 100 μg to about 2000 μg, optionally about 100 μg to about 1500 μg by one inhalation administration.
(26) The method of (25), wherein the recombinant interferon is administered in an amount in a range of about 150 μg to about 800 μg by one inhalation administration.
(27) The method of (26), wherein the recombinant interferon is administered in an amount in a range of about 200 μg to about 600 μg by one inhalation administration.
(28) The method of any one of (22)-(27), wherein the recombinant interferon is administered by inhalation administration once every about 1 to about 3 days.
(29) The method of (28), wherein the recombinant interferon is administered by inhalation administration once every about 1 day.
(30) The method of any one of (1)-(29), wherein the subject has the pleural effusion, ascites, and/or pericardial effusion.
(31) The method of (30), wherein the pleural effusion comprises a malignant pleural effusion, the ascites comprises a malignant ascites, and/or the pericardial effusion comprises a malignant pericardial effusion.
(32) The method of (30) or (31), wherein the recombinant interferon is administered to the subject by intrapleural administration, abdominal administration, and/or pericardial administration.
(33) The method of (32), wherein the intrapleural administration comprises intrapleural perfusion.
(34) The method of (32), wherein the abdominal administration comprises abdominal perfusion.
(35) The method of (32), wherein the pericardial administration comprises pericardial perfusion.
(36) The method of any one of (32)-(35), wherein the recombinant interferon is administered in an amount in a range of about 30 μg to about 2000 μg, optionally about 10 μg to about 1500 μg, further optionally about 150 μg to about 1000 μg, still optionally about 200 μg to about 800 μg by one intrapleural, abdominal, and/or pericardial administration.
(37) The method of (36), wherein the recombinant interferon is administered in an amount in a range of about 200 μg to about 400 μg by one intrapleural, abdominal, and/or pericardial administration.
(38) The method of any one of (32)-(37), wherein the recombinant interferon is administered by intrapleural, abdominal, and/or pericardial administration once every about 1 to about 10 days, optionally every about 1 to about 7 days, such as every about 1, 2, 3, 4, 5, 6, or 7 days.
(39) The method of any one of (1)-(13), wherein the recombinant interferon is administered to the subject by intratumoral administration.
(40) The method of (39), wherein the intratumoral administration comprises intratumoral injection.
(41) The method of (39) or (40), wherein the recombinant interferon is administered in an amount in a range of about 60 μg to about 600 μg, optionally about 60 μg to about 500 μg by one intratumoral administration.
(42) The method of (41), wherein the recombinant interferon is administered in an amount in a range of about 80 μg to about 400 μg by one intratumoral administration.
(43) The method of (42), wherein the recombinant interferon is administered in an amount in a range of about 100 μg to about 250 μg by one intratumoral administration.
(44) The method of any one of (39)-(43), wherein the recombinant interferon is administered by intratumoral administration once every about 1 day to about 10 days, optionally every about 1 day to about 7 days such as every about 1, 2, 3, 4, 5, 6, or 7 days.
(45) The method of any one of (39)-(44), wherein the protocol of intratumoral administration is as follow: the recombinant interferon is administered by intratumoral injection once every about 1 day for about 4 to about 8 times, and then the recombinant interferon is administered by intratumoral injection once every about 3 days to about 5 days for about 4 to about 8 times, and then the recombinant interferon is administered by intratumoral injection once every about 7 days, the intratumoral administration is stopped when the tumor disappears or becomes too small to conduct the intratumoral injection.
(46) The method of any one of (1)-(45), wherein the lung cancer in the subject comprises tumor metastasis in at least one of: skin, mucosa, superficial lymph nodes, and subcutaneous tissue.
(47) The method of (46), wherein the recombinant interferon is administered to the subject by spray administration.
(48) The method of (47), wherein the spray administration comprises at least one of: percutaneous spray administration, transdermal spray administration, epidermal spray administration, and transmucosal spray administration.
(49) The method of (47) or (48), wherein the recombinant interferon is administered in an amount in a range of about 6 μg to about 100 μg by one spray administration.
(50) The method of (49), wherein the recombinant interferon is administered in an amount in a range of about 10 μg to about 40 μg, optionally about 20 μg to about 40 μg by one spray administration.
(51) The method of any one of (47)-(50), wherein the recombinant interferon is administered by spray administration about 1 to about 6 times such as about 1, 2, 3, 4, 5, or 6 times per day.
(52) The method of any one of (1)-(51), wherein the recombinant interferon is administered to the subject by an administration route, the administration route comprises at least one of: subcutaneous administration, intramuscular administration, inhalation administration, infiltration administration, intrapleural administration, abdominal administration, pericardial administration, intratumoral administration, and spray administration.
(53) The method of any one of (1)-(52), wherein the recombinant interferon is administered to the subject as monotherapy.
(54) The method of any one of (1)-(52), further comprising at least one other anti-cancer therapy administered to the subject, optionally, the at least one other anti-cancer therapy is administered to the subject before, simultaneously, and/or after administration of the recombinant interferon.
(55) The method of (54), wherein the at least one other anti-cancer therapy comprises at least one of: chemotherapy, radiotherapy, surgical therapy, interventional therapy, biotherapy, gene therapy, ablation therapy, immunotherapy, targeted therapy, and traditional Chinese medicine therapy.
(56) The method of (55), wherein the at least one other anti-cancer therapy comprises chemotherapy.
(57) The method of (56), wherein the chemotherapy is the first-line chemotherapy.
(58) The method of (57), wherein at least one chemotherapeutic drugs used for the first-line chemotherapy comprise platinum compounds, such as Cisplatin.
(59) The method of (55), wherein the at least one other anti-cancer therapy comprises radiotherapy.
(60) The method of (59), wherein the radiotherapy comprises head gamma knife therapy when the lung cancer metastasizes to brain.
(61) The method of (55), wherein the at least one other anti-cancer therapy comprises surgical therapy.
(62) The method of (55), wherein the at least one other anti-cancer therapy comprises targeted therapy.
(63) The method of (62), wherein the targeted therapy comprises administering Gefitinib, Erlotinib, and/or recombinant human endostatin.
(64) The method of (55), wherein the at least one other anti-cancer therapy comprises biotherapy.
(65) The method of any one of (1)-(64), wherein the recombinant interferon is administered in at least one treatment cycle, optionally, the at least one treatment cycle comprises 2, 3, 4, 5, 6, 7, 8, 9, or 10 treatment cycles, or optionally, more than 10 treatment cycles.
(66) The method of (65), wherein the duration of the treatment cycle is at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years and the like, or the recombinant interferon can be administered for a long time, including over the life time of the subject; or the duration can also be about 1 day to about 6 years, about 1 week to about 4 years, about 2 weeks to about 3 years, about 1 month to about 1 year, or about 2 months to about 9 months and the like.
(67) The method of (65) or (66), wherein the time interval between any two adjacent treatment cycles of the more treatment cycles is at least about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years and the like; or the time interval can also be about 2 days to about 6 years, about 4 days to about 3 years, about 1 week to about 1 year, about 2 months to about 9 months, or about 3 months to about 6 months and the like.
(68) The method of any one of (1)-(67), wherein the therapies eliminate the tumor of the lung or reduce the size of the tumor of the lung compared to the tumor size before treatment.
(69) A method for treating lung cancer in a subject, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2 and one or more chemotherapeutic drugs in two or more treatment cycles, and then administering to the subject a recombinant interferon encoded by SEQ ID NO: 2 and one or more targeted drugs in one or more treatment cycles.
(70) The method of (69), wherein the therapies eliminate the tumor of the lung or reduce the size of the tumor of the lung compared to the tumor size before treatment.
(71) The method of (69) or (70), wherein the one or more chemotherapeutic drugs comprise platinum compounds, such as Cisplatin.
(72) The method of any one of (69)-(71), wherein the one or more targeted drugs comprise Gefitinib, Erlotinib, and/or recombinant human endostatin.
(73) The method of any one of (69)-(72), wherein an effective amount of recombinant interferon, encoded by the nucleotide sequence of SEQ ID NO: 2, is administered to the subject, optionally, the effective amount is a therapeutically effective amount.
(74) The method of any one of (1)-(73), wherein the therapies are the non-surgical therapies.
In another aspect, another embodiment of the present invention provides:
(1) A method for treating lung cancer in a subject, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2 by subcutaneous administration and/or intramuscular administration, wherein the recombinant interferon is administered in an amount in a range of about 2 μg to about 70 μg, optionally about 4 μg to about 50 μg, further optionally about 4 μg to about 30 μg by one subcutaneous administration and/or intramuscular administration, the recombinant interferon is administered by subcutaneous administration and/or intramuscular administration once every about 1 to about 7 days, optionally every about 1 to about 2 days, lasting at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years and the like, or the recombinant interferon can be administered for a long time, including over the life time of the subject; or the duration can also be about 1 day to about 6 years, about 1 week to about 4 years, about 2 weeks to about 3 years, about 1 month to about 1 year, or about 2 months to about 9 months and the like.
(2) The method of (1), wherein the lung cancer comprises small cell lung cancer (SCLC), non small cell lung cancer (NSCLC), or both.
(3) The method of (1) or (2), wherein the lung cancer in the subject comprises a metastasized tumor.
(4) The method of any one of (1)-(3), wherein the subject is an early, medium-term, or advanced cancer patient, optionally, the subject is a medium-term, or advanced cancer patient, further optionally, the subject is an advanced cancer patient.
(5) The method of any one of (1)-(3), wherein the subject is a stage 0, I, II, III, or IV cancer patient, optionally, the subject is a stage III or IV cancer patient.
(6) The method of any one of (1)-(5), wherein the lung cancer is a lung cancer that is indicated or appropriate for surgery.
(7) The method of any one of (1)-(5), wherein the lung cancer is a lung cancer that is not indicated nor appropriate for surgery.
(8) The method of any one of (1)-(5), wherein the lung cancer is a lung cancer that is capable of being resected.
(9) The method of any one of (1)-(5), wherein the lung cancer is a lung cancer that is not capable of being resected.
(10) The method of (8) or (9), wherein the lung cancer is resected by a surgical resection.
(11) The method of any one of (1)-(10), wherein the subcutaneous administration comprises subcutaneous injection.
(12) The method of any one of (1)-(10), wherein the intramuscular administration comprises intramuscular injection.
(13) The method of any one of (1)-(12), further comprising administering to the subject the recombinant interferon by inhalation administration.
(14) The method of (13), wherein the inhalation administration is conducted before, simultaneously, and/or after the subcutaneous administration and/or intramuscular administration.
(15) The method of (13) or (14), wherein the inhalation administration comprises pulmonary and/or nasal inhalation administration.
(16) The method of any one of (13)-(15), wherein the inhalation administration comprises aerosol inhalation.
(17) The method of any one of (13)-(16), wherein the recombinant interferon is administered in an amount in a range of about 100 μg to about 2000 μg, optionally about 100 μg to about 1500 μg, further optionally about 150 μg to about 800 μg, still optionally about 200 μg to about 600 μg by one inhalation administration, the recombinant interferon is administered by inhalation administration once every about 1 day to about 3 days, optionally every about 1 day, lasting at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years and the like, or the recombinant interferon can be administered for a long time, including over the life time of the subject; or the duration can also be about 1 day to about 6 years, about 1 week to about 4 years, about 2 weeks to about 3 years, about 1 month to about 1 year, or about 2 months to about 9 months and the like.
(18) The method of any one of (1)-(17), further comprising administering to the subject the recombinant interferon by intratumoral administration.
(19) The method of (18), wherein the intratumoral administration is conducted before, simultaneously, and/or after the subcutaneous administration and/or intramuscular administration.
(20) The method of (18), wherein the intratumoral administration is conducted before, simultaneously, and/or after the inhalation administration.
(21) The method of any one of (18)-(20), wherein the intratumoral administration comprises intratumoral injection.
(22) The method of any one of (18)-(21), wherein the recombinant interferon is administered in an amount in a range of about 60 μg to about 600 μg, optionally about 60 μg to about 500 μg, further optionally about 80 μg to about 400 μg, still further optionally about 100 μg to about 250 μg by one intratumoral administration, and the recombinant interferon is administered by intratumoral administration once every about 1 day to about 10 days, optionally every about 1 day to about 7 days such as every about 1, 2, 3, 4, 5, 6, or 7 days, the duration of the intratumoral administration is at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years and the like, or the recombinant interferon can be administered for a long time, including over the life time of the subject; or the duration can also be about 1 day to about 6 years, about 1 week to about 4 years, about 2 weeks to about 3 years, about 1 month to about 1 year, or about 2 months to about 9 months and the like.
(23) The method of any one of (18)-(22), wherein the protocol of intratumoral administration is as follows: the recombinant interferon is administered by intratumoral injection once every about 1 day for about 4 to about 8 times, and then the recombinant interferon is administered by intratumoral injection once every about 3 days to about 5 days for about 4 to about 8 times, and then the recombinant interferon is administered by intratumoral injection once every about 7 days, the intratumoral administration is stopped when the tumor disappears or becomes too small to conduct the intratumoral injection.
(24) The method of any one of (1)-(23), wherein the subject has the pleural effusion, ascites, and/or pericardial effusion.
(25) The method of (24), wherein the pleural effusion is a malignant pleural effusion, the ascites is a malignant ascites, and/or the pericardial effusion is a malignant pericardial effusion.
(26) The method of (24) or (25), wherein the recombinant interferon is administered to the subject by an administration route, the administration route comprises at least one of: intrapleural administration, abdominal administration, and pericardial administration.
(27) The method of (26), wherein the intrapleural administration comprises intrapleural perfusion.
(28) The method of (26), wherein the abdominal administration comprises abdominal perfusion.
(29) The method of (26), wherein the pericardial administration comprises pericardial perfusion.
(30) The method of any one of (26)-(29), wherein the recombinant interferon is administered in an amount in a range of about 30 μg to about 2000 μg, optionally about 100 μg to about 1500 μg, further optionally about 150 μg to about 1000 μg, still optionally about 200 μg to about 800 μg by one intrapleural, abdominal, and/or pericardial administration.
(31) The method of (30), wherein the recombinant interferon is administered in an amount in a range of about 200 μg to about 400 μg by one intrapleural, abdominal, and/or pericardial administration.
(32) The method of any one of (26)-(31), wherein the recombinant interferon is administered by intrapleural, abdominal, and/or pericardial administration once every about 1 day to about 10 days, optionally every about 1 day to about 7 days, such as every about 1, 2, 3, 4, 5, 6, or 7 days.
(33) The method of any one of (1)-(32), wherein the lung cancer in the subject comprises tumor metastasis in at least one of: skin, mucosa, superficial lymph nodes, and subcutaneous tissue.
(34) The method of (33), wherein the recombinant interferon is administered to the subject by spray administration.
(35) The method of (34), wherein the spray administration comprises at least one of: percutaneous spray administration, transdermal spray administration, epidermal spray administration, and transmucosal spray administration.
(36) The method of (34) or (35), wherein the recombinant interferon is administered in an amount in a range of about 6 μg to about 100 μg by one spray administration.
(37) The method of (36), wherein the recombinant interferon is administered in an amount of about 10 μg to about 40 μg, optionally about 20 μg to about 40 μg by one spray administration.
(38) The method of any one of (34)-(37), wherein the recombinant interferon is administered by spray administration about 1 to about 6 times per day, such as about 1, 2, 3, 4, 5, or 6 times per day.
(39) The method of any one of (1)-(38), wherein the recombinant interferon is administered to the subject as monotherapy.
(40) The method of any one of (1)-(38), further comprising at least one other anti-cancer therapy administered to the subject, optionally, the at least one other anti-cancer therapy is administered to the subject before, simultaneously, and/or after administration of the recombinant interferon.
(41) The method of (40), wherein the at least one other anti-cancer therapy comprises one or more of: chemotherapy, radiotherapy, surgical therapy, interventional therapy, biotherapy, gene therapy, ablation therapy, immunotherapy, targeted therapy, and traditional Chinese medicine therapy.
(42) The method of (41), wherein the at least one other anti-cancer therapy comprises chemotherapy.
(43) The method of (42), wherein the chemotherapy is the first-line chemotherapy.
(44) The method of (43), wherein one or more chemotherapeutic drugs used for the first-line chemotherapy comprise platinum compounds, such as Cisplatin.
(45) The method of (41), wherein the at least one other anti-cancer therapy comprises radiotherapy.
(46) The method of (45), wherein the radiotherapy comprises head gamma knife therapy when the lung cancer metastasizes to brain.
(47) The method of (41), wherein the at least one other anti-cancer therapy comprises surgical therapy.
(48) The method of (41), wherein the at least one other anti-cancer therapy comprises targeted therapy.
(49) The method of (48), wherein the targeted therapy comprises administering Gefitinib, Erlotinib, and/or recombinant human endostatin.
(50) The method of (41), wherein the at least one other anti-cancer therapy comprises biotherapy.
(51) The method of any one of (1)-(50), wherein the therapies eliminate the tumor or reduce the size of the tumor or the number of tumor metastasis compared to the tumor before treatment.
(52) The method of any one of (1)-(51), wherein the therapies are the non-surgical therapies.
In another aspect, another embodiment of the present invention provides:
(1) A method for treating lung cancer in a subject, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2 by subcutaneous administration and/or intramuscular administration, wherein the recombinant interferon is administered one or more times by subcutaneous administration and/or intramuscular administration at an induction dose in a range of about 2 μg to about 10 μg each time, optionally about 4 μg to about 10 μg each time, further optionally about 4.5 μg to about 9 μg each time, such as about 4.5 μg each time or about 9 μg each time, and then the recombinant interferon is administered more times by subcutaneous administration and/or intramuscular administration at a therapeutic dose in a range of about 10 μg to about 70 μg each time, optionally about 12 μg to about 50 μg each time, further optionally about 12 μg to about 30 μg each time.
(2) The method of (1), wherein the lung cancer comprises small cell lung cancer (SCLC), non small cell lung cancer (NSCLC), or both.
(3) The method of (1) or (2), wherein the tumor in the subject comprises a metastasized tumor.
(4) The method of any one of (1)-(3), wherein the subject is an early, medium-term, or advanced cancer patient, optionally, the subject is a medium-term, or advanced cancer patient, further optionally, the subject is an advanced cancer patient.
(5) The method of any one of (1)-(3), wherein the subject is a stage 0, I, II, III, or IV cancer patient, optionally, the subject is a stage III or IV cancer patient.
(6) The method of any one of (1)-(5), wherein the lung cancer is a lung cancer that is indicated or appropriate for surgery.
(7) The method of any one of (1)-(5), wherein the lung cancer is a lung cancer that is not indicated nor appropriate for surgery.
(8) The method of any one of (1)-(5), wherein the lung cancer is a lung cancer that is capable of being resected.
(9) The method of any one of (1)-(5), wherein the lung cancer is a lung cancer that is not capable of being resected.
(10) The method of (8) or (9), wherein the lung cancer is resected by a surgical resection.
(11) The method of any one of (1)-(10), wherein the subcutaneous administration comprises subcutaneous injection.
(12) The method of any one of (1)-(10), wherein the intramuscular administration comprises intramuscular injection.
(13) The method of any one of (1)-(12), wherein the time interval between administration of induction dose and administration of therapeutic dose is about 1 day to about 1 month, optionally about 1 day to about 1 week, further optionally about 1 day to about 3 days, comprising such as about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, or about 1 month.
(14) The method of any one of (1)-(13), the recombinant interferon is administered once every about 1 day to about 10 days, optionally every about 1 day to about 7 days, further optionally every about 1 to about 2 days, comprising such as every about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days when the recombinant interferon is administered more times at an induction dose.
(15) The method of any one of (1)-(14), wherein the recombinant interferon is administered at a therapeutic dose once every about 1 day to about 10 days, optionally every about 1 day to about 7 days, further optionally every about 1 to about 2 days, comprising such as every about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days.
(16) The method of any one of (1)-(15), wherein the duration of administration of induction dose and therapeutic dose is at least about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years and the like, or the recombinant interferon can be administered for a long time, including over the life time of the subject.
(17) The method of any one of (1)-(16), further comprising administering to the subject the recombinant interferon by inhalation administration.
(18) The method of (17), wherein the inhalation administration is conducted before, simultaneously, and/or after the subcutaneous administration and/or intramuscular administration.
(19) The method of (17) or (18), wherein the inhalation administration comprises pulmonary and/or nasal inhalation administration.
(20) The method of any one of (17)-(19), wherein the inhalation administration comprises aerosol inhalation.
(21) The method of any one of (17)-(20), wherein the recombinant interferon is administered in an amount in a range of about 100 μg to about 2000 μg, optionally about 100 μg to about 1500 μg, further optionally about 150 μg to about 800 μg, still further optionally about 200 μg to about 600 μg by one inhalation administration, the recombinant interferon is administered by inhalation administration once every about 1 day to about 3 days, optionally every about 1 day, lasting at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years and the like, or the recombinant interferon can be administered for a long time, including over the life time of the subject; or the duration can also be about 1 day to about 6 years, about 1 week to about 4 years, about 2 weeks to about 3 years, about 1 month to about 1 year, or about 2 months to about 9 months and the like.
(22) The method of any one of (1)-(21), further comprising administering to the subject the recombinant interferon by intratumoral administration.
(23) The method of (22), wherein the intratumoral administration is conducted before, simultaneously, and/or after the subcutaneous administration and/or intramuscular administration.
(24) The method of (22), wherein the intratumoral administration is conducted before, simultaneously, and/or after the inhalation administration.
(25) The method of any one of (22)-(24), wherein the intratumoral administration comprises intratumoral injection.
(26) The method of any one of (22)-(25), wherein the recombinant interferon is administered in an amount in a range of about 60 μg to about 600 μg, optionally about 60 μg to about 500 μg, further optionally about 80 μg to about 400 μg, still further optionally about 100 μg to about 250 μg by one intratumoral administration, and the recombinant interferon is administered by intratumoral administration once every about 1 day to about 10 days, optionally every about 1 day to about 7 days such as every about 1, 2, 3, 4, 5, 6, or 7 days, the duration of the intratumoral administration is at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years and the like, or the recombinant interferon can be administered for a long time, including over the life time of the subject; or the duration can also be about 1 day to about 6 years, about 1 week to about 4 years, about 2 weeks to about 3 years, about 1 month to about 1 year, or about 2 months to about 9 months and the like.
(27) The method of any one of (22)-(26), wherein the protocol of intratumoral administration is as follows: the recombinant interferon is administered by intratumoral injection once every about 1 day for about 4 to about 8 times, and then the recombinant interferon is administered by intratumoral injection once every about 3 days to about 5 days for about 4 to about 8 times, and then the recombinant interferon is administered by intratumoral injection once every about 7 days, the intratumoral administration is stopped when the tumor disappears or becomes too small to conduct the intratumoral injection.
(28) The method of any one of (1)-(27), wherein the subject has the pleural effusion, ascites, and/or pericardial effusion.
(29) The method of (28), wherein the pleural effusion is a malignant pleural effusion, the ascites is a malignant ascites, and/or the pericardial effusion is a malignant pericardial effusion.
(30) The method of (28) or (29), wherein the recombinant interferon is administered to the subject by an administration route, the administration route comprises at least one of: intrapleural administration, abdominal administration, and pericardial administration.
(31) The method of (30), wherein the intrapleural administration comprises intrapleural perfusion.
(32) The method of (30), wherein the abdominal administration comprises abdominal perfusion.
(33) The method of (30), wherein the pericardial administration comprises pericardial perfusion.
(34) The method of any one of (30)-(33), wherein the recombinant interferon is administered in an amount in a range of about 30 μg to about 2000 μg, optionally about 100 μg to about 1500 μg, further optionally about 150 μg to about 1000 μg, still optionally about 200 μg to about 800 μg by one intrapleural administration, abdominal administration, and/or pericardial administration.
(35) The method of (34), wherein the recombinant interferon is administered in an amount in a range of about 200 μg to about 400 μg by one intrapleural administration, abdominal administration, and/or pericardial administration.
(36) The method of any one of (30)-(35), wherein the recombinant interferon is administered by intrapleural administration, abdominal administration, and/or pericardial administration once every about 1 day to about 10 days, optionally every about 1 day to about 7 days, such as every about 1, 2, 3, 4, 5, 6, or 7 days.
(37) The method of any one of (1)-(36), wherein the lung cancer in the subject comprises tumor metastasis in at least one of: skin, mucosa, superficial lymph nodes, and subcutaneous tissue.
(38) The method of (37), wherein the recombinant interferon is administered to the subject by spray administration.
(39) The method of (38), wherein the spray administration comprises at least one of: percutaneous spray administration, transdermal spray administration, epidermal spray administration, and transmucosal spray administration.
(40) The method of (38) or (39), wherein the recombinant interferon is administered in an amount in a range of about 6 μg to about 100 μg by one spray administration.
(41) The method of (40), wherein the recombinant interferon is administered in an amount in a range of about 10 μg to about 40 μg, optionally about 20 μg to about 40 μg by one spray administration.
(42) The method of any one of (38)-(41), wherein the recombinant interferon is administered by spray administration about 1 to about 6 times per day, such as about 1, 2, 3, 4, 5, or 6 times per day.
(43) The method of any one of (1)-(42), wherein the recombinant interferon is administered to the subject as monotherapy.
(44) The method of any one of (1)-(42), further comprising at least one other anti-cancer therapy administered to the subject, optionally, the at least one other anti-cancer therapy is administered to the subject before, simultaneously, and/or after administration of the recombinant interferon.
(45) The method of (44), wherein the at least one other anti-cancer therapy comprises one or more of: chemotherapy, radiotherapy, surgical therapy, interventional therapy, biotherapy, gene therapy, ablation therapy, immunotherapy, targeted therapy, and traditional Chinese medicine therapy.
(46) The method of (45), wherein the at least one other anti-cancer therapy comprises chemotherapy.
(47) The method of (46), wherein the chemotherapy is the first-line chemotherapy.
(48) The method of (47), wherein one or more chemotherapeutic drugs are used for the first-line chemotherapy and comprise platinum compounds, such as Cisplatin.
(49) The method of (45), wherein the at least one other anti-cancer therapy comprises radiotherapy.
(50) The method of (49), wherein the radiotherapy comprises head gamma knife therapy when the lung cancer metastasizes to brain.
(51) The method of (45), wherein the at least one other anti-cancer therapy comprises surgical therapy.
(52) The method of (45), wherein the at least one other anti-cancer therapy comprises targeted therapy.
(53) The method of (52), wherein the targeted therapy comprises administering Gefitinib, Erlotinib, and/or recombinant human endostatin.
(54) The method of (45), wherein the at least one other anti-cancer therapy comprises biotherapy.
(55) The method of any one of (1)-(54), wherein the therapies eliminate the tumor of the lung or reduce the size of the tumor of the lung compared to the tumor size before treatment.
(56) The method of any one of (1)-(55), wherein the therapies are the non-surgical therapies.
In another aspect, another embodiment of the present invention provides:
(1) A method for treating cancer in a subject, wherein the cancer originates from lung cancer in the subject and metastasizes to brain, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2, wherein the recombinant interferon is administered one or more times by subcutaneous administration and/or intramuscular administration at an induction dose in a range of about 2 μg to about 10 μg each time, optionally about 4 μg to about 10 μg each time, further optionally about 4.5 μg to about 9 μg each time, such as about 4.5 μg each time or about 9 μg each time, and then the recombinant interferon is administered more times by subcutaneous administration and/or intramuscular administration at a therapeutic dose in a range of about 10 μg to about 70 μg each time, optionally about 12 μg to about 50 μg each time, further optionally about 12 μg to about 30 μg each time, and the recombinant interferon is administered to the subject by inhalation administration before, simultaneously, and/or after the subcutaneous administration and/or intramuscular administration, the recombinant interferon is administered in an amount in a range of about 100 μg to about 2000 μg, optionally about 100 μg to about 1500 μg, further optionally about 150 μg to about 800 μg, still further optionally about 200 μg to about 600 μg by one inhalation administration, and the recombinant interferon is administered by inhalation administration once every about 1 day to about 3 days, optionally every about 1 day.
(2) The method of (1), wherein the subject is a medium-term, advanced, or stage III or stage IV cancer patient, optionally, the subject is an advanced, or stage III or stage IV cancer patient.
(3) The method of (1) or (2), wherein the cancer is a cancer that is not indicated nor appropriate for surgery.
(4) The method of (1) or (2), wherein the tumor is a tumor that is not capable of being resected.
(5) The method of (4), wherein the tumor is resected by a surgical resection.
(6) The method of any one of (1)-(5), wherein the subcutaneous administration comprises subcutaneous injection.
(7) The method of any one of (1)-(5), wherein the intramuscular administration comprises intramuscular injection.
(8) The method of any one of (1)-(7), wherein the inhalation administration comprises pulmonary and/or nasal inhalation administration.
(9) The method of any one of (1)-(8), wherein the inhalation administration comprises aerosol inhalation.
(10) The method of any one of (1)-(9), wherein the time interval between administration of induction dose and administration of therapeutic dose is about 1 day to about 1 month, optionally about 1 day to about 1 week, further optionally about 1 day to about 3 days, comprising such as about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, or about 1 month.
(11) The method of any one of (1)-(10), wherein the recombinant interferon is administered once every about 1 day to about 10 days, optionally every about 1 day to about 7 days, further optionally every about 1 to about 2 days, comprising such as every about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days when the recombinant interferon is administered more times at an induction dose.
(12) The method of any one of (1)-(11), wherein the recombinant interferon is administered at a therapeutic dose once every about 1 day to about 10 days, optionally every about 1 day to about 7 days, further optionally every about 1 to about 2 days, comprising such as every about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days.
(13) The method of any one of (1)-(12), wherein the duration of administration of induction dose and therapeutic dose is at least about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years and the like, or the recombinant interferon can be administered for a long time, including over the life time of the subject.
(14) The method of any one of (1)-(13), wherein the duration of the inhalation administration is at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years and the like, or the recombinant interferon can be administered for a long time, including over the life time of the subject; or the duration can also be about 1 day to about 6 years, about 1 week to about 4 years, about 2 weeks to about 3 years, about 1 month to about 1 year, or about 2 months to about 9 months and the like.
(15) The method of any one of (1)-(14), wherein the recombinant interferon is administered to the subject as monotherapy.
(16) The method of any one of (1)-(15), further comprising at least one other anti-cancer therapy administered to the subject, optionally, the at least one other anti-cancer therapy is administered to the subject before, simultaneously, and/or after administration of the recombinant interferon.
(17) The method of (16), wherein the at least one other anti-cancer therapy comprises one or more of: chemotherapy, radiotherapy, surgical therapy, interventional therapy, biotherapy, gene therapy, ablation therapy, immunotherapy, targeted therapy, and traditional Chinese medicine therapy.
(18) The method of (17), wherein the chemotherapy is the first-line chemotherapy, optionally, one or more chemotherapeutic drugs are used for the first-line chemotherapy and comprise platinum compounds, such as Cisplatin.
(19) The method of (17), wherein the targeted therapy comprises administering Gefitinib, Erlotinib, and/or recombinant human endostatin.
(20) The method of (17), wherein the at least one other anti-cancer therapy comprises radiotherapy.
(21) The method of (20), wherein the radiotherapy comprises gamma knife therapy.
(22) The method of (21), wherein the gamma knife therapy comprises head gamma knife therapy.
(23) The method of any one of (1)-(22), wherein the therapies eliminate the tumor or reduce the size of the tumor compared to the tumor before treatment.
(24) The method of any one of (1)-(23), wherein the therapies are the non-surgical therapies.
In another aspect, another embodiment of the present invention provides:
(1) A method for treating cancer in a subject, wherein the cancer originates from lung cancer in the subject and metastasizes to bone or liver, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2, wherein the recombinant interferon is administered one or more times by subcutaneous administration and/or intramuscular administration at an induction dose in a range of about 2 μg to about 10 μg each time, optionally about 4 μg to about 10 μg each time, further optionally about 4.5 μg to about 9 μg each time, such as about 4.5 μg each time or about 9 μg each time, and then the recombinant interferon is administered more times by subcutaneous administration and/or intramuscular administration at a therapeutic dose of about 10 μg-about 70 μg each time, optionally about 12 μg to about 50 μg each time, further optionally about 12 μg to about 30 μg each time.
(2) The method of (1), wherein the subject is a medium-term, advanced, or stage III or stage IV cancer patient, optionally, the subject is an advanced, or stage III or stage IV cancer patient.
(3) The method of (1) or (2), wherein the cancer is a cancer that is not indicated nor appropriate for surgery.
(4) The method of (1) or (2), wherein the tumor is a tumor that is not capable of being resected.
(5) The method of (4), wherein the tumor is resected by a surgical resection.
(6) The method of any one of (1)-(5), wherein the subcutaneous administration comprises subcutaneous injection.
(7) The method of any one of (1)-(5), wherein the intramuscular administration comprises intramuscular injection.
(8) The method of any one of (1)-(7), wherein the time interval between administration of induction dose and administration of therapeutic dose is about 1 day to about 1 month, optionally about 1 day to about 1 week, further optionally about 1 day to about 3 days, comprising such as about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, or about 1 month.
(9) The method of any one of (1)-(8), wherein the recombinant interferon is administered once every about 1 day to about 10 days, optionally every about 1 day to about 7 days, further optionally every about 1 to about 2 days, comprising such as every about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days when the recombinant interferon is administered more times at an induction dose.
(10) The method of any one of (1)-(9), wherein the recombinant interferon is administered at a therapeutic dose once every about 1 day to about 10 days, optionally every about 1 day to about 7 days, further optionally every about 1 to about 2 days, comprising such as every about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days.
(11) The method of any one of (1)-(10), wherein the duration of administration of induction dose and therapeutic dose is at least about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years and the like, or the recombinant interferon can be administered for a long time, including over the life time of the subject.
(12) The method of any one of (1)-(11), further comprising administering to the subject the recombinant interferon by inhalation administration.
(13) The method of (12), wherein the inhalation administration is conducted before, simultaneously, and/or after the subcutaneous administration and/or intramuscular administration.
(14) The method of (12) or (13), wherein the inhalation administration comprises pulmonary and/or nasal inhalation administration.
(15) The method of any one of (12)-(14), wherein the inhalation administration comprises aerosol inhalation.
(16) The method of any one of (12)-(15), wherein the recombinant interferon is administered in an amount in a range of about 100 μg to about 2000 μg, optionally about 100 μg to about 1500 μg, further optionally about 150 μg to about 800 μg, still further optionally about 200 μg to about 600 μg by one inhalation administration, the recombinant interferon is administered by inhalation administration once every about 1 day to about 3 days, optionally every about 1 day, and the duration of the inhalation administration is at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years and the like, or the recombinant interferon can be administered for a long time, including over the life time of the subject; or the duration can also be about 1 day to about 6 years, about 1 week to about 4 years, about 2 weeks to about 3 years, about 1 month to about 1 year, or about 2 months to about 9 months and the like.
(17) The method of any one of (1)-(16), wherein the recombinant interferon is administered to the subject as monotherapy.
(18) The method of any one of (1)-(16), further comprising at least one other anti-cancer therapy administered to the subject, optionally, the at least one other anti-cancer therapy is administered to the subject before, simultaneously, and/or after administration of the recombinant interferon.
(19) The method of (18), wherein the at least one other anti-cancer therapy comprises one or more of: chemotherapy, radiotherapy, surgical therapy, interventional therapy, biotherapy, gene therapy, ablation therapy, immunotherapy, targeted therapy, and traditional Chinese medicine therapy.
(20) The method of (19), wherein the at least one other anti-cancer therapy comprises chemotherapy.
(21) The method of (20), wherein the chemotherapy is first-line chemotherapy.
(22) The method of (21), wherein one or more chemotherapeutic drugs are used for the first-line chemotherapy and comprise platinum compounds, such as Cisplatin.
(23) The method of (19), wherein the at least one other anti-cancer therapy comprises targeted therapy.
(24) The method of (23), wherein the targeted therapy comprises administering Gefitinib, Erlotinib, and/or recombinant human endostatin.
(25) The method of (19), wherein the at least one other anti-cancer therapy comprises biotherapy.
(26) The method of any one of (1)-(25), wherein the therapies eliminate the tumor or reduce the size of the tumor compared to the tumor before treatment.
(27) The method of any one of (1)-(26), wherein the therapies are the non-surgical therapies.
In another aspect, another embodiment of the present invention provides:
(1) A method for treating cancer in a subject, wherein the cancer originates from lung cancer in the subject and metastasizes to lymph nodes, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2, wherein the recombinant interferon is administered one or more times by subcutaneous administration and/or intramuscular administration at an induction dose in a range of about 2 μg to about 10 μg each time, optionally about 4 μg to about 10 μg each time, further optionally about 4.5 μg to about 9 μg each time, such as about 4.5 μg each time or about 9 μg each time, and then the recombinant interferon is administered more times by subcutaneous administration and/or intramuscular administration at a therapeutic dose of about 10 μg to about 70 μg each time, optionally about 12 μg to about 50 μg each time, further optionally about 12 μg to about 30 μg each time, and the recombinant interferon is administered to the tumor and/or the lymph nodes metastases by topical or local administration before, simultaneously, and/or after the subcutaneous administration and/or intramuscular administration.
(2) The method of (1), wherein the subject is a medium-term, advanced, or stage III or stage IV cancer patient, optionally, the subject is an advanced, or stage III or stage IV cancer patient.
(3) The method of (1) or (2), wherein the cancer is a cancer that is not indicated nor appropriate for surgery.
(4) The method of (1) or (2), wherein the tumor is a tumor that is not capable of being resected.
(5) The method of (4), wherein the tumor is resected by a surgical resection.
(6) The method of any one of (1)-(5), wherein the subcutaneous administration comprises subcutaneous injection.
(7) The method of any one of (1)-(5), wherein the intramuscular administration comprises intramuscular injection.
(8) The method of any one of (1)-(7), wherein the time interval between administration of induction dose and administration of therapeutic dose is about 1 day to about 1 month, optionally about 1 day to about 1 week, further optionally about 1 day to about 3 days, comprising such as about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, or about 1 month.
(9) The method of any one of (1)-(8), wherein the recombinant interferon is administered once every about 1 day to about 10 days, optionally every about 1 day to about 7 days, further optionally every about 1 to about 2 days, comprising such as every about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days when the recombinant interferon is administered more times at an induction dose.
(10) The method of any one of (1)-(9), wherein the recombinant interferon is administered at a therapeutic dose once every about 1 day to about 10 days, optionally every about 1 day to about 7 days, further optionally every about 1 to about 2 days, comprising such as every about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days.
(11) The method of any one of (1)-(10), wherein the duration of administration of induction dose and therapeutic dose is at least about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years and the like, or the recombinant interferon can be administered for a long time, including over the life time of the subject.
(12) The method of any one of (1)-(11), wherein the local administration comprises intratumoral administration when the lymph nodes are the deep lymph nodes.
(13) The method of (12), wherein the intratumoral administration comprises intratumoral injection.
(14) The method of (12) or (13), wherein the recombinant interferon is administered in an amount in a range of about 60 μg to about 600 μg, optionally about 60 μg to about 500 μg, further optionally about 80 μg to about 400 μg, still further optionally about 100 μg to about 250 μg by one intratumoral administration, and the recombinant interferon is administered by intratumoral administration once every about 1 day to about 10 days, optionally every about 1 day to about 7 days such as every about 1, 2, 3, 4, 5, 6, or 7 days, the duration of the intratumoral administration is at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years and the like, or the recombinant interferon can be administered for a long time, including over the life time of the subject; or the duration can also be about 1 day to about 6 years, about 1 week to about 4 years, about 2 weeks to about 3 years, about 1 month to about 1 year, or about 2 months to about 9 months and the like.
(15) The method of any one of (12)-(14), wherein the protocol of intratumoral administration is as follow: the recombinant interferon is administered by intratumoral injection once every about 1 day for about 4 to about 8 times, and then the recombinant interferon is administered by intratumoral injection once every about 3 days to about 5 days for about 4 to about 8 times, and then the recombinant interferon is administered by intratumoral injection once every about 7 days, the intratumoral administration is stopped when the tumor and/or metastasized lymph nodes are disappeared or become too small to conduct the intratumoral injection.
(16) The method of any one of (1)-(11), wherein the topical or local administration comprises at least one of: infiltration administration, percutaneous administration, transdermal administration, epidermal administration, and transmucosal administration when the lymph nodes are superficial lymph nodes.
(17) The method of (16), wherein the local administration comprises infiltration administration.
(18) The method of (17), wherein the infiltration administration is conducted by perfusion.
(19) The method of (16), wherein the percutaneous administration, transdermal administration, epidermal administration, or transmucosal administration comprises percutaneous spray administration, transdermal spray administration, epidermal spray administration, or transmucosal spray administration, respectively.
(20) The method of (19), wherein the recombinant interferon is administered in an amount in a range of about 6 μg to about 100 μg by one spray administration.
(21) The method of (20), wherein the recombinant interferon is administered in an amount of about 10 μg to about 40 μg, optionally about 20 μg to about 40 μg by one spray administration.
(22) The method of any one of (19)-(21), wherein the recombinant interferon is administered by spray administration about 1 to about 6 times such as about 1, 2, 3, 4, 5, or 6 times per day.
(23) The method of any one of (1)-(22), wherein the recombinant interferon is administered to the subject as monotherapy.
(24) The method of any one of (1)-(22), further comprising at least one other anti-cancer therapy administered to the subject, optionally, the at least one other anti-cancer therapy is administered to the subject before, simultaneously, and/or after administration of the recombinant interferon.
(25) The method of (24), wherein the at least one other anti-cancer therapy comprises one or more of: chemotherapy, radiotherapy, surgical therapy, interventional therapy, biotherapy, gene therapy, ablation therapy, immunotherapy, targeted therapy, and traditional Chinese medicine therapy.
(26) The method of (25), wherein the at least one other anti-cancer therapy comprises chemotherapy.
(27) The method of (26), wherein the chemotherapy is first-line chemotherapy.
(28) The method of (27), wherein one or more chemotherapeutic drugs are used for the first-line chemotherapy and comprise platinum compounds, such as Cisplatin.
(29) The method of (25), wherein the at least one other anti-cancer therapy comprises targeted therapy.
(30) The method of (29), wherein the targeted therapy comprises administering Gefitinib, Erlotinib, and/or recombinant human endostatin.
(31) The method of (25), wherein the at least one other anti-cancer therapy comprises biotherapy.
(32) The method of any one of (1)-(31), wherein the therapies eliminate the tumor or reduce the size of the tumor compared to the tumor before treatment.
(33) The method of any one of (1)-(32), wherein the therapies are the non-surgical therapies.
In another aspect, another embodiment of the present invention provides:
(1) A method for treating lung cancer in a subject, wherein the subject has pleural effusion, ascites and/or pericardial effusion, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2 by topical or local administration.
(2) The method of (1), wherein the subject is a medium-term, advanced, or stage III or stage IV cancer patient, optionally, the subject is an advanced, or stage III or stage IV cancer patient.
(3) The method of (1) or (2), wherein the lung cancer is a lung cancer that is not indicated nor appropriate for surgery.
(4) The method of (1) or (2), wherein the lung cancer is a lung cancer that is not capable of being resected.
(5) The method of (4), wherein the tumor is resected by a surgical resection.
(6) The method of any one of (1)-(5), wherein the pleural effusion is a malignant pleural effusion, the ascites is a malignant ascites, and/or the pericardial effusion is a malignant pericardial effusion.
(7) The method of any one of (1)-(6), wherein the local administration comprises at least one of: infiltration administration, intrapleural administration, abdominal administration, and pericardial administration.
(8) The method of (7), wherein the local administration is conducted by perfusion.
(9) The method of (8), wherein the recombinant interferon is administered in an amount in a range of about 30 μg to about 2000 μg, optionally about 100 μg to about 1500 μg, further optionally about 150 μg to about 1000 μg, still optionally about 200 μg to about 800 μg, still further optionally about 200 μg to about 400 μg by one perfusion administration.
(10) The method of (8) or (9), wherein the recombinant interferon is administered by perfusion administration once every about 1 to about 10 days, optionally every about 1 to about 7 days, such as every about 1, 2, 3, 4, 5, 6, or 7 days.
(11) The method of (10), wherein the recombinant interferon is administered by perfusion administration once every about 1 day, lasting about 4 to about 6 times.
(12) The method of any one of (1)-(11), wherein the recombinant interferon is administered to the subject by systemic administration before, simultaneously, and/or after the topical or local administration.
(13) The method of (12), wherein the systemic administration comprises subcutaneous and/or intramuscular administration.
(14) The method of (13), wherein the subcutaneous administration comprises subcutaneous injection.
(15) The method of (13), wherein the intramuscular administration comprises intramuscular injection.
(16) The method of any one of (13)-(15), wherein the recombinant interferon is administered one or more times by subcutaneous administration and/or intramuscular administration at an induction dose in a range of about 2 μg to about 10 μg each time, optionally about 4 μg to about 10 μg each time, further optionally about 4.5 μg to about 9 μg each time, such as about 4.5 μg each time or about 9 μg each time, and then the recombinant interferon is administered more times by subcutaneous administration and/or intramuscular administration at a therapeutic dose of about 10 μg to about 70 μg each time, optionally about 12 μg to about 50 μg each time, further optionally about 12 μg to about 30 μg each time.
(17) The method of (16), wherein the time interval between administration of induction dose and administration of therapeutic dose is about 1 day to about 1 month, optionally about 1 day to about 1 week, further optionally about 1 day to about 3 days, comprising such as about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, or about 1 month.
(18) The method of (16) or (17), wherein the recombinant interferon is administered once every about 1 day to about 10 days, optionally every about 1 day to about 7 days, further optionally every about 1 to about 2 days, comprising such as every about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days when the recombinant interferon is administered more times at an induction dose.
(19) The method of any one of (16)-(18), wherein the recombinant interferon is administered at a therapeutic dose once every about 1 day to about 10 days, optionally every about 1 day to about 7 days, further optionally every about 1 to about 2 days, comprising such as every about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days.
(20) The method of any one of (16)-(19), wherein the duration of administration of induction dose and therapeutic dose is at least about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years and the like, or the recombinant interferon can be administered for a long time, including over the life time of the subject.
(21) The method of any one of (1)-(20), wherein other therapeutic drugs are further administered by topical, local and/or systemic administration
(22) The method of (21), wherein the other therapeutic drugs comprise antitumor drugs.
(23) The method of (22), wherein the antitumor drugs comprise one or more chemotherapeutic drugs, targeted drugs, or biological drugs.
(24) The method of (23), wherein one or more chemotherapeutic drugs comprise platinum compounds, such as Cisplatin.
(25) The method of (23), wherein one or more targeted drugs comprise Gefitinib, Erlotinib, and/or recombinant human endostatin
(26) The method of any one of (1)-(25), wherein the therapies eliminate the tumor or reduce the size of the tumor compared to the tumor size before treatment.
(27) The method of any one of (1)-(26), wherein the therapies are the non-surgical therapies.
More specifically, in one embodiment, in any one of the methods of the present invention mentioned above, the tumor is a solid tumor; optionally, the solid tumor comprises one or more of: lung cancer, liver cancer, hepatocellular carcinoma (HCC), esophageal cancer, cholangiocarcinoma, gallbladder carcinoma, stomach cancer, abdominal cancer, gastrointestinal cancer, gastric cancer, pancreatic cancer, renal cell carcinoma, renal cancer, bone cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, endometrial cancer, colorectal cancer, colon cancer, rectal cancer, bladder cancer, superficial bladder cancer, prostate cancer, adrenal tumors, squamous cell carcinoma, neuroma, malignant neuroma, myoepithelial carcinoma, synovial sarcoma, rhabdomyosarcoma, gastrointestinal interstitial cell tumor, skin cancer, basal cell carcinoma, malignant melanoma, thyroid cancer, nasopharyngeal carcinoma, hemangioma, epidermoid carcinoma, head and neck cancer, glioma, or Kaposi's sarcoma.
In any one of methods of the present invention mentioned above, the tumor is a tumor such as cancer or solid tumor without indications for surgery or not indicated or appropriate for surgery; and/or the subject is a medium-term, advanced cancer patient, or III or IV stage cancer patient, optionally, the subject is an advanced, or III or IV stage cancer patient.
In any one of methods of the present invention mentioned above, the recombinant interferon is administered to the subject as monotherapy; or, further comprising one or more other anti-cancer therapies administered to the subject, optionally, other anti-cancer therapies are administered to the subject before, simultaneously, and/or after administration of the recombinant interferon. Optionally, the other anti-cancer therapies comprise one or more of: chemotherapy, radiotherapy, surgical therapy, interventional therapy, biotherapy, gene therapy, ablation therapy, immunotherapy, targeted therapy, and traditional Chinese medicine therapy.
And, in another aspect, another embodiment of the present invention also provides:
(1) A method of treating a tumor in a subject comprising administering to the subject a recombinant interferon that comprises an anti-tumor effect as a first line monotherapy.
(2) The method of (1), wherein the tumor comprises one of: lung cancer, uterine cancer, cervical cancer, and pancreatic cancer.
(3) The method of (2), wherein the lung cancer comprises non-small cell lung cancer.
(4) The method of (1), wherein the tumor is not a kidney cancer.
(5) A method of treating a tumor in a subject comprising administering to the subject a recombinant interferon that comprises an antitumor effect as a second line monotherapy.
(6) The method of (5), wherein the tumor comprises one of: lung cancer, colorectal cancer, malignant melanoma, ovarian cancer, cervical cancer, liver cancer, breast cancer, gastrointestinal cancer, prostate cancer, neuroma, and squamous cell carcinoma.
(7) The method of (6), wherein the colorectal cancer comprises colon cancer.
(8) The method of (6), wherein the colorectal cancer comprises rectal cancer.
(9) The method of (6), wherein the lung cancer comprises non-small cell lung cancer.
(10) The method of (6), wherein the liver cancer comprises HCC.
(11) The method of (6), wherein the gastrointestinal cancer comprises gastric cancer.
(12) A method of treating a tumor in a subject comprising administering to the subject a recombinant interferon that comprises an anti-tumor effect as a first line therapy in combination with one or more other anti-cancer therapy.
(13) The method of (12), wherein the tumor comprises one of: lung cancer, prostate cancer, and lymphoma.
(14) The method of (13), wherein the lung cancer comprises at least one of non-small cell lung cancer and small cell lung cancer.
(15) The method of (12), wherein the tumor is not an ovarian cancer.
(16) A method of treating a tumor in a subject comprising administering to the subject a recombinant interferon that comprises an anti-tumor effect as a second line therapy in combination with one or more other anti-cancer therapies.
(17) The method of (16), wherein the tumor comprises one of: lung cancer, lymphoma, cervical cancer, and cholangioadenocarcinoma.
(18) The method of (17), wherein the lung cancer comprises at least one of non-small cell lung cancer and small cell lung cancer.
(19) The method of (17), wherein the lymphoma is non-Hodgkins lymphoma.
(20) The method of any of (12), (13), (14), (15), (16), (17), (18), or (19), wherein the one or more other anti-cancer therapies comprise at least one of: radiotherapy, small molecule therapy, chemotherapy, biologics therapy, TCM, and surgery.
(21) The method of (20), wherein the small molecule in the small molecule therapy comprises Getifinib.
(22) The method of (20), wherein the biologics therapy comprises treatment with at least one of: a recombinant protein and isolated cells.
(23) The method of (22), wherein the recombinant protein comprises Endostar.
(24) The method of (22), wherein the isolated cells comprises at least one of: stem cells and NK cells.
(25) The method of (20), wherein the recombinant interferon is administered after surgical treatment of cancer.
(26) The method of any of (20)-(24), wherein the recombinant interferon is administered prior to surgical treatment of cancer.
(27) The method of any of (1)-(26), wherein the recombinant interferon is administered by at least one of the following routes: systemically and locally.
(28) The method of any of (1)-(26), wherein the recombinant interferon is administered by at least one of the following routes: intramuscularly, intraperitoneally, intravenously, intra-arterially, intratumorally, by injection into lymph nodes, topically, locally on the tumor, intranasally, subcutaneously, by spraying, by inhalation, by perfusion, and by infusion.
(29) The method of any of (1)-(28), wherein the recombinant interferon comprises rSIFN-co.
(30) The method of (29), wherein the recombinant interferon is administered at a dose in a range of about 2 μg to about 2500 μg per treatment.
(31) The method of (29), wherein recombinant interferon is administered at a dose in a range of about 9 μg to about 2100 μg per treatment.
(32) The method of (29), wherein recombinant interferon is administered at a dose of one or more of the following doses: 2 μg, 4 μg, 9 μg, 13.5 μg, 15 μg, 18 μg, 21 μg, 24 μg, 25.5 μg, 30 μg, 36 μg, 45 μg, 70 μg, 84 μg, 90 μg, 100 μg, 105 μg, 120 μg, 126 μg, 139 μg, 150 μg, 168 μg, 180 μg, 189 μg, 198 μg, 200 μg, 207 μg, 210 μg, 240 μg, 252 μg, 273 μg, 300 μg, 315 μg, 400 μg, 500 μg, 600 μg, 1000 μg, 2000 μg, 2100 μg.
(33) The method of any of (1)-(32), wherein the recombinant interferon comprises a specified activity.
(34) The method of (33), wherein the recombinant interferon comprises an activity in the range of about 4.4×108 IU/mg to about 1.0×109 IU/mg, and optionally greater than 5.5×108 IU/mg.
(35) A method of preventing tumor recurrence in a subject comprising administering an amount of a recombinant interferon that comprises an amino acid sequence that is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 2 after surgery, chemotherapy, radiotherapy, cryoablation, radiofrequency ablation, biologics therapy, intervention therapy, and/or rSIFN-co therapy, whereby the recombinant interferon is administered after tumor bulk in the subject has been reduced.
(36) A method of prolonging tumor-free survival in a subject comprising administering an amount of a recombinant interferon that comprises an amino acid sequence that is encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 2 after surgery, chemotherapy, radiotherapy, cryoablation, radiofrequency ablation, biologics therapy, intervention therapy, and/or rSIFN-co therapy, whereby the recombinant interferon is administered after tumor bulk in the subject has been reduced.
The inventor found that rSIFN-co can be advantageously used to control cancer, either alone or in combination with other anti-cancer therapies, as a first line or second line monotherapy or in combination with other treatment modalities. The advantages are: Firstly, the recombinant interferon (rSIFN-co) has broad-spectrum anti-tumor effects, which is effective to treat both solid tumors and non-solid tumors. At the same time, rSIFN-co has good synergetic effect with existing treatment means such as surgical therapy, chemotherapy, radiotherapy, other biotherapies and other anti-tumor drugs. Secondly, rSIFN-co has low toxicity, which means that little or no harm to normal cells has been observed when rSIFN-co is used in large doses. Thirdly, rSIFN-co is convenient to use and can be directly applied to tumors located in any part of the body. Thus, rSIFN-co can be used by subcutaneous or intramuscular injection to control systemic progression of tumor, by intrapleural or abdominal perfusion to eliminate effusion and intrapleural or abdominal tumors, by topical or local injection to eliminate primary or metastatic tumors, and by infiltration (transdermal) administration to treat tumor lesions in bone, skin, muscle, prostate and the like. Also, rSIFN-co can be administered by aerosol inhalation or by nasal spray.
According to the above advantages of rSIFN-co, its effective rate on tumors, as a monotherapy and as one element of a combination therapy, is not lower than 90%. With regard to early or medium-term cancer cases, rSIFN-co can be used after surgery in place of chemotherapy and effectively prevent recurrence and tumor metastasis or prolong the period of disease-free survival; with regard to advanced cancer cases or cancer cases that are not indicated for surgery, rSIFN-co can be used to eliminate or reduce the size of tumors without surgery; with regard to tumors that are not indicated for surgery, rSIFN-co can be used to transform the tumors into ones for which surgery is possible, that is, turning a non-resectable tumor into a resectable tumor, thereby creating conditions appropriate for surgery. Therefore, rSIFN-co, alone or in combination with other one or more anti-tumor therapy, is capable of controlling cancer in a large number of instances.
1. The Recombinant Interferon (rSIFN-co) and Preparation Method Thereof
In one aspect, the amino acid sequence of the present recombinant interferon, as well as the nucleotide sequence encoding the same (together with a termination codon), are shown below as SEQ ID NO:1 and SEQ ID NO:2, respectively. These sequences are also referenced in U.S. Pat. Nos. 7,585,647; 7,364,724; 8,114,395 and 8,287,852:
Compared with the IFN-α2b as published and the interferon such as interferon alfacon-1 (INFERGEN®), which has the amino acid sequence of SEQ ID NO: 1, but is not encoded by the nucleotide sequence of SEQ ID NO: 2, the three-dimensional structure of the present recombinant interferon (rSIFN-co) is different from the three-dimensional structure of IFN-α2b (see
In addition, after intramuscular injection of the present recombinant interferon into subjects whose BMI ranged from about 18 to about 23, the time of blood sample collection was plotted against the concentration of 2-5 A oligonucleotidase (also referred to as 2′, 5′-OAS) in the serum of the subjects. The chart generally shows a two-peak pattern, and the resulting area under the curve of this chart is significantly greater than that of interferon alfacon-1 (INFERGEN®) after injection under the same conditions. Furthermore, the half-life period of this recombinant interferon is longer than that of interferon alfacon-1 (INFERGEN®) after injection into the body (see CN 1740197A; Zeng, J. P. et al. Modern Preventive Medicine, 2008, 35(5), 982-984).
The experimental results have also confirmed that the present recombinant interferon is more effective than any interferon used clinically at present (including interferon alfacon-1 (INFERGEN®)). For example, for HBV, the present recombinant interferon is capable of not only inhibiting DNA replication of HBV, but also inhibiting secretion of both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg). The efficiency of inhibiting DNA replication of hepatitis B core antigen (HBcAg) by this interferon is about twice that of interferon alfacon-1 (INFERGEN®). The in vitro pharmacodynamics of the present recombinant interferon shows that it is capable of not only inhibiting the DNA replication of HBV, but also inhibiting secretion of both hepatitis B surface antigen and hepatitis B e antigen. The cytotoxicity of the present recombinant interferon is only ⅛ that of the current clinically used interferons, but its antiviral activity is as much as 5-20 times greater; meanwhile, the biological responses of the present recombinant interferon is more effective, more broad-spectrum and longer lasting in the human body (see CN 1740197A).
Furthermore, with respect to prevention of viral diseases or treatment of tumor, the present recombinant interferon shows higher antiviral activity and less side effects compared with any other interferons (including interferon alfacon-1 (INFERGEN®)). For example, this recombinant interferon possesses not only an antiviral activity 20 times as great as that of the interferons currently in clinical use, but also a more effective inhibiting tumor cell growth or promoting apoptosis function compared with recombinant human interferon ca.
Thus, the present recombinant interferon has a different spatial configuration, enhanced biologic activities and/or different pharmacokinetics characteristics as compared with the interferon such as interferon alfacon-1 (INFERGEN®), which has the amino acid sequence of SEQ ID NO: 1, but is not encoded by the nucleotide sequence of SEQ ID NO: 2.
Therefore, in some embodiments, the present recombinant interferon has the amino acid sequence of SEQ ID NO: 1, such as consisting of the amino acid sequence of SEQ ID NO: 1. In some embodiments, the present recombinant interferon is encoded by the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the present recombinant interferon has the amino acid sequence of SEQ ID NO: 1, and is encoded by the nucleotide sequence of SEQ ID NO: 2. Further, the recombinant interferon comprises the amino acid sequence of SEQ ID NO: 1, and is encoded by the nucleotide sequence of SEQ ID NO: 2. Still further, the recombinant interferon is consisted of the amino acid sequence of SEQ ID NO: 1, and is encoded by the nucleotide sequence of SEQ ID NO: 2.
In some embodiments, in comparison with interferon such as interferon alfacon-1 (INFERGEN®), which has the amino acid sequence of SEQ ID NO: 1, but is not encoded by the nucleotide sequence of SEQ ID NO: 2, the present recombinant interferon has a changed spatial configuration and/or enhanced biologic activities and/or different pharmacokinetics characteristics. For example, the present recombinant interferon has a changed spatial configuration and enhanced biologic activities, changed spatial configuration and different pharmacokinetics characteristics, or changed spatial configuration, enhanced biologic activities and different pharmacokinetics characteristics. The enhanced biological activities include: enhanced antiviral activity, enhanced tumor cell growth inhibition or proapoptotic effect, less side effects and/or could be used in large dose (e.g. each dose>10 million IU). For example, the enhanced biological activities can be enhanced antiviral activity and/or enhanced tumor cell (such as breast cancer cell or cervical cancer cell) growth inhibition or proapoptotic effect (see Zheng, J. et al. J Sichuan Univ (Med Sci Edi), 2010, 41(1), 29-34; Chen, Y, et al. J Sichuan Univ (Med Sci Edi), 2008, 39(5), 715-718). The different pharmacokinetics characteristics include: after intramuscular injection of the recombinant interferon in subjects whose BMI ranged from about 18 to about 23, the time of blood sample collection was plotted against the concentration of 2-5 A oligonucleotidase in the serum of the subjects, and the resulting area under the curve of this chart is significantly greater and/or the half-life of this recombinant interferon in the body is longer than those of the interferon such as interferon alfacon-1 (INFERGEN®), which has the amino acid sequence of SEQ ID NO: 1, but is not encoded by the nucleotide sequence of SEQ ID NO: 2 after injection under the same conditions.
In some embodiments, the present recombinant interferon has the amino acid sequence of SEQ ID NO: 1, and is encoded by the nucleotide sequence of SEQ ID NO: 2, wherein the recombinant interferon has increased inhibitory activities on the expression of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) of Hepatitis B Virus as compared to an interferon interferon such as interferon alfacon-1 (INFERGEN®), which has the amino acid sequence of SEQ ID NO: 1, but is not encoded by the nucleotide sequence of SEQ ID NO: 2.
In another aspect, the recombinant interferon (rSIFN-co) used in the present invention can be produced by the methods disclosed in, for example, U.S. Pat. No. 7,364,724, U.S. Pat. No. 7,585,647, U.S. Pat. No. 8,114,395, CN 1740197 A, CN 101001644 A, US 2009/0123417, US 2011/0158941 and WO 2011072487A1. In a specific embodiment, the present recombinant interferon can be produced by the method comprising the following steps: introducing a nucleotide sequence comprising SEQ ID NO: 2 that encodes the recombinant interferon into an isolated host cell; culturing the host cell under appropriate condition for expression of the recombinant interferon; and harvesting the recombinant interferon, wherein the recombinant interferon has an amino acid sequence of SEQ ID NO: 1, and the recombinant interferon inhibits secretion of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) of Hepatitis B Virus. Further, the host cell is Escherichia coli, such as Escherichia coli LGM 194. Further, the nucleotide sequence comprising SEQ ID NO: 2 is under the control of the promoter PBAD. Further, the harvesting step comprises extraction of the interferon from the fermentation broth, collection of the inclusion bodies, denaturation and renaturation of the harvested interferon. Still further, the harvesting step also comprises separation and purification of the recombinant interferon.
The person skilled in the art can prepare intramuscular injection dosage form, spray dosage form, or inhalation dosage form and the like of the present recombinant interferon with reference to the contents of the following part D with title of Pharmaceutical composition and administration route.
The specific activity of the present recombinant interferon is in a range of about 4.4×108 IU/mg to about 1.0×109 IU/mg, and optionally greater than 5.5×108 IU/mg. Such specific activity is the ratio of the biological activity and the content of protein. The biological activity is measured by a method well-known by the person skilled in the art such as the biological activity measurement method for the interferon (i.e. the cell lesion inhibition method) published in the Appendix X C in Chinese Pharmacopoeia (the third book), Edition 2010; and the content of the protein is measured by a method well-known by the person skilled in the art such as the second method (i.e. the Lowry method) of protein measurement method published in the Appendix VI B in Chinese Pharmacopoeia (the third book), Edition 2010.
2. Therapeutic UsesThe inventor has found that the present recombinant interferon (rSIFN-co) can be effectively used for treating tumors, in particular, solid tumors such as lung cancers and the like. Monotherapy using the present recombinant interferon, rSIFN-co, can suppress the growth of the tumors in patients, reduce the size of tumors in the patients effectively, even non-surgically directly eliminate tumors in the patients, reduce and even eliminate malignant pleural effusion, malignant ascites and/or malignant pericardial effusion, reduce tumor markers, effectively prolong the survival and/or tumor-free survival of the tumor patients and prevent postoperative cancer recurrence and/or metastasis of the tumor in the patients, and effectively treat advanced cancer patients and the cancer patients that are not indicated or appropriate for surgery. Combining other anti-cancer therapies such as one or more of chemotherapy, radiotherapy, surgical therapy, or targeted therapy, the present recombinant interferon can effectively eliminate the tumors of the patients so as to achieve the effect of cure in some embodiments. In addition, compared with existing interferons such as INFERGEN®, the present recombinant interferon has less side effects, so that it can be used in larger doses.
A. Diseases and ConditionsThe diseases and conditions suitable for the treatment and/or prevention method of the invention include tumors. As used herein, the term “tumor” refers to all uncontrolled and malignant neoplastic cell growth and proliferation as well as all cancerous cells and tissues, and abnormally or aberrantly proliferative cells. In some embodiments, the tumors include malignant tumors. As used herein, the term “cancer” refers to physiological conditions of mammal generally characterized by unregulated cell growth and/or proliferation. In the context, the terms “cancer” and “malignant tumor” can be used interchangeably.
In some embodiments, the tumors include solid tumors and non-solid tumors, optionally, the solid tumors. As used herein, the term “solid tumor” refers to the abnormal growth or caking of tissues, and generally does not include cyst or liquid areas. As used herein, the term “non-solid tumor” refers to neoplasia of the hemopoietic system, such as lymphoma, myeloma and leukemia, or neoplasia without solid formation generally and with spread substantially.
In some embodiment, the solid tumors include but not limited to lung cancer, liver cancer, hepatocellular carcinoma (HCC), esophageal cancer, cholangiocarcinoma, gallbladder carcinoma, stomach cancer, abdominal cancer, gastrointestinal cancer, gastric cancer, pancreatic cancer, renal cell carcinoma, renal cancer, bone cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, endometrial cancer, colorectal cancer, colon cancer, rectal cancer, bladder cancer, superficial bladder cancer, prostate cancer, adrenal tumors, squamous cell carcinoma, neuroma, malignant neuroma, myoepithelial carcinoma, synovial sarcoma, rhabdomyosarcoma, gastrointestinal interstitial cell tumor, skin cancer, basal cell carcinoma, malignant melanoma, thyroid cancer, nasopharyngeal carcinoma, hemangioma, epidermoid carcinoma, head and neck cancer, glioma, or Kaposi's sarcoma.
In some embodiments, the non-solid tumors include but not limited to leukemia, acute leukemia, chronic leukemia, chronic myelocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell leukemia, hairy cell leukemia, polycythemia, myelodysplastic syndrome, multiple myeloma, lymphadenoma, Hodgkin's lymphoma, and Non-Hodgkin's lymphoma.
In some embodiments, the tumors are lung tumors, and include but not limited to abnormally proliferative or aberrantly proliferative lung cells and/or malignant lung tumor. As used herein, the term “lung tumor” refers to any lung tumors, therefore, such tumors can be primary lung tumors and/or metastatic lung tumors, for example, the tumors are formed in a way that tumors at other positions are metastasized to the lung through various metastasis modes. The lung tumors can be benign (non-carcinous), preinvasive lesion (precancerous lesion), or malignant (carcinous) lung tumors, such as lung cancers.
In a specific embodiment, the lung tumors are the lung cancers, and include but not limited to small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). As used herein, the term “lung cancer” refers to all types of lung cancers, and include but not limited to small cell lung cancer (SCLC) and the non-small cell lung cancer (NSCLC, including but not limited to adenocarcinoma, squamous cell carcinoma, large cell carcinoma, adenosquamous carcinoma and sarcomatoid carcinoma). Further, the SCLC includes but not limited to complex small cell lung cancer; and the NSCLC includes but not limited to adenocarcinoma, squamous cell carcinoma, large cell carcinoma, adenosquamous carcinoma, sarcomatoid carcinoma, carcinoid and salivary gland cancer. As used herein, the term “complex small cell lung cancer” refers to one lung cancer, wherein the ingredients of the non-small cell lung cancer, such as large cell carcinoma, are mixed in the small cell lung cancer.
In an embodiment, the lung tumors are preinvasive lesion (precancerous lesion), and include but not limited to squamous epithelial dysplasia of the lung, lung carcinoma in situ, atypical adenomatous hyperplasia of the lung, and diffuse and idiopathic neuroendocrine cell proliferation of the lung. In one embodiment, the metastatic lung tumors are the tumors formed in a way that breast cancer, colorectal cancer, stomach cancer, pancreatic cancer, renal cancer, malignant melanoma, prostate cancer, liver cancer, thyroid cancer and adrenal tumors and the like are metastasized to the lung.
In some embodiments, the tumors are metastasized, and such metastasis can be in situ and in the distance. As used herein and related to cancers or malignant tumors, the term “metastasis” refers to the spread of cancers or malignant tumors from the in-situ position to other in-vivo positions. Cancer cells can separate from in-situ tumors, penetrate into lymphatic vessels and blood vessels, and then grow in distant lesions in normal tissues at other in-vivo positions through blood circulation. The metastasis can be in situ or at the distance. The lung tumors such as lung cancers can metastasize to lymph nodes, brain, central nervous system, bone, liver, adrenal, skin, intestine, thyroid, ovary, prostate and the like. Therefore, the present recombinant interferon can be used for treating these metastasized tumors such as metastasized lung cancers; particularly, the present recombinant interferon can relieve the symptoms caused by partial stress and invasion of the lung cancers to adjacent tissues, and treat the distant metastasis of the lung cancers. The symptoms caused by the partial stress and invasion of the lung cancers include but not limited to dyscatabrosis caused by the metastasis and hyperplasia of lymph node around esophagus as well as dyspnea caused by the spread of tumors through the lung parenchyma lymphatic vessels. The distant metastases of the lung cancers include but not limited to brain metastases of the lung cancers, central nervous system metastases of the lung cancers, bone metastases of the lung cancers, liver metastases of the lung cancers, adrenal metastases of the lung cancers, and other metastases such as skin metastases, thyroid metastases, ovary metastases, prostate metastases and the like of the lung cancers.
In some embodiments, the tumors can be multiple primary cancers, for example, in the condition that the tumors are the lung cancers, such lung cancers can be multiple primary lung cancers such as the multiple primary lung cancers at different pulmonary segments or pulmonary lobes. As used herein, the term “multiple primary cancers” refers to more than two kinds of multiple primary malignant tumors that are formed at the same time or successively on a same body. Such multiple primary malignant tumors must be confirmed to be malignant and non-external metastasis tumors by histology. As used herein, the term “multiple primary lung cancers” refers to more than two multiple primary malignant tumors which are identical in histology and independent in existence, do not have metastasis between each other, and are generated at different pulmonary segments or pulmonary lobes.
The disease suitable for the treatment and/or prevention method of the invention also includes cancer emergencies, for example advanced cancer emergencies such as pleural effusion, ascites and/or pericardial effusion. In some embodiments, the pleural effusion, ascites and/or pericardial effusion are malignant pleural effusion, malignant ascites and/or malignant pericardial effusion. In some embodiments, the malignant pleural effusion can be caused by pleural primary tumors or pleural metastasized tumors, and is the common emergencies in the advanced lung cancers. The pleural primary tumors include malignant and diffuse mesothelioma, and the pleural metastasized tumors are originated from lung cancer, breast cancer, lymphoma, ovarian cancer, endometrial cancer, cervical cancer, stomach cancer, colorectal cancer, pancreatic cancer, bladder cancer, liver cancer and the like. In some embodiments, the malignant pericardial effusion can be caused by lung cancer, breast cancer and the like. For example, the malignant pericardial effusion can be caused in a way that the lung cancer can be metastasized or can directly invade pericardium, which is also the common expression of the advanced lung cancers. In some embodiments, the malignant ascites can be caused by malignant tumors, wherein excessive liquid is accumulated in enterocoelia, and the malignant ascites is one of the advanced emergencies of cancers, and the malignant ascites are generally caused by ovarian cancer, cervical cancer, endometrial cancer, digestive tract tumor, lymphoma, breast cancer, peritoneal mesothelioma and the like.
B. SubjectsThe subject suitable for the treatment and/or prevention method of the invention includes mammal, which comprises but not limited to human and non-human mammal, optionally, the subject is human. In the context, the terms “subject” and “patient” can be used interchangeably. In some embodiments, the subject with tumors is the subject previously diagnosed with tumors such as malignant tumors.
In some embodiments, the subjects include but not limited to a subject with tumors such as malignant tumors that are not capable of being resected, a subject with tumors such as malignant tumors that are capable of being resected, a subject with cancers, a subject with metastasized tumors such as metastasized malignant tumors, and/or a subject with pleural effusion, ascites and/or pericardial effusion such as malignant pleural effusion, malignant ascites and/or malignant pericardial effusion. In some embodiments, the tumor is optionally resected by a surgical resection. In some embodiments, the subjects suffered from solid tumors. In some embodiments, the solid tumors are capable of being resected or are not capable of being resected, such as solid tumors that are capable of being resected or are not capable of being resected surgically. In some embodiments, the solid tumors that are capable of being resected or are not capable of being resected, such as solid tumors that are capable of being resected or are not capable of being resected surgically, are advanced, or stage III or stage IV solid tumors. In some embodiments, the subjects are the subjects with or without indications for cancers or tumors surgery such as lung cancers surgery. In some embodiments, the solid tumors are solid tumors with or without indications for surgery such as indications for tumor surgery. In some embodiments, the solid tumors with or without indications for surgery such as indications for tumor surgery, are advanced, or stage III or stage IV solid tumors. In some embodiments, the solid tumors are lung cancers.
As used herein, the term “indication for surgery” or “indicated for surgery” or “appropriate for surgery” refers to a surgical method which is employed when a disease is in accordance with the standard specified by treatment routine and cannot be cured by a non-surgical method and the surgical method can be employed for being helpful for the treatment of the disease. In some embodiments, the cancers without indications or not indicated for surgery include: (1) non-solid tumors or systematic tumors, such as leukemia, malignant lymphoma, bone tumor and the like; (2) cancers with extensive systematic metastases for which surgical treatment is of no value; (3) cancers at a position which is difficult for surgical resection, such as nasopharyngeal carcinoma, upper esophageal carcinoma, radix linguae carcinoma and the like; (4) cancers which easily metastasize at a very early stage, such as undifferentiated small cell lung cancer, so that surgical resection is generally not suggested; and (5) cancers with carcinoma cells which infiltrate into surrounding tissues while growing, have unclear boundary and cannot be completely resected by surgery, such as tonsil carcinoma, pancreas carcinoma and the like. In some embodiments, the solid tumors without indications or not indicated for surgery include: (1) systematic solid tumors such as bone tumor and the like; (2) solid tumors with extensive systematic metastases for which surgical treatment is of no value; (3) solid tumors at a position which is difficult for surgical resection, such as nasopharyngeal carcinoma, upper esophageal carcinoma, radix linguae carcinoma and the like; (4) solid tumors which easily metastasize at a very early stage, such as undifferentiated small cell lung cancer; and (5) solid tumors with carcinoma cells which infiltrate into surrounding tissues while growing, have unclear boundary and cannot be completely resected by surgery, such as tonsil carcinoma, pancreas carcinoma and the like.
As used herein, the term “tumors that are capable of being resected” are tumors which are limited to primary organs and are suitable for surgical therapy, such as malignant tumors. A subject with tumors such as malignant tumors that are not capable of being resected also includes a subject with tumors such as malignant tumors that are not capable of being resected surgically. Such surgery can include surgical procedures, minimally invasive operation and the like. In a specific embodiment, the subject with tumors such as malignant tumors that are capable of being resected includes a subject with tumors such as malignant tumors which can be resected surgically.
In some embodiments, the subjects include but not limited to early cancer patients, medium-term and advanced cancer patients, optionally medium-term or advanced cancer patients. As used herein, the term “early cancer” includes cancer in situ and stage I cancer, the term “medium-term cancer” includes stage II and stage III cancers, and the term “advanced cancer” refers to metastatic cancers with extensive infiltration in situ or with metastises at remote organs, such as stage IV cancer. In some embodiments, the subjects include but not limited to stage 0, I, II, III or IV cancer patients, optionally stage III or stage IV cancer patients; and the subjects with metastasized tumors such as metastasized malignant tumors includes but not limited to subjects with tumors such as malignant tumors which are metastasized in situ or in the distance. It should be understood that when the tumor or cancer is referred to as stage 0, I, II, III, or IV tumor or cancer, the stages of the tumor or cancer is defined by the TNM staging method well known in the art (see AJCC Cancer Staging Manual (Sixth Edition), Greene, F. L. et al. editor. LIAONING SCIENCE AND TECHNOLOGY PUBLISHING HOUSE, August 2005). For example, in the TNM staging method, the Stage 0 means T0N0M0; the Stage Ia means T1N0M0; the Stage Ib means T2N0M0; the Stage IIa means T1N1M0; the Stage IIb means T2N1M0 and T3N0M0; the Stage IIIa stage means T3N1M and T1-3N2M0; the Stage IIIb means any T, N3 and M0, T4, and any N and M0; and Stage IV means any T, and any N and M1. In some embodiments, the subjects are medium-term, advanced, or Stage III or Stage IV cancer patients. In some embodiments, the subjects are advanced, or Stage III or Stage IV cancer patients.
In some embodiments, the subjects with malignant pleural effusion, malignant ascites and/or malignant pericardial effusion include the subjects with malignant pleural effusion, malignant ascites and/or malignant pericardial effusion caused by cancers such as advanced, or Stage III or Stage IV cancers. In one embodiment, the cancers are lung cancers.
In some embodiments, the subjects suffered from tumors which can be lung tumors, such as lung cancers. In one embodiment, the subjects can be lung cancer patients, such as patients of lung cancer that is not capable of being resected surgically, the medium-term and advanced lung cancer patients, the Stage 0, I or II lung cancer patients, or Stage III or IV lung cancer patients, and the metastasized lung cancer patients or the lung cancer patients with malignant pleural effusion, malignant ascites and/or malignant pericardial effusion. In one embodiment, the lung cancer patients include but not limited to small cell lung cancer patients and non-small cell lung cancer patients.
C. Combination TherapyIn some embodiments of the method of the invention, other therapies or drugs can be administered to the subject before, simultaneously, and/or after administration of the present recombinant interferon. In some embodiments, the therapies are optionally anti-cancer therapies, and the drugs are optionally anti-tumor drugs. As used herein, the term “administration” refers to giving a substance to achieve the therapeutic purposes. As used herein, the term “combination therapy” refers to employing two or more treatment means for the subjects in the process of the treatment period, such as employing the present recombinant interferon and extra treatment means. The extra treatment means can be employed for the subjects before, simultaneously, and/or after administration of the present recombinant interferon. As used herein, the term “anti-cancer therapy” refers to a useful therapy in the cancer treatment.
In some embodiments, the other anti-cancer therapies include but not limited to chemotherapy, radiotherapy, surgical therapy, interventional therapy, biotherapy, gene therapy, ablation therapy, immune therapy, targeted therapy, traditional Chinese medicine therapy and any combination thereof. The other anti-cancer therapies can be easily determined by the person skilled in the art. In some embodiments, the other anti-cancer therapies are optionally chemotherapy, radiotherapy, surgical therapy, targeted therapy and/or biotherapy. In some embodiments, the other anti-cancer therapies are optionally chemotherapy and/or radiotherapy.
As used herein, the term “chemotherapy” refers to a drug therapy affecting cell growth and cell division, namely, the drug therapy is taken as a cell proliferation inhibitor or is used for inducing cell death (cell apoptosis). Compared with normal cells, cancer cells grow and divide uncontrollably so that the chemotherapy should be more effective to the cancer cells. In a specific embodiment, chemotherapy includes arterial infusion chemotherapy and embolism-form chemotherapy. In a specific embodiment, for different cancers, the chemotherapy can be the common first-line chemotherapy for the cancers. For example, chemotherapeutic drugs used in the first-line chemotherapy for treating lung cancer include but not limited to platinum compounds such as Cisplatin.
The chemotherapeutic drugs used in the chemotherapy for the cancers in the invention include but not limited to alkylating agents such as nitrogen mustards including but not limited to chlormethine hydrochloride, chlorambucil, phenylalanine mustard, chlornaphazine, estramustine, cyclophosphamide, ifosfamide, Mechlorethamine, mustron, Melphalan, novembichin, phenesterin, Prednimustine, Trofosfamide and Uramustine; ethyleneimines and methyl melamines including but not limited triethylenemelamine, Thiotepa, MST-16, altretamine, triethylene melamine, triethylene phosphamide, triethylene Thiophosphoramide and trimethylol melamine; sulfoacid alkyl esters including but not limited to busulfan, improsulfan and piposulfan; and nitrosoureas including but not limited to carmustine, Semustine, Streptozotocin, chlorozotocin, Fotemustine, Lomustine, Nimustine and Ranimustine; antimetabolites such as anti-folate antimetabolite including but not limited to methopterin (MTX), trimethyl-oxy quinazoline, dimethyl folate, pteropterin, trimetrexate, leucovorin and Pemetrexed (Alimta); pyrimidine antimetabolites including 5-fluorouracil (5-FU), floxuridine, ftorafur (Tegafur), Capecitabine (Xeloda), Ancitabine, Carmofur, di-deoxyuridine, Doxifluridine and enocitabine; cytidines antimetabolites including but not limited to cytarabine, Azacytidine, ancitabine and Gemcitabine (Gemzar); purines antimetabolites including but not limited to 6-mercaptopurine, 6-thioguanine, deoxycoformycin, Fludarabine and thiamiprine; plant-origin anti-tumor drugs such as Vinca Alkaloids including but not limited to vinblastine, vindesine, vincristine, vindesine, Vinorelbine, vinblastine sulfate, vincristine sulfate, Vinorelbine Tartrate and Vinflunine; Harringtonine and Homoharringtonine; Indirubin and analogue thereof including but not limited to N-methyllisoinidog-tin; etoposide drugs including but not limited to Teniposide (VM-26) and Etoposide (VP-16); Camptotheca and Camptothecin compounds including but not limited to Camptothecin, Topotecan (TPT) and Irinotecan (CPT-11); Paclitaxel compound including but not limited to Paclitaxel (Paclitaxel Liposome For Injection), Docetaxel (Docetaxel Injection, Taxotere) and paclitaxel liposome; antitumor antibiotics such as anthracyclines including but not limited to daunorubicin, adriamycin, aclacinomycin A, Epirubicin, mitoxantrone and marcellomycin; Glycopeptides including but not limited to bleomycin, tallysomycine, Leroymycin, pepreomycin and Pingyangmycin; actinomycins including but not limited to actinomycin C, actinomycin D, aurantin and dactinomycin; glucosides including but not limited to mithramycin, chromomycin A3 and Olivomycin; mitomycins including but not limited to mitomycin C; and Streptozotocin; the platinum compounds include but not limited to Spiroplatin, Cisplatin, Carboplatin, Nedaplatin, oxaliplatin, Lobaplatin, JM-216, Ring Platinum, SKI2053R, L-NDDP and TRK-710; retinoid compounds include but not limited to all-trans retinoic acid and 13-cis-retinoic acid; hormones include androgens including but not limited to Testosterone Propionate, Methyltestosterone, Fluoxymesterone, durabolin, calusterone, propionic-acid methyl androstane pregnanolone, epithioandrostanol, mepitiostane and testolactone; antiandrogens including but not limited to flutamide, Nilutamide, Bicalutamide (Casodex), Goserelin, Leuprorelin and Androcur; estrogens including but not limited to diethylstilbestrol, estradiol and ethinyloestradiol; estrogen receptor blocker and composite drug formed by transplanting estrogen, including but not limited to Tamoxifen, Toremifene, Anastrozole and Exemestane; progesterones including but not limited to Methylhydroxyprogesterone and Megestrol Acetate; Gonadotropin releasing hormone analogues including but not limited to Leuprorelin, Gonadorelin and Dingsi-relin and naphthoxy-propyl-relin; adrenocortical hormone including but not limited to metacortandracin (prednisone) and dexamethasone (DXM); adrenal-cortex selective damaging agent including but not limited to Mitotane; thyroid hormones including but not limited to thyroxine; and others including but not limited to Bacillus Calmette Guerin (BCG), Asparaginase, hydroxycarbamide, Ibenzmethyzin and Dacarbazine (DTIC); and pharmaceutically acceptable salts, acids or derivatives of any above substance.
In some embodiments, chemotherapy protocols used for treating cancers such as lung cancers in the invention include but not limited to a CMC protocol (cyclohexyl nitrosourea, cyclophosphamide and Methotrexate), an EP protocol (etoposide and Cisplatin), an IVP protocol (ifosfamide, vindesine and Cisplatin), an ICE protocol (ifosfamide, Cisplatin and etoposide), a NIP protocol (Navelbine, ifosfamide and Cisplatin), a Paclitaxel+DDP/CBP protocol (Paclitaxel and Cisplatin/carboplatin), a docetaxel+DDP/CBP protocol (docetaxel and Cisplatin/carboplatin), a topotecan+DDP protocol (topotecan and Cisplatin), an IP protocol (Irinotecan and carboplatin), a MVP protocol (mitomycin, vindesine and Cisplatin), a NP protocol (Navelbine and Cisplatin), a docetaxel protocol, a GEM+DDP (GP) protocol or GEM+CBP protocol (Gemzar and Cisplatin/carboplatin) and the like (see Lung Oncology Phymatology, First Edition, September 2008, Liao, M. L. editor, Shanghai Scientific and Technical Publisher, pages 323-326).
In addition, other chemotherapy protocols used for treating tumors such as cancers in the invention include but not limited to an FOLFOX protocol (see Newest Chemotherapy Development of Malignant Tumors, July, 2009, chief editor: Zheng Cuiping, Beijing: People's Military Medical Press, 1031), a DP protocol (see Newest Chemotherapy Development of Malignant Tumors, July, 2009, chief editor: Zheng Cuiping, Beijing: People's Military Medical Press, 232), a CHOPE protocol, a MTX protocol, a GCE protocol, an ESAP protocol, a CMOP protocol, a CHOP protocol (see Practical Anti-tumor Pharmacotherapeutics, 2002, chief editor: Liu Xinchun etc., Beijing: People's Medical Publishing House, 1031), a bleomycin+CHOP+Methotrexate protocol, a GP+Endostar protocol, a GP-T2 protocol, a TP protocol (see Practical Anti-tumor Pharmacotherapeutics, 2002, chief editor: Liu Xinchun etc., Beijing: People's Medical Publishing House, 668 and 744), a Cisplatin+mitomycin protocol and the like.
As used herein, the term “radiotherapy” refers to employing high-energy radiation for treating tumors such as cancers. The radiotherapy includes external radiation such as external radiotherapy from a linear accelerator, and brachytherapy for which radioactive sources are placed near the surface of the human body or in the body cavity. In the radiotherapy of the invention, the radioactive sources include but not limited to α, β and γ rays generated by radioactive nuclides, and electron beams, proton beams. Neutron beams, −π meson beams and other heavy particle beams generated by various accelerators. The radioactive nuclides include but not limited to 137Cs, 60C, 131I, 125I, 32P, 198Au, 192Ir, 90Y, 186Re and 109Pd. Such radioactive sources can perform radiation in vitro and/or in vivo.
It should be understood that many methods known in the art can be used for determining the accumulation and duration of the radiotherapy. The typical radiotherapy is employed as one-time administration, and the usual dose is in the range of about 1 to about 200 grays/day, such as about 2 to about 150 grays/day, about 5 to about 100 grays/day, about 10 to about 70 grays/day, about 10 to about 50 grays/day and the like. In one embodiment, the radiotherapy used in the invention includes but not limited to two-dimensional conventional radiotherapy, three-dimensional conformal radiotherapy (3D-CRT), proton radiotherapy, brachytherapy, intensity modulated radiotherapy (IMRT), stereotactic radiotherapy (SRT), respiratory gating four-dimensional radiotherapy (4DRT) and gamma knife therapy, such as systematic gamma knife therapy and head gamma knife therapy.
As used herein, the term “targeted therapy” refers to a therapy aiming at identifying specific target molecules which can be, for example, play a role in tumorigenesis or tumor proliferation or cell repairing. Such identification may be, for example, lead to the combination between the targeted therapy and the target molecules, and can enhance or reduce the activity of the target molecules. Drugs used for the targeted therapy includes antibodies, in particular to monoclonal antibodies and small molecule drugs. Potential targets include EGFR receptors, which playing a role in vasculogenesis, VEGFA ligands, which being important in vasculogenesis, or PARP1, which being important in cell repairing, because the tumors with cancer gene defect can be more sensitive to the chemical therapy due to the suppression to the PARP1.
In the targeted therapy of the present invention, the targeted drug includes but not limited to an anti-angiogenesis drug, Kinase inhibitor, pan Kinase inhibitor or growth factor inhibitor. The anti-angiogenesis drug includes but not limited to EGF inhibitor, EGFR inhibitor, VEGF inhibitor, VEGFR inhibitor, TIE2 inhibitor, IGF1R inhibitor, COX-II (cyclo-oxygenase-II) inhibitor, MMP-2 (matrix metalloproteinase-2) inhibitor and MMP-9 (matrix metalloproteinase-9) inhibitor. A targeted drug that can be used herein includes but not limited to at least one of: Gefitinib (Iressa), Erlotinib (TARCEVA®), Lapatinib (GSK572016), Vatalanib (PTK787), Imatinib (GLEEEVEC®), Dasatinib (Sprycel), Sunitinib (SUTENT®), Nilotinib (Tasigna), Semaxanib (SU5416), Pazopanib (GW-786034), Erbitux (IMC-C225), Panitumumab (Vectibix), Trastuzumab (Herceptin), Recombinant Human Endostatin (Endostar), Sorafenib (NEXAVAR®), Bevacizumab (Avastin), Alemtuzumab (Campath), Gemtuzumab (Mylotarg), ibritumomab tiuxetan (Zevalin), tositumomab (Bexxar), Affinitak (LY90003/ISI3521), Farnesyltransferase inhibitors, Tipifanib, Lonafanib, BMS214-662, R115777 (Zarnestra), SCH-66336 (Sarasar), L-778,123, ZD6474 (ZACTIMA®), AZD2171, OSI-7904, ZD6126 (ANG453), ZD1839, AMG706, AG013736, MLN-518, CEP-701, PKC-412, VELCADE®, XL880 and CHIR-265. In some embodiments, the targeted drug in the targeted therapy used for treating cancers such as lung cancers in the invention includes but not limited to Gefitinib (Iressa), Erlotinib (TARCEVA®), and Recombinant Human Endostatin (Endostar).
The dose and duration of the drugs and/or the radioactive sources used in the chemical therapy, radiotherapy and/or targeted therapy can be easily determined by skilled physicians according to the experience and the practical situations of patients such as age, weight, general health state, gender, diet, administration time, drug interaction and illness severity.
As used herein, the term “surgical therapy” refers to an invasive cancer therapy aiming at physically eliminating cancer cells. The surgical therapy includes, for example, tumor resection and lymph node dissection.
As used herein, the term “gene therapy” refers to a therapy by delivering recombinant genetic materials by virus or non-virus carriers ex vivo or in vivo so as to treat or prevent diseases or medical conditions, such as cancers.
As used herein, the term “ablation therapy” refers to a well known tissue damage method, such as high-temperature ablation such as radio frequency, microwave and laser ablation, low-temperature ablation such as cryocare knife cryotherapy, chemical ablation, radioactive ablation and the like.
As used herein, the term “immunotherapy” refers to a treatment strategy which is employed for regulating the immune system so as to prevent and/or treat specific diseases such as cancers. For example, vaccination is one immunotherapy. The vaccine used in the present immunotherapy includes but limited to ALLOVECTIN® vaccine, LEUVECTIN® vaccine, VAXID® vaccine and the like.
As used herein, the term “interventional therapy” refers to a treatment method with smallest trauma for performing local treatment to the lesion under the condition that the lesion is not operated through tiny channels made on the skin or original channels of the human body under the guidance of imaging equipment (such as a Digital Subtraction Angiography, a perspective machine, CT, MR and B ultrasonic). When being used for treating the tumors, the interventional therapy includes but not limited to transcatheter arterial chemoembolization, arterial infusion chemotherapy, high-temperature ablation such as radio frequency, microwave and laser ablation, low-temperature ablation such as cryocare knife cryotherapy, chemical ablation, radioactive ablation, gene drug arterial infusion, stent implantation and the like.
As used herein, the term “biotherapy” refers to all treatment methods employing modern biotechnologies and the products (small molecule compounds, polypeptide, polysaccharide, protein, cells, tissues, genes, RNAs and the like) thereof. When being used for treating the tumors, the biotherapy can directly or indirectly mediate anti-tumor and tumor-killing effects. The biotherapy used for treating the tumors includes but not limited to the application of non-specific immunologic stimulant, Biological Response Modifier (BRM), a tumor cell factor treatment and immunological effect cell treatments such as NK cell anti-tumor therapy, biology supporting therapy, tissue and cell transplanting therapy and the like.
As used herein, the term “traditional Chinese medicine therapy” refers to all methods employing the traditional Chinese medicine and drugs guided by Chinese medicine theories for treating diseases such as cancers.
In addition, other anti-tumor drugs which can be administered together with the present recombinant interferon include but not limited to biological agents used in the biotherapy such as tumor necrosis factors including TNF-α or TNF-β and the like; interferon such as interferon α including interferon α-1a, interferon α-1b, interferon α-2a, interferon α-2b and the like, interferon β including interferon β-1a, interferon β-1b and the like, interferon γ including interferon γ-1b and the like, consensus interferon such as interferon α-con1, long-acting interferon such as PEGylation interferon, fusion protein of interferon and albumin, and fusion protein of interferon and IgG Fc fragment; colony stimulating factors (CSF) such as macrophage-colony stimulating factor (M-CSF), granulocyte-macrophage (GM-CSF) and granulocyte-colony stimulating factor (G-CSF); interleukin (IL) such as IL-1, IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, and Thymosin; antisense oligonucleotide, especially those for inhibition of the expression of genes (such as PKC-α, Raf and H-Ras) in signaling pathway involved in the proliferation of adherent cells; siRNA and the like.
D. Pharmaceutical Composition and Administration RouteThe present recombinant interferon can be incorporated into pharmaceutical compositions, so as to be administered to subjects. Generally, the pharmaceutical composition comprises the present recombinant interferon and pharmaceutically acceptable carriers. The “pharmaceutically acceptable carrier” herein includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the present recombinant interferon.
The pharmaceutical compositions of the invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, aqueous solutions, tablets, capsules, oral solutions, patches, sprays, suppositories, powders and lyophilized powders. The form appropriate for use depends on the intended mode of administration and therapeutic application. Typical pharmaceutical compositions are in the form of injectables or infusible solutions, lyophilized powders, sprays, and aqueous solutions.
The pharmaceutical composition can be prepared by any well known method in the pharmaceutical field with reference to: Gilman, etc., (editor) 1990, The Pharmacological Bases of Therapeutics, the 8th version, Pergamon Press; A. Gennaro (editor), Remington's Pharmaceutical Sciences, the 18th version, 1990, Mack Publishing Co., Easton, Pa.; Avis, etc., (editor) 1993, Pharmaceutical Dosage Forms: Parenteral Medications Dekke, New York; Lieberman, etc., (editor) 1990, Pharmaceutical Dosage Forms: Tablets Dekker, New York; and Lieberman, etc., (editor) 1990, Pharmaceutical Dosage Forms: Disperse Systems Dekker, New York.
The present recombinant interferon can be administered to the subjects through at least one of: systemic administration, topical administration, and local administration. As used herein, the term “systemic administration” refers to a mode for administering compositions or drugs to a subject, in a manner that leads to systemic circulation of the drugs or compositions in the subject, such as the spreading or distribution of the administered compositions or drugs to all parts of the body. Examples of systemic administration include, but are not limited to: intravenous injection, intra-arterial injection, intramuscular injection, subcutaneous injection, intra-lymphatic injection, oral administration, and the like.
As used herein, the term “local administration” refers to administering a composition or drug into a limited or partial anatomy space. Examples of local administration include but are not limited to: intratumoral, intra-lymph node, intra-pleural space, intraperitoneal cavity and the like.
As used herein, the term “topical administration” refers to administering a drug or composition on the surface of skin or mucous membrane. For example, topical administration includes but is not limited to spraying the drug or composition onto the skin of a subject.
In some embodiments, the present recombinant interferon can be administered to the subject by at least one administration route, the administration route comprises but not limited to: oral, rectal, sublingual, intravenous, intra-arterial, intramuscular, subcutaneous, intra-bone, intracutaneous, intra-articular, intraperitoneal, intrathecal, intracerebral, vaginal, percutaneous, transdermal, epidermal, transmucosal, transocular, pulmonary, nasal, abdominal, intrapleural, intraventricular, pericardial, inhalation, intratumoral, uterine, infiltration, and intravesical administration. In some embodiments, the present recombinant interferon can be administered to the subject by injection route, such as subcutaneous, intramuscular, intravenous, intra-arterial, intracerebral, intraperitoneal and/or intratumoral injection. In some embodiments, the present recombinant interferon can be administered to the subject by inhalation, such as pulmonary inhalation and nasal inhalation. In some embodiments, the inhalation can be dry powder inhalation and/or aerosol inhalation. In some embodiments, the present recombinant interferon can be administered to the subject by perfusion, such as intrapleural perfusion, abdominal perfusion, pericardial perfusion, uterine perfusion and/or intravesical perfusion. In some embodiments, the present recombinant interferon can be administered to lesion (such as the surfaces of skin and mucosa, superficial lymph nodes and/or subcutaneous tissue) by spray, such as percutaneous, epidermal, transdermal and/or transmucosal spray administration. In some embodiments, the infiltration administration includes pulmonary infiltration administration, percutaneous infiltration administration, epidermal infiltration administration, transmucosal infiltration administration, intrapleural infiltration administration, abdominal infiltration administration, uterine infiltration administration, vaginal infiltration administration, intravesical infiltration administration, pericardial infiltration administration and the like.
Injection/Perfusion AdministrationThe pharmaceutical compositions suitable for injection/perfusion include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases, the composition must be sterile and should be fluid so as to be administered using a syringe. Such compositions should be stable during manufacture and storage and must be preserved against contamination from microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures. Various antibacterial and antifungal agents; for example, parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal; isotonic agents; for example, sugars, polyalcohols such as manitol, sorbitol, and sodium chloride can be included in the composition. Compositions that can delay absorption include agents such as aluminum monostearate and gelatin.
Sterile injection/perfusion solutions can be prepared by incorporating the present recombinant interferon in the required amount in an appropriate solvent with one or a combination of ingredients as required, followed by sterilization. Generally, dispersions are prepared by incorporating the present recombinant interferon into a sterile vehicle that contains a basic dispersion medium, and the other required ingredients. Sterile powders for the preparation of sterile injection/perfusion solutions, methods of preparation include vacuum drying and freeze-drying that yield a powder containing the active ingredient and any desired ingredient from a sterile solutions.
Inhalation AdministrationThe present recombinant interferon can be delivered by any of a variety of inhalation devices know in the art for administration of a therapeutic agent by inhalation. These devices include metered dose inhalers, nebulizers, dry powder generators, sprayers, and the like. Other devices suitable for inhalation administration of the present recombinant interferon are also known in the art.
Metered dose inhalers like the Ventolin® metered dose inhaler, typically use a propellent gas and require actuation during inspiration (See, e.g., WO 94/16970, WO 98/35888). Dry powder inhalers like Turbuhaler™ (Astra), Rotahaler® (Glaxo), Diskus® (Glaxo), Spiros™ inhaler (Dura), devices marketed by Inhale Therapeutics, and the Spinhaler® powder inhaler (Fisons), use breath-actuation of a mixed powder (U.S. Pat. No. 4,668,218 Astra, EP 237507 Astra, WO 97/25086 Glaxo, WO 94/08552 Dura, U.S. Pat. No. 5,458,135 Inhale, WO 94/06498 Fisons). Nebulizers like AERx™ Aradigm, the Ultravent® nebulizer (Mallinckrodt), the Acorn II® nebulizer (Marquest Medical Products) (U.S. Pat. No. 5,404,871 Aradigm, WO 97/22376), and the AP-100200 type spray inhaler (Taiwan Albert incorporated company). Producing aerosols from solutions, while metered dose inhalers, dry powder inhalers, etc. generate small particle aerosols.
Optionally, the present recombinant interferon is delivered by a nebulizer. The inhalation devices for administering the present recombinant interferon have several desirable features. For example, delivery by the inhalation device is advantageously reliable, reproducible, and accurate. The inhalation device can optionally deliver small dry particles or aerosol, e.g., less than about 10 μm, for example about 0.5 μm to about 5 μm, for good respirability.
Spray AdministrationA spray including the present recombinant interferon can be produced by forcing a suspension or solution of the recombinant interferon through a nozzle under pressure. The nozzle size and configuration, the applied pressure, and the liquid feed rate can be chosen to achieve the desired output and particle size. An electrospray can be produced, for example, by an electric field in connection with a capillary or nozzle feed. Advantageously, particles delivered by a sprayer have a particle size less than about 10 μm, optionally, in the range of about 0.5 μm to about 5 μm.
Formulations of the present recombinant interferon suitable for use with a sprayer typically include ones at a concentration in a range of about 0.01 mg to about 5 mg, such as about 0.03 mg to about 2 mg, about 0.05 mg to about 1 mg, and about 0.1 mg to about 0.5 mg of the recombinant interferon per ml of solution. The formulation can include an excipient or agent for stabilization of the present recombinant interferon, such as a buffer, a reducing agent, a bulk protein, or a carbohydrate. Bulk proteins useful in formulating the recombinant interferon include albumin, protamine, or the like. Typical carbohydrates useful in formulating the recombinant interferon include sucrose, mannitol, lactose, trehalose, glucose, or the like. The present recombinant interferon formulation can also include a surfactant, which can reduce or prevent surface-induced aggregation of the recombinant interferon caused by atomization of the solution in forming an aerosol.
E. Administration Dosage and Administration ProtocolEffective amount of the present recombinant interferon can be administered to the subjects such as cancer subjects, and such effective amount can be a therapeutically effective amount or a prophylactically effective amount according to the method of the invention. As used herein, the term “effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. A therapeutically effective amount of the present recombinant interferon may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the recombinant interferon to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the recombinant interferon are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically but no surely, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
The present recombinant interferon can be administered to the subjects such as the cancer subjects in different amounts of single doses. For example, the single doses of the present recombinant interferon can be in the range of about 2 μg to about 2000 μg, optionally about 4 μg to about 1500 μg, and further optionally about 9 μg to about 1000 μg. As used herein, the term “single dose” refers to an amount of drug which can be at administered one time, that can be therapeutically or prophylactically effective by itself or cumulatively with other single doses. Such administration includes systemic administration, local administration and/or topical administration.
When the present recombinant interferon is systemically administered via injection administration (such as subcutaneous injection, intramuscular injection, intravenous injection, intra-arterial injection, intracerebral injection and/or intraperitoneal injection), the single dose of the recombinant interferon can be in the range of about 4 μg to about 70 μg, optionally, about 4 μg to about 50 μg, and further optionally, about 4 μg to about 30 μg, wherein the single dose can be about 4 μg, about 4.5 μg, about 5 μg, about 6 μg, about 7 μg, about 8 μg, about 9 μg, about 10 μg, about 11 μg, about 12 μg, about 13 μg, about 13.5 μg, about 14 μg, about 15 μg, about 16 μg, about 17 μg, about 18 μg, about 19 μg, about 20 μg, about 21 μg, about 22 μg, about 23 μg, about 24 μg, about 25 μg, about 25.5 μg, about 26 μg, about 27 μg, about 28 μg, about 29 μg, about 30 μg, about 31 μg, about 32 μg, about 33 μg, about 34 μg, about 35 μg, about 36 μg, about 37 μg, about 38 μg, about 39 μg, about 40 μg, about 41 μg, about 42 μg, about 43 μg, about 44 μg, about 45 μg, about 46 μg, about 47 μg, about 48 μg, about 49 μg, about 50 μg, about 51 μg, about 52 μg, about 53 μg, about 54 μg, about 55 μg, about 56 μg, about 57 μg, about 58 μg, about 59 μg, about 60 μg, about 61 μg, about 62 μg, about 63 μg, about 64 μg, about 65 μg, about 66 μg, about 67 μg, about 68 μg, about 69 μg, and about 70 μg.
When the present recombinant interferon is locally administered via injection administration (such as the intratumoral injection), the single dose of the recombinant interferon can be in a range of about 60 μg to about 600 μg, optionally, about 60 μg to about 500 μg, further optionally, about 80 μg to about 400 μg, and still further optionally, about 100 μg to about 250 μg, wherein the single dose can be about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 110 μg, about 120 μg, about 130 μg, about 140 μg, about 150 μg, about 160 μg, about 170 μg, about 180 μg, about 190 μg, about 200 μg, about 210 μg, about 220 μg, about 230 μg, about 240 μg, about 250 μg, about 260 μg, about 270 μg, about 280 μg, about 290 μg, about 300 μg, about 310 μg, about 320 μg, about 330 μg, about 340 μg, about 350 μg, about 360 μg, about 370 μg, about 380 μg, about 390 μg, about 400 μg, about 410 μg, about 420 μg, about 430 μg, about 440 μg, about 450 μg, about 460 μg, about 470 μg, about 480 μg, about 490 μg, about 500 μg, about 510 μg, about 520 μg, about 530 μg, about 540 μg, about 550 μg, about 560 μg, about 570 μg, about 580 μg, about 590 μg, and about 600 μg.
When the present recombinant interferon is administered through inhalation administration (such as pulmonary inhalation and nasal inhalation, including dry powder inhalation and aerosol inhalation), the single dose of the recombinant interferon can be in a range of about 100 μg to about 2000 μg, optionally, about 100 μg to about 1500 μg, further optionally, about 150 μg to about 800 μg, and still further optionally, about 200 μg to about 600 μg, wherein the single dose can be about 100 μg, about 110 μg, about 120 μg, about 130 μg, about 140 μg, about 150 μg, about 160 μg, about 170 μg, about 180 μg, about 190 μg, about 200 μg, about 210 μg, about 220 μg, about 230 μg, about 240 μg, about 250 μg, about 260 μg, about 270 μg, about 280 μg, about 290 μg, about 300 μg, about 310 μg, about 320 μg, about 330 μg, about 340 μg, about 350 μg, about 360 μg, about 370 μg, about 380 μg, about 390 μg, about 400 μg, about 410 μg, about 420 μg, about 430 μg, about 440 μg, about 450 μg, about 460 μg, about 470 μg, about 480 μg, about 490 μg, about 500 μg, about 510 μg, about 520 μg, about 530 μg, about 540 μg, about 550 μg, about 560 μg, about 570 μg, about 580 μg, about 590 μg, about 600 μg, about 610 μg, about 620 μg, about 630 μg, about 640 μg, about 650 μg, about 660 μg, about 670 μg, about 680 μg, about 690 μg, about 700 μg, about 710 μg, about 720 μg, about 730 μg, about 740 μg, about 750 μg, about 760 μg, about 770 μg, about 780 μg, about 790 μg, about 800 μg, about 810 μg, about 820 μg, about 830 μg, about 840 μg, about 850 μg, about 860 μg, about 870 μg, about 880 μg, about 890 μg, about 900 μg, about 910 μg, about 920 μg, about 930 μg, about 940 μg, about 950 μg, about 960 μg, about 970 μg, about 980 μg, about 990 μg, about 1000 μg, about 1100 μg, about 1200 μg, about 1300 μg, about 1400 μg, about 1500 μg, about 1600 μg, about 1700 μg, about 1800 μg, about 1900 μg, and about 2000 μg.
When the present recombinant interferon is administered through perfusion or infiltration administration (such as intrapleural perfusion, abdominal perfusion, pericardial perfusion, uterine perfusion and intravesical perfusion), the single dose of the recombinant interferon can be in a range of about 30 μg to about 2000 μg, optionally, about 100 μg to about 1500 μg, further optionally, about 150 μg to about 1000 μg, still optionally, about 200 μg to about 800 μg, and still further optionally, about 200 μg to about 400 μg, wherein the single dose can be about 30 μg, about 40 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 110 μg, about 120 μg, about 130 μg, about 140 μg, about 150 μg, about 160 μg, about 170 μg, about 180 μg, about 190 μg, about 200 μg, about 210 μg, about 220 μg, about 230 μg, about 240 μg, about 250 μg, about 260 μg, about 270 μg, about 280 μg, about 290 μg, about 300 μg, about 310 μg, about 320 μg, about 330 μg, about 340 μg, about 350 μg, about 360 μg, about 370 μg, about 380 μg, about 390 μg, about 400 μg, about 410 μg, about 420 μg, about 430 μg, about 440 μg, about 450 μg, about 460 μg, about 470 μg, about 480 μg, about 490 μg, about 500 μg, about 510 μg, about 520 μg, about 530 μg, about 540 μg, about 550 μg, about 560 μg, about 570 μg, about 580 μg, about 590 μg, about 600 μg, about 610 μg, about 620 μg, about 630 μg, about 640 μg, about 650 μg, about 660 μg, about 670 μg, about 680 μg, about 690 μg, about 700 μg, about 710 μg, about 720 μg, about 730 μg, about 740 μg, about 750 μg, about 760 μg, about 770 μg, about 780 μg, about 790 μg, about 800 μg, about 810 μg, about 820 μg, about 830 μg, about 840 μg, about 850 μg, about 860 μg, about 870 μg, about 880 μg, about 890 μg, about 900 μg, about 910 μg, about 920 μg, about 930 μg, about 940 μg, about 950 μg, about 960 μg, about 970 μg, about 980 μg, about 990 μg, about 1000 μg, about 1100 μg, about 1200 μg, about 1300 μg, about 1400, about 1500 μg, about 1600 μg, about 1700 μg, about 1800 μg, about 1900 μg, and about 2000 μg.
When the present recombinant interferon is administered to the lesions (such as surfaces of the skin and the mucosa, superficial lymph nodes and/or subcutaneous tissue) by spray administration such as percutaneous spray, epidermal spray, transdermal spray, transmucosal spray, the single dose of the recombinant interferon can be in a range of about 6 μg to about 100 μg, optionally, about 10 μg to about 40 μg, and further optionally, about 20 μg to about 40 μg, wherein the single dose can be about 6 μg, about 7 μg, about 8 μg, about 9 μg, about 10 μg, about 11 μg, about 12 μg, about 13 μg, about 14 μg, about 15 μg, about 16 μg, about 17 μg, about 18 μg, about 19 μg, about 20 μg, about 21 μg, about 22 μg, about 23 μg, about 24 μg, about 25 μg, about 26 μg, about 27 μg, about 28 μg, about 29 μg, about 30 μg, about 31 μg, about 32 μg, about 33 μg, about 34 μg, about 35 μg, about 36 μg, about 37 μg, about 38 μg, about 39 μg, about 40 μg, about 41 μg, about 42 μg, about 43 μg, about 44 μg, about 45 μg, about 46 μg, about 47 μg, about 48 μg, about 49 μg, about 50 μg, about 51 μg, about 52 μg, about 53 μg, about 54 μg, about 55 μg, about 56 μg, about 57 μg, about 58 μg, about 59 μg, about 60 μg, about 61 μg, about 62 μg, about 63 μg, about 64 μg, about 65 μg, about 66 μg, about 67 μg, about 68 μg, about 69 μg, about 70 μg, about 71 μg, about 72 μg, about 73 μg, about 74 μg, about 75 μg, about 76 μg, about 77 μg, about 78 μg, about 79 μg, about 80 μg, about 81 μg, about 82 μg, about 83 μg, about 84 μg, about 85 μg, about 86 μg, about 87 μg, about 88 μg, about 89 μg, about 90 μg, about 91 μg, about 92 μg, about 93 μg, about 94 μg, about 95 μg, about 96 μg, about 97 μg, about 98 μg, about 99 μg, and about 100 μg.
The present recombinant interferon can be administered to the subjects through different administration protocols. For example, for the purpose of treatment, the present recombinant interferon can be administered to the subject about 1, 2, 3, 4, 5, 6, 7, 8, or more times per day, or the present recombinant interferon can be administered to the subject once at the time interval of every about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days, every month, every 2 months, or longer time. For the purpose of prevention, the present recombinant interferon can be administered to the subject once at the time interval of every about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, every 2 weeks, every 3 weeks, every month, every 2 months, every 3 months, every half year, every 1 year, or a longer time.
The present recombinant interferon can be administered to the subjects in one or more treatment cycles. As used herein, the term “treatment cycle” refers to a biological or medical response time length reached by the present recombinant interferon or the pharmaceutical composition comprising the recombinant interferon, and explored for researchers, veterinarians, medical practitioners or other clinicians observed in tissues, systems, animals, individuals or human beings. The duration of such one treatment cycle is at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years and the like, or the duration can also be about 1 day to about 6 years, about 1 week to about 4 years, about 2 weeks to about 3 years, about 1 month to about 1 year, or about 2 months to about 9 months and the like. The present recombinant interferon can be administered for a long time, namely, namely, the lasting prolonged time in one treatment cycle includes over the life time of the subject so as to improve or control or limit the symptom of the subjects. In one treatment cycle, the present recombinant interferon can be administered to the subjects one or more times.
Alternatively, the present recombinant interferon can be administered to the subjects in more treatment cycles. For example, such treatment cycles can be 2, 3, 4, 5, 6, 7, 8, 9, 10, or more treatment cycles; and the duration of the treatment cycles can include over the life time of the subject. The time intervals (i.e. withdrawal period) of any two adjacent treatment cycles in all the treatment cycles can be the same or different, for example, the time interval can be at least about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years and the like; and such time interval can also be about 2 days to about 6 years, about 4 days to about 3 years, about 1 week to about 1 year, about 2 months to about 9 months, or about 3 months to about 6 months and the like.
When the present recombinant interferon is administered for more times in one treatment cycle, the dose in every administration can be the same or different, for example, the present recombinant interferon is administered for one or more times in a lower dose, and then the present recombinant interferon is administered for one or more times in an increased or gradually-increased dose; or, the present recombinant interferon is administered for one or more times in a smaller dose, then the present recombinant interferon is administered for one or more times in an increased or gradually-increased dose, and the present recombinant interferon is administered for one or more times in a decreased or gradually-decreased dose; or, the present recombinant interferon is administered for one or more times in a larger dose, and then the present recombinant interferon is administered for one or more times in a decreased or gradually-decreased dose; or, the present recombinant interferon is administered for one or more times in a larger dose, then the present recombinant interferon is administered for one or more times in a decreased or gradually-decreased dose, and the present recombinant interferon is administered for one or more times in an increased or gradually-increased dose. In some embodiments, the smaller dose can be the induction dose.
Compared with the previously administered dose, the later increasingly administered dose can be about 110% to about 500%, including, for example about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 220%, about 240%, about 260%, about 280%, about 300%, about 350%, about 400%, about 450% and about 500%, of the previously administered dose. Compared with the previously administered dose, the later gradually-increased administered dose can be about 110% to about 500% including, for example about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 220%, about 240%, about 260%, about 280%, about 300%, about 350%, about 400%, about 450% and about 500%, of the previously administered dose sequentially. The gradually-increased dose can be increased by 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, or more times, and then the last dose can be kept till the end of the treatment cycle.
Compared with the previously administered dose, the later decreasingly administered dose can be about 5% to about 99% including, for example, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% and about 99%, of the previously administered dose. Compared with the previously administered dose, the later gradually-decreased administered dose can be about 5% to about 99% including, for example, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% and 99%, of the previously administered dose sequentially. The gradually-decreased dose can be decreased by 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, or more times, and then the last dose can be kept till the end of the treatment cycle.
In addition, when the present recombinant interferon is administered for one or more times in the same single dose in each of the treatment cycles, the single doses of the present recombinant interferon in two different treatment cycles can be the same or different. For example, the single dose can be gradually increased or decreased. Compared with the previously administered dose, the increasing or decreasing degree is as mentioned above.
In some embodiments, the gradually increasing or the gradually decreasing can be linear increasing or decreasing, for example, the first administered drug is 9 μg, then the later increased dose is 18 μg, 36 μg, 72 μg and the like sequentially, namely, the sequential increasing rate is 100%; or, the gradually increasing or the gradually decreasing can be non-linear increasing or decreasing, for example, the first administered drug is 9 μg, then the later increased dose can be 15 μg, 18 μg, 21 μg and the like, namely, compared with the previous administered drug, the drug increasing degree at every time can be different.
It should be noted that the administration dosage and the administration protocol can be changed reasonably by the person skilled in the art based on the teaching of the invention, with the type and severity of the disorder to be released, the subject, the administration methods and the like.
F. Specific Treatment Methods and Pharmaceutical Applications.Specific treatment methods and pharmaceutical applications with use of the present recombinant interferon are provided herein.
In one aspect, the present invention provides a method for treating a tumor in a subject, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2.
In one embodiment, the present invention provides a method for treating tumor in a subject, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2, and at least one other anti-cancer therapy, wherein the at least one other anti-cancer therapy is administered to the subject before, simultaneously, and/or after administration of the recombinant interferon, and wherein the tumor is a cancer or solid tumor that is not indicated nor appropriate for surgery, or the tumor is a solid tumor that cannot be resected, and the combination of the recombinant interferon and the at least one other anti-cancer therapy eliminate the tumor or reduce the size of the tumor compared to the tumor before treatment.
In one embodiment, the present invention provides a method for preventing tumor recurrence and/or metastasis or prolonging or maintaining a tumor-free status in a subject with a tumor after at least one anti-cancer therapy, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2.
In one embodiment, the present invention provides a non-surgical method for eliminating a tumor in a subject or reducing the size of a tumor in a subject, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2.
In one embodiment, the present invention provides a method for eliminating or reducing the pleural effusion, ascites, and/or pericardial effusion in a subject with tumor, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2.
In one embodiment, the present invention provides a method for treating tumor in a subject, comprising topically or locally administering to the tumor lesions of the subject a recombinant interferon encoded by SEQ ID NO: 2.
In one embodiment, the present invention provides a method for eliminating or reducing metastatic tumor lesions in a subject, comprising topically or locally administering to the metastatic tumor lesions of the subject a recombinant interferon encoded by SEQ ID NO: 2.
In one embodiment, the present invention provides a method for eliminating or reducing the bone metastatic lesions of tumor in a subject, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2 by topical or local administration, wherein the topical or local administration comprises transdermal administration and/or infiltration administration, optionally, the recombinant interferon is administered to the bone metastatic lesions of tumor of the subject.
In one embodiment, the present invention provides a method for eliminating or reducing the bone lesions of tumor such as bone metastatic lesions of tumor, muscular lesions of tumor such as muscular metastatic lesions of tumor, subcutaneous tissue lesions of tumor such as subcutaneous tissue metastatic lesions of tumor, prostatic lesions of tumor such as prostatic metastatic lesions of tumor, and/or lymph node lesions of tumor such as lymph node metastatic lesions of tumor in a subject, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2 by any administration route through the skin, so that eliminating or reducing the bone lesions of tumor such as bone metastatic lesions of tumor, muscular lesions of tumor such as muscular metastatic lesions of tumor, subcutaneous tissue lesions of tumor such as subcutaneous tissue metastatic lesions of tumor, prostatic lesions of tumor such as prostatic metastatic lesions of tumor, and/or lymph node lesions of tumor such as lymph node metastatic lesions of tumor, optionally, the recombinant interferon is administered to the metastatic lesions of tumor of the subject.
In another aspect, the present invention provides a method for treating lung cancer in a subject, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2.
In one embodiment, the present invention provides a method for treating lung cancer in a subject, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2 and one or more chemotherapeutic drugs in two or more treatment cycles, and then administering to the subject a recombinant interferon encoded by SEQ ID NO: 2 and one or more targeted drugs in one or more treatment cycles.
In one embodiment, the present invention provides a method for treating lung cancer in a subject, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2 by subcutaneous administration and/or intramuscular administration, wherein the recombinant interferon is administered in an amount in a range of about 2 μg to about 70 μg, optionally about 4 μg to about 50 μg, further optionally about 4 μg to about 30 μg by one subcutaneous administration and/or intramuscular administration, the recombinant interferon is administered by subcutaneous administration and/or intramuscular administration once every about 1 to about 7 days, optionally every about 1 to about 2 days, lasting at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years and the like, or the recombinant interferon can be administered for a long time, including over the life time of the subject; or the duration can also be about 1 day to about 6 years, about 1 week to about 4 years, about 2 weeks to about 3 years, about 1 month to about 1 year, or about 2 months to about 9 months and the like.
In one embodiment, the present invention provides a method for treating lung cancer in a subject, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2 by subcutaneous administration and/or intramuscular administration, wherein the recombinant interferon is administered one or more times by subcutaneous administration and/or intramuscular administration at an induction dose in a range of about 2 μg to about 10 μg each time, optionally about 4 μg to about 10 μg each time, further optionally about 4.5 μg to about 9 μg each time, such as about 4.5 μg each time or about 9 μg each time, and then the recombinant interferon is administered more times by subcutaneous administration and/or intramuscular administration at a therapeutic dose in a range of about 10 μg to about 70 μg each time, optionally about 12 μg to about 50 μg each time, further optionally about 12 μg to about 30 μg each time.
In one embodiment, the present invention provides a method for treating cancer in a subject, wherein the cancer originates from lung cancer in the subject and metastasizes to brain, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2, wherein the recombinant interferon is administered one or more times by subcutaneous administration and/or intramuscular administration at an induction dose in a range of about 2 μg to about 10 μg each time, optionally about 4 μg to about 10 μg each time, further optionally about 4.5 μg to about 9 μg each time, such as about 4.5 μg each time or about 9 μg each time, and then the recombinant interferon is administered more times by subcutaneous administration and/or intramuscular administration at a therapeutic dose in a range of about 10 μg to about 70 μg each time, optionally about 12 μg to about 50 μg each time, further optionally about 12 μg to about 30 μg each time, and the recombinant interferon is administered to the subject by inhalation administration before, simultaneously, and/or after the subcutaneous administration and/or intramuscular administration, the recombinant interferon is administered in an amount in a range of about 100 μg to about 2000 μg, optionally about 100 μg to about 1500 μg, further optionally about 150 μg to about 800 μg, still further optionally about 200 μg to about 600 μg by one inhalation administration, and the recombinant interferon is administered by inhalation administration once every about 1 day to about 3 days, optionally every about 1 day.
In one embodiment, the present invention provides a method for treating cancer in a subject, wherein the cancer originates from lung cancer in the subject and metastasizes to bone or liver, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2, wherein the recombinant interferon is administered one or more times by subcutaneous administration and/or intramuscular administration at an induction dose in a range of about 2 μg to about 10 μg each time, optionally about 4 μg to about 10 μg each time, further optionally about 4.5 μg to about 9 μg each time, such as about 4.5 μg each time or about 9 μg each time, and then the recombinant interferon is administered more times by subcutaneous administration and/or intramuscular administration at a therapeutic dose of about 10 μg-about 70 μg each time, optionally about 12 μg to about 50 μg each time, further optionally about 12 μg to about 30 μg each time.
In one embodiment, the present invention provides a method for treating cancer in a subject, wherein the cancer originates from lung cancer in the subject and metastasizes to lymph nodes, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2, wherein the recombinant interferon is administered one or more times by subcutaneous administration and/or intramuscular administration at an induction dose in a range of about 2 μg to about 10 μg each time, optionally about 4 μg to about 10 μg each time, further optionally about 4.5 μg to about 9 μg each time, such as about 4.5 μg each time or about 9 μg each time, and then the recombinant interferon is administered more times by subcutaneous administration and/or intramuscular administration at a therapeutic dose of about 10 μg to about 70 μg each time, optionally about 12 μg to about 50 μg each time, further optionally about 12 μg to about 30 μg each time, and the recombinant interferon is administered to the tumor and/or the lymph nodes metastases by topical or local administration before, simultaneously, and/or after the subcutaneous administration and/or intramuscular administration.
In one embodiment, the present invention provides a method for treating lung cancer in a subject, wherein the subject has pleural effusion, ascites and/or pericardial effusion, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2 by topical or local administration.
In another aspect, the present invention provides uses of a recombinant interferon encoded by SEQ ID NO: 2 in preparation of drugs for treating tumors in a subject.
In one embodiment, the present invention provides uses of a recombinant interferon encoded by SEQ ID NO: 2 and other anti-tumor drugs in preparation of drugs for treating tumors in a subject.
In one embodiment, the present invention provides uses of a recombinant interferon encoded by SEQ ID NO: 2 in preparation of drugs for preventing tumor recurrence and/or metastasis after anti-tumor therapies in a subject.
In one embodiment, the present invention provides uses of a recombinant interferon encoded by SEQ ID NO: 2 in preparation of drugs for eliminating a tumor or reducing the size of a tumor in a subject by non-surgical method.
In one embodiment, the present invention provides uses of a recombinant interferon encoded by SEQ ID NO: 2 in preparation of drugs for eliminating or reducing pleural effusion, ascites, and/or pericardial effusion in a subject with tumor.
In one embodiment, the present invention provides a uses of a recombinant interferon encoded by SEQ ID NO: 2 in preparation of drugs for treating lung cancer in a subject.
In one embodiment, the present invention provides uses of a recombinant interferon encoded by SEQ ID NO: 2 in preparation of drugs for treating lung cancer in a subject in combination with chemotherapeutic drugs, targeted drugs.
In some embodiments, the subject is an early, medium-term, or advanced cancer patient, optionally, the subject is a medium-term, or advanced cancer patient, further optionally, the subject is an advanced cancer patient, such as an advanced lung cancer patient.
In some embodiments, the subject can be a stage 0, I, II, III, or IV cancer patient, optionally, the subject is an stage III or stage IV cancer patient, such as an stage III or stage IV lung cancer patient. Such cancer patient can be a patient with metastasized tumors, such as the tumors which are metastasized in situ or in the distance.
In some embodiments, the subject is a medium-term, advanced cancer patient, or stage III or stage IV cancer patient, optionally, the subject is an advanced, or stage III or stage IV cancer patient.
In some embodiments, the tumor is a cancer or a solid tumor with or without indications for surgery.
In some embodiments, the tumor in a subject is a tumor that is capable of being resected. In some embodiments, the tumor in a subject is a tumor that is not capable of being resected. In some embodiments, the surgeries include but not limited to surgical procedures.
In some embodiments, the subject is a subject with solid tumors.
In some embodiments, the solid tumor is a solid tumor that is capable of or is not capable of being resected.
In some embodiments, the solid tumor that is capable of or is not capable of being resected is an advanced solid tumor.
In some embodiments, the solid tumor is a solid tumor with or without indications for surgery, such as indications for tumor surgery.
In some embodiments, the solid tumor with or without indications for surgery such as indications for tumor surgery is an advanced, or stage III or stage IV solid tumor.
In some embodiments, the tumor is a solid tumor. The solid tumor comprises one or more of: lung cancer, liver cancer, hepatocellular carcinoma (HCC), esophageal cancer, cholangiocarcinoma, gallbladder carcinoma, stomach cancer, abdominal cancer, gastrointestinal cancer, gastric cancer, pancreatic cancer, renal cell carcinoma, renal cancer, bone cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, endometrial cancer, colorectal cancer, colon cancer, rectal cancer, bladder cancer, superficial bladder cancer, prostate cancer, adrenal tumors, squamous cell carcinoma, neuroma, malignant neuroma, myoepithelial carcinoma, synovial sarcoma, rhabdomyosarcoma, gastrointestinal interstitial cell tumor, skin cancer, basal cell carcinoma, malignant melanoma, thyroid cancer, nasopharyngeal carcinoma, hemangioma, epidermoid carcinoma, head and neck cancer, glioma, or Kaposi's sarcoma; optionally, lung cancer; further optionally, the lung cancer comprises small cell lung cancer (SCLC), non small cell lung cancer (NSCLC), or both.
In some embodiments, the tumor is a non-solid tumor. The non-solid tumor comprises one or more of leukemia, acute leukemia, chronic leukemia, chronic myelocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell leukemia, hairy cell leukemia, polycythemia, myelodysplastic syndrome, multiple myeloma, lymphadenoma, Hodgkin's lymphoma, or Non-Hodgkin's lymphoma.
In some embodiments, the effective amount is a therapeutically effective amount or a prophylactically effective amount. In some embodiments, the present recombinant interferon can be administered to the subject in single dose of about 2 μg to about 2000 μg, optionally, about 4 μg to about 1500 μg, further optionally, about 9 μg to about 1000 μg, and still further optionally, about 9 μg to about 600 μg. In certain embodiments, when the present recombinant interferon is administered by systemic administration, the therapeutically effective amount is about 2 μg to about 70 μg, optionally about 4 μg to about 50 μg, further optionally about 4 μg to about 30 μg, and still further optionally, about 9 μg to about 30 μg. In specific embodiments, when the present recombinant interferon is administered by systemic administration, the prophylactically effective amount is about 2 μg to about 70 μg, optionally about 4 μg to about 50 μg, further optionally about 4 μg to about 30 μg, and still further optionally, about 9 μg to about 30 μg.
In some embodiments, the present recombinant interferon and/or chemotherapeutic drugs, targeted drugs, biological drugs and the like combined with the present recombinant interferon can be administered to the subject by at least one of: systemic administration, topical administration, and local administration. In some embodiments, the present recombinant interferon and/or chemotherapeutic drugs, targeted drugs, biological drugs and the like combined with the present recombinant interferon can be administered to the subject by an administration route, the administration route comprises one or more of oral, rectal, sublingual, intravenous, intra-arterial, intramuscular, subcutaneous, intra-bone, intracutaneous, intra-articular, intraperitoneal, intrathecal, intracerebral, vaginal, percutaneous, transdermal, epidermal, transmucosal, transocular, pulmonary, nasal, abdominal, intrapleural, intraventricular, pericardial, inhalation, intratumoral, uterine, infiltration, or intravesical administration. In some specific embodiments, the present recombinant interferon and/or chemotherapeutic drugs, targeted drugs, biological drugs and the like combined with the present recombinant interferon can be administered to the subject by subcutaneous, intramuscular, inhalation, infiltration, intrapleural, abdominal, pericardial, intratumoral, spary administration or any combination thereof. In some embodiments, the present recombinant interferon and/or chemotherapeutic drugs, targeted drugs, biological drugs and the like combined with the present recombinant interferon can be administered to the subject by intramuscular and/or subcutaneous administration. In some embodiments, when the present recombinant interferon and/or chemotherapeutic drugs, targeted drugs, biological drugs and the like combined with the present recombinant are administered to the operative site, which can be administered to the subject by topical or local administration, such as infiltration, intrapleural, abdominal, pericardial, uterine, intravesical, intratumoral, pulmonary, nasal, percutaneous, transdermal, epidermal, and/or transmucosal administration.
In some embodiments, the present recombinant interferon and/or chemotherapeutic drugs, targeted drugs, biological drugs and the like combined with the present recombinant interferon can be administered to the subject by injection, such as subcutaneous, intramuscular, intravenous, intra-arterial, intracerebral, intraperitoneal, intratumoral, intra-articular, intrathecal and intra-bone injection and the like. In some embodiments, when administering by inhalation, the inhalation can be pulmonary and/or nasal inhalation. In some specific embodiments, the inhalation administration can be dry powder inhalation or aerosol inhalation. In some embodiments, when administering by intrapleural, abdominal, uterine, intravesical, pericardial administration, the present recombinant interferon and/or chemotherapeutic drugs, targeted drugs, biological drugs and the like combined with the present recombinant interferon can be further administered to the subject by perfusion, such as intrapleural, abdominal, uterine, intravesical, and/or pericardial perfusion. In some embodiments, when administering by percutaneous, transdermal, epidermal or transmucosal administration, the present recombinant interferon and/or chemotherapeutic drugs, targeted drugs, biological drugs and the like combined with the present recombinant interferon can be further administered to the subject by spray, such as percutaneous, epidermal, transdermal and/or transmucosal spray.
When the present recombinant interferon is systemically administered via injection administration (such as subcutaneous injection, intramuscular injection), the single dose can be about 2 μg to about 70 μg, optionally about 4 μg to about 50 μg, and further optionally about 4 μg to about 30 μg, including but not limited to about 2 μg, about 3 μg, about 4 μg, about 4.5 μg, about 9 μg, about 13.5 μg, about 15 μg, about 18 μg, about 21 μg, about 25.5 μg, about 30 μg, about 40 μg, about 50 μg, about 60 μg, and about 70 μg. In some embodiments, the present recombinant interferon is administered by subcutaneous and/or intramuscular administration once every about 1 day to about 7 days, optionally once every about 1 day to about 2 days. In some embodiments, the injection lasts at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years and the like, or the recombinant interferon can be administered for a long time, including over the life time of the subject; or the duration can also be about 1 day to about 6 years, about 1 week to about 4 years, about 2 weeks to about 3 years, about 1 month to about 1 year, or about 2 months to about 9 months and the like.
When the present recombinant interferon is locally administered via injection administration (such as the intratumoral injection), the single dose of the recombinant interferon can be in the range of about 60 μg to about 600 μg, optionally about 60 μg to about 500 μg, further optionally about 80 μg to about 400 μg, and still further optionally about 100 μg to about 250 μg. In some embodiments, the present recombinant interferon is administered via intratumoral administration once every about 1 day to about 10 days, optionally once every about 1 day to about 7 days such as every about 1, 2, 3, 4, 5, 6 or 7 days. In some embodiments, the intratumoral administration such as intratumoral injection lasts at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years and the like, or the recombinant interferon can be administered for a long time, including over the life time of the subject; or the duration can also be about 1 day to about 6 years, about 1 week to about 4 years, about 2 weeks to about 3 years, about 1 month to about 1 year, or about 2 months to about 9 months and the like. In specific embodiments, when the present recombinant interferon is administered via intratumoral administration, the protocol of intratumoral administration is as follow: the recombinant interferon is administered by intratumoral injection once every about 1 day for about 4 to about 8 times, and then the recombinant interferon is administered by intratumoral injection once every about 3 days to about 5 days for about 4 to about 8 times, and then the recombinant interferon is administered by intratumoral injection once every about 7 days, the intratumoral administration is stopped when the tumor disappears or becomes too small to conduct the intratumoral injection, wherein the recombinant interferon is administered in an amount of about 60 μg to about 600 μg, optionally about 60 μg to about 500 μg, further optionally about 80 μg to about 400 μg, still further optionally about 100 μg to about 250 μg by once intratumoral injection.
When the present recombinant interferon is administered via inhalation (such as pulmonary and nasal inhalation, including dry powder inhalation and aerosol inhalation), the single dose of the recombinant interferon can be about 100 μg to about 2000 μg, optionally about 100 μg to about 1500 μg, further optionally about 150 μg to about 800 μg, and still further optionally about 200 μg to about 600 μg, including but not limited to about 100 μg, about 200 μg, about 300 μg, about 400 μg, about 500 μg, about 600 μg, about 700 μg, about 800 μg, about 900 μg and about 1000 μg. In some embodiments, the present recombinant interferon is administered via inhalation once every about 1 day to about 3 days, optionally every about 1 day. In some embodiments, the inhalation lasts at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years and the like, or the recombinant interferon can be administered for a long time, including over the life time of the subject; or the duration can also be about 1 day to about 6 years, about 1 week to about 4 years, about 2 weeks to about 3 years, about 1 month to about 1 year, or about 2 months to about 9 months and the like.
When the present recombinant interferon is administered via perfusion (such as intrapleural, abdominal, uterine, intravesical, pericardial perfusion), the single dose of the recombinant interferon can be about 30 μg to about 2000 μg, optionally about 100 μg to about 1500 μg, further optionally about 150 to about 1000 μg, still optionally about 200 to about 800 μg, and still further optionally about 200 to about 400 μg. In some embodiments, the present recombinant interferon is administered via intrapleural, abdominal and/or pericardial administration once every about 1 day to about 10 days, optionally once every about 1 day to about 7 days such as every about 1, 2, 3, 4, 5, 6, or 7 days. In some embodiments, the perfusion lasts at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years and the like, or the recombinant interferon can be administered for a long time, including over the life time of the subject; or the duration can also be about 1 day to about 6 years, about 1 week to about 4 years, about 2 weeks to about 3 years, about 1 month to about 1 year, or about 2 months to about 9 months and the like.
When the present recombinant interferon is administered to the lesions (such as the surfaces of skin and mucosa) by spray, such as percutaneous, epidermal, transdermal, transmucosal spray, the single dose of the recombinant interferon can be about 6 μg to about 100 μg, optionally about 10 μg to about 40 μg, and further optionally about 20 μg to about 40 μg. In some embodiments, the present recombinant interferon is administered by spray administration about 1 to about 6 times such as about 1, 2, 3, 4, 5, or 6 times per day. In some embodiments, the spray lasts at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years and the like, or the recombinant interferon can be administered for a long time, including over the life time of the subject; or the duration can also be about 1 day to about 6 years, about 1 week to about 4 years, about 2 weeks to about 3 years, about 1 month to about 1 year, or about 2 months to about 9 months and the like.
In some embodiments, for the purpose of treatment, the present recombinant interferon can be administered to the subject about 1, 2, 3, 4, 5, 6, 7, 8, or more times per day, or the present recombinant interferon can be administered to the subject once at the time interval of every about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days, every month, every 2 months, or a longer time. In some embodiments, for the purpose of prevention, the present recombinant interferon can be administered to the subject once at the time interval of every about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, every 2 weeks, every 3 weeks, every month, every 2 months, every 3 months, every half year, every 1 year, or a longer time.
In some embodiments, the present recombinant interferon is administered in one or more treatment cycles. Optionally, the more cycles can be 2, 3, 4, 5, 6, 7, 8, 9, 10, or more treatment cycles. In specific embodiments, duration of the one treatment cycle is at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years and the like, or the duration can also be about 1 day to about 6 years, about 1 week to about 4 years, about 2 weeks to about 3 years, about 1 month to about 1 year, or about 2 months to about 9 months and the like. In specific embodiments, the present recombinant interferon can be administered for a long time, including over the life time of the subject, so as to improve or control or limit the symptom of the subjects.
In some embodiments, the present recombinant interferon could be administered in more treatment cycles. In certain embodiments, the treatment cycles are 2 or more treatment cycles. In specific embodiments, the duration of the multiple treatment cycles may include over the life time of the subject. In some embodiments, the time intervals of any two adjacent treatment cycles in all the treatment cycles can be the same or different. In specific embodiments, the time intervals can be at least about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years and the like; or the time intervals can be about 2 days to about 6 years, about 4 days to about 3 years, about 1 weeks to about 1 years, about 2 months to about months, about 3 months to about 6 months and the like.
In some embodiments, when the present recombinant interferon is administered more times in one treatment cycle, the present recombinant interferon can be administered for one or more times in a smaller dose, then the present recombinant interferon is administered for one or more times in an increased or gradually-increased dose. In specific embodiments, when the present recombinant interferon is systemically administered via subcutaneous, intramuscular administration (such as subcutaneous, intramuscular injection), the present recombinant interferon can be administered once at a smaller dose such as about 4.5 μg or 9 μg, then the recombinant interferon can be administered for more times in an increased (such as to be about 15 μg, about 18 μg, about 21 μg) or gradually-increased dose. In embodiments, the present recombinant interferon is administered once every about 1 day to abut 2 days. In embodiments, the duration for administration of the present recombinant interferon is about 1 week to about 2 years, optionally about 2 weeks to about 1 year, or further optionally about 1 month to about 9 months, including about 2 months to about 6 months, or over the life time of the subject. In embodiments, the gradually-increased administered dose can be about 110% to about 500% of the previously administered dose sequentially. In embodiments, a smaller dose of the present recombinant interferon (such as about 4.5 μg or about 9 μg) can be administered, followed by about 12 μg to about 18 μg (such as about 13.5 μg, about 15 μg, about 18 μg), and then about 15 μg to about 30 μg (such as about 18 μg, about 21 μg, about 25.5 μg, about 30 μg), once every about 2 days, and for about 2 months to about 3 years, or over the life time of the subject.
In some embodiments, the recombinant interferon can be administered one or more times at an induction dose, and then one or more times at a therapeutic dose. In some embodiments, the induction dose is about 2 μg to about 10 μg each time, optionally about 4 μg to about 10 μg each time, further optionally about 4.5 μg to 9 μg each time, for example, about 4.5 μg each time or about 9 μg each time. In some embodiments, the therapeutic dose is about 10 μg to about 70 μg each time, optionally about 12 μg to about 50 μg each time, further optionally about 12 μg to about 30 μg each time. In some embodiments, the induction dose is about 4 μg to about 10 μg each time, and the therapeutic dose is about 12 μg to about 50 μg each time. In some embodiments, the induction dose is usually lower than the therapeutic dose. In some embodiments, the time interval between administration of the induction dose and the therapeutic dose is about 1 day to about 1 month, optionally about 1 day to 1 week, further optionally about 1 day to about 3 days, including, for example, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 1 week, about 2 weeks, about 3 weeks and about 1 month. In some embodiments, when the induction dose is administered more times, it is administered once every about 1 day to about 10 days, optionally every about 1 day to about 7 days, further optionally every about 1 day to about 2 days, including, for example every about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days. In some embodiments, when the therapeutic dose is administered more times, it is administered once every about 1 day to about 10 days, optionally every about 1 day to about 7 days, further optionally every about 1 day to about 2 days, including, for example, every about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days. In some embodiments, the total administration time of the induction and therapeutic dose should last at least about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years and the like, o or the recombinant interferon can be administered for a long time, including over the life time of the subject.
In some embodiments, the treatment has reduced the tumor size of the subject, for example, by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 100% or more, or even completely eliminate the tumor, according to the tumor size at the beginning of treatment. In some embodiments, the treatment has reduced the number of cancer cells in tumor, malignant pleural effusion, malignant ascites and/or malignant pericardial effusion of the subjects, for example, by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 100% or more, or even the number of cancer cells is zero, according to the number of cancer cells at the beginning of treatment. In some embodiments, the treatment has inhibited (including reduced to some degree and/or terminated) the infiltration of tumor cells into peripheral organs; inhibited or prevented tumor metastasis, such as the in-situ or distant metastasis of tumors, or micrometastasis of tumors; reduced the size of the lesions; brought about downstaging of tumor; and also inhibited or killed micrometastasis in the blood and lymphatic channels; thereby allowing complete resection of initially unresectable tumors or helping to resect tumor which is capable of being resected, such resection is for example a surgical resection. As for the method, it can be a “neoadjuvant method” or an “introducing method”. As used herein, term “neoadjuvant method” or “introducing method” refers to a therapy given prior to surgery, the goal of the therapy is to reduce the size of the lesions, bring about downstaging of tumor, inhibit or kill micrometastases in the blood and lymphatic channels, reduce the tumor size thereby allowing more conveniently resect tumors or completely resect of initially unresectable tumors. In addition, the present recombinant interferon can be further administered to the subject to prevent recurrence and/or metastasis of the tumors after resection of the tumors.
In some embodiments, the method has reduced or eliminated malignant pleural effusion, malignant ascites and/or malignant pericardial effusion, for example, by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 100% or more, or even completely eliminated malignant pleural effusion, malignant ascites and/or malignant pericardial effusion, according to the volume of malignant pleural effusion, malignant ascites and/or malignant pericardial effusion at the beginning of treatment.
In some embodiments, the method for preventing recurrence of tumor has reduced the possibility of tumor recurrence after the subject with tumors received treatment. In some embodiments, the subject with tumors has been identified and treated prior to administration of the present recombinant interferon (rSIFN-co); such treatments may be the method with the present recombinant interferon, or one or more other different anti-cancer therapies such as chemotherapy, radiotherapy, surgical therapy, interventional therapy, biotherapy, gene therapy, ablation therapy, immunotherapy, targeted therapy, traditional Chinese medicine therapy or any combination thereof. The treatment results can be clinical or basic healing. In some embodiments, such preventive therapies can inhibit or eliminate possible micrometastasis in the blood channel and lymphatic channel, so as to prevent recurrence and/or metastasis of the tumor, such micrometastasis can or cannot be clinically detected.
In some embodiments, the present recombinant interferon could delay the growth of tumor in the subject, for example, by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95% or more, according to the tumor growth speed at the beginning of the treatment.
In some embodiments, the present recombinant interferon is administered to the subject as monotherapy. In some embodiments, further comprising one or more other anti-cancer therapies administered to the subject, optionally, other anti-cancer therapies are administered to the subject before, simultaneously, and/or after administration of the recombinant interferon. In some embodiments, the other anti-cancer therapies comprise one or more of: chemotherapy, radiotherapy, surgical therapy, interventional therapy, biotherapy, gene therapy, ablation therapy, immunotherapy, targeted therapy, and traditional Chinese medicine therapy. In certain embodiments, the other anti-cancer therapies comprise one or more of chemotherapy, radiotherapy, surgical therapy, targeted therapy, and biotherapy. In some embodiments, the other anti-cancer therapies comprise chemotherapy, radiotherapy, or both. In some embodiments, the other anti-cancer therapies comprise chemotherapy such as first-line chemotherapy, for example, chemotherapeutic drugs and/or chemotherapeutic protocols comprising platinum compounds, such as Cisplatin.
In some embodiments, when in the treatment for lung cancer, chemotherapeutic drugs used in the chemotherapy combined with the present recombinant interferon include but not limited to platinum compounds such as Cisplatin, Carboplatin, Eloxatin and the like; Paclitaxel compounds such as Docetaxel (Docetaxel Injection, Taxotere) and the like; cytidine antimetabolite such as Gemcitabine (Gemzar) and the like; antifolic antimetabolite such as Pemetrexed (Alimta) and the like; pyrimidine antimetabolite such as Capecitabine (Xeloda) and the like; as well as any combination of the chemotherapeutic agents. Or otherwise the following chemotherapy protocols are used, including but not limited to chemotherapy protocols containing platinum compounds, such as GP, TP, EP, GP-T2 protocols and the like. In specific embodiments, when in the treatment for the lung cancer, the chemotherapy protocol applied in conjunction with the present recombinant interferon includes Cisplatin nebulized inhalation, Cisplatin pericardial perfusion and the like.
In some embodiments, when in the treatment for lung cancer, the targeted drugs used in the targeted therapy combined with the present recombinant interferon include but not limited to Gefitinib, Erlotinib and/or recombinant human endostatin and the like.
In some embodiments, when in the treatment for the lung cancer, other anti-cancer therapies applied in combination with the present recombinant interferon include any combination of the chemotherapeutic drugs/chemotherapy protocols and targeted drugs.
In specific embodiments, when in the treatment for the lung cancer, other anti-cancer therapies applied in combination with the present recombinant interferon include GP protocol combined with recombinant human endostatin, EP protocol combined with Cisplatin nebulized inhalation and the like.
In some embodiments, the method of the present invention is a non-surgical therapy.
G. Evaluation Standard of Curative Effect and Adverse EffectThe curative effect evaluation on the present recombinant interferon in the aspect of clinical treatment for tumors such as solid tumors adopts the Response Evaluation Criteria in Solid Tumors standard (RECIST standard) published in 1999 (see James, K. et al. J Natl Cancer Inst, 1999, 91, 523-528).
The tumor lesions are divided into measurable lesions and un-measurable lesions, wherein the measurable lesions are defined as target lesions; the longest diameter represents the size of each lesion; at most 5 lesions can be selected in each involved organ, the sum of the measured lesions of all the involved organ is not more than 10, and the sum of the longest diameters of all the lesions is the overall diameter of the target lesion. The un-measurable lesions are defined as non-target lesions, only the existence of the lesions are recorded and tracked, but the sizes of the lesions are not measured.
The curative effect evaluation standard of the target lesion is divided into 4 grades, the curative effect evaluation standard of the non-target lesion is divided into 3 grades, and the overall curative effect evaluation is obtained by combining the curative effects of the two kinds of lesions. It is specifically described as follows:
The curative effect evaluation standard of the target lesions: (1) CR (complete remission): all the target lesions disappear; (2) PR (partial remission): the overall diameter of the target lesions is decreased by more than 30%; (3) NC or SD (no change or stable disease): the target lesions are neither decreased to “PR” nor increased to “PD”; and (4) PD (progression disease): the overall diameter of the target lesions is increased by more than 20%, or one or more new lesions appear.
The curative effect evaluation standard of the non-target lesion: (1) CR: all the non-target lesions disappear, and the tumor marker level is normal; (2) IR (incomplete response)/SD: one or more non-target lesions is/are not changed, and/or the tumor markers exceed the normal limit; and (3) PD: one or more new lesions appear, and/or the non-target lesions are obviously developed.
The overall curative effect evaluation standard of solid tumors.
The adverse effect evaluation on the present recombinant interferon for clinical treatment for the tumors such as the solid tumors takes the reference to the “WHO” Toxicity Grading Standard.
Compared with the prior art, the recombinant interferon has the beneficial effects as follows:
The recombinant interferon rSIFN-co used in the present invention has obvious different structural features and physiological activities compared with the existing interferons such as INFERGEN® (interferon alfacon-1) of the US Amgen. On one hand, the recombinant interferon can be singly used and/or can be combined with radiotherapy, chemotherapy, biological agents, and/or targeted drugs and the like, so as to non-surgically eliminate or reduce the tumors of the solid tumor subjects, particularly advanced tumors; specifically, the recombinant interferon can eliminate or reduce the solid tumors without indications for surgery, particularly the advanced solid tumors without indications for surgery. On the other hand, the recombinant interferon can be singly administered through topical or local administration such as intratumoral injection/epidermal spray administration and the like, or through the combination of the topical or local administration together with the systemic administration (using the present recombinant interferon or radiotherapy/other anti-tumor drugs and the like), so as to non-surgically (namely, without surgery) eliminate or reduce the solid tumors. Further, the recombinant interferon has obvious effect in replacing the chemotherapy drugs for preventing post-surgery recurrence or metastasis of the tumors, particularly various metastatic lesions such as bone metastasis which cannot be eliminated by existing treatment means; however, drugs can be directly administered to the lesions by the present invention, especially by the topical or local administration, to obviously reduce or eliminate the tumors. In addition, the recombinant interferon can be singly administered through intrapleural or abdominal perfusion so as to for effectively eliminate or decrease malignant pleural effusion and/or malignant ascites.
Furthermore, cancer can be controlled by the rSIFN-co combination therapy. Firstly, the present recombinant interferon (rSIFN-co) has broad-spectrum anti-tumor effects, which is effective on both solid tumors and non-solid tumors while, at the same time, rSIFN-co has a good synergetic effect with existing treatment means such as surgical therapy, chemotherapy, radiotherapy, biotherapy and other anti-tumor drugs. Secondly, rSIFN-co has low toxicity which means no harm to normal cells has been observed when rSIFN-co is used in large doses. Thirdly, rSIFN-co is convenient to use and can be directly applied to tumors in any position. The rSIFN-co can be used by subcutaneous/intramuscular injection to control systemic progress of tumor, by intrapleural/abdominal perfusion to eliminate effusion and intrapleural/abdominal tumors, by topical or local injection to eliminate primary or metastatic tumors, and by infiltration (transdermal) administration to treat tumor lesions in bone, skin, muscle, prostate and the like; and rSIFN-co can also be administered by aerosol inhalation. According to above three advantages of rSIFN-co, effective rate of the combination therapy is no lower than 90%. With regard to early or medium-term cancer cases, rSIFN-co can be used after surgery to replace chemotherapy and effectively prevent recurrence and metastasis; with regard to advanced cancer cases or cancer cases without indications for therapy, rSIFN-co can be used to eliminate tumors without surgery; with regard to cases without indications for surgery, rSIFN-co can be used to transformed the cases into ones with indications for surgery, thereby creating surgical conditions. Therefore, we believe the rSIFN-co combination therapy is capable of curing cancer.
In one embodiment, the present invention provides a method for eliminating or reducing the malignant pleural effusion, malignant ascites, and/or malignant pericardial effusion in a subject with tumor, the method comprises administering to the subject a recombinant interferon encoded by SEQ ID NO: 2. In one embodiment, the tumor is a solid tumor.
In one embodiment, the recombinant interferon is administered to the subject by an administration route comprising one or more of: infiltration administration, intrapleural administration, abdominal administration, pericardial administration, thoracic administration and intraperitoneal administration. In one embodiment, the recombinant interferon is administered in an amount in a range of about 30 μg to about 2000 μg by one administration. In another embodiment, the recombinant interferon is additionally administered to the subject by systemic administration. In one embodiment, the subject is administered with at least one other anti-cancer drug. In another embodiment, the other anti-cancer drug is chemotherapeutic drug, targeted drug, or biological drug.
In one embodiment, the present invention provides a method for preventing tumor recurrence or metastasis, or prolonging or maintaining a tumor-free status in a subject with a tumor, the method comprises administering to the subject a recombinant interferon encoded by the nucleotide sequence SEQ ID NO: 2, and the subject has been treated with at least one anti-cancer therapy before the administration of said recombinant interferon.
In one embodiment, the anti-cancer therapy is chemotherapy, radiotherapy, surgical therapy, interventional therapy, biotherapy, gene therapy, ablation therapy, immunotherapy, targeted therapy, or traditional Chinese medicine therapy. In another embodiment, the recombinant interferon is administered to the subject in a single dose of the range of about 2 μg to about 2000 μg.
In one embodiment, the present invention provides a method for eliminating or reducing metastatic tumor lesion in a subject, the method comprises administering a recombinant interferon encoded by SEQ ID NO: 2 topically or locally to the tumor lesion. In one embodiment, the metastatic tumor lesion comprises at least one of a bone lesion, a muscular lesion, a subcutaneous tissue lesion, a prostatic lesion, and a lymph node lesion.
In one embodiment, the recombinant interferon is administered to the lesion by an administration route comprising at least one of infiltration administration, percutaneous administration, transdermal administration, epidermal administration and transmucosal administration. In another embodiment, the recombinant interferon is administered topically. In another embodiment, the recombinant interferon is further administered systemically.
In one embodiment, the present invention provides a non-surgical method for eliminating a tumor in a subject or reducing the size of a tumor in a subject, the method comprises administering to the subject a recombinant interferon encoded by SEQ ID NO: 2. In one embodiment, the tumor is a non-resectable tumor.
In one embodiment, the recombinant interferon is administered to the subject by at least one of systemic administration, local administration, and topical administration. In one embodiment, the local administration or topical administration comprises one or more of intratumoral administration and spray administration.
In one embodiment, the subject is administered at least one other anti-cancer therapy. In one embodiment, the anti-cancer therapy is chemotherapy, radiotherapy, surgical therapy, interventional therapy, biotherapy, gene therapy, ablation therapy, immunotherapy, targeted therapy, or traditional Chinese medicine therapy.
In one embodiment, the present invention provides a method for treating lung cancer in a subject, the method comprises administering to the subject a recombinant interferon encoded by SEQ ID NO: 2, and the recombinant interferon is administered to the subject by at least one of systemic administration, topical administration, and local administration.
In one embodiment, the recombinant interferon is administered systemically and via inhalation. In one embodiment, the systemic administration comprises at least one of subcutaneous administration and intramuscular administration, and inhalation comprises at least one of: pulmonary inhalation and nasal inhalation. In another embodiment, the recombinant interferon is administered locally by perfusion.
In one embodiment, the at least one other anti-cancer therapy is administered to the subject before, simultaneously, and/or after administration of the recombinant interferon.
The present invention will be specifically described in the following examples that are only used to elaborate the purpose but not to limit the scope of the present invention. The present invention can be modified without deviating from its scope. All publications, patents and patent applications that are referenced, the contents of which are hereby incorporated by reference into this application as every independent publication, patent and patent application are separately incorporated by reference into this application.
Informed Consent Forms have been signed by all patients involved in the following embodiments, and Confidentiality Agreements have been signed by and between the applicants and hospitals. At the same time, the test processes are conducted in accordance with the requirements set forth by Ethics Committee for Clinical Drug Trials.
Example 1: Preparation of the Composition of the Recombinant InterferonIngredients of Recombinant Interferon Freeze-Dried Injection (Freeze-Dried Powder)
Preparation procedures: raw materials were weighed by the ingredients and dissolved by sterile and pyrogen-free water for injected; then filtered by a membrane of 0.22 μm pore diameter for sterilization, and preserved at 6-10° C.; the materials were sampled for sterile and pyrogen inspections and then separately loaded in vials after qualified inspections, each with a single dose of 0.3-0.5. And then, the materials were put into freeze dryer for freezing and drying.
Ingredients of Recombinant Interferon Water Solution Injection
Preparation procedures: raw materials were weighed by the ingredients and dissolved by sterile and pyrogen-free water for injection; then filtered by a membrane of 0.22 μm pore diameter for sterilization, and preserved at 6-10° C.; the materials were sampled for sterile and pyrogen inspections and then separately loaded in sealed containers after qualified inspections, each with a single dose of 0.3-0.5. And then, the finished product were preserved at 2-10° C. in dark places.
Ingredients of Recombinant Interferon Spray
The ingredient content percentages in the table below are based on weight percentages.
The preparation method refers to conventional preparation method of spray.
Preparation of Recombinant Interferon Inhalant
Conventional preparation methods of interferon inhalant were adopted. The recombinant interferon inhalant of the present invention was prepared according to conventional preparation methods of interferon inhalant.
Example 2: Clinical Data of Patients Treated by the Present Recombinant Interferon (58 Cases)Following is a summary clinical treatment table (table 2) of 58 patients of various cancer types who have been treated by the present recombinant interferon until Jul. 1, 2012.
Table 2: Summary of Clinical Treatment of Multiple Types of Cancers in 58 Patients
Clinical data collected until Jul. 1, 2012 of 19 patients treated with the recombinant interferon of the invention are provided below (Patients numbered by 1-19 correspond to Patients 1-19, respectively, in the “Summary of Clinical Treatment of Multiple Types of Cancers in 58 Patients” in aforementioned Table 2 of Example 2).
Patient 1.
Non-small-cell lung cancer; the primary lesions in the right pulmonary hilum and the mediastinal lymph node metastasis disappeared after treatment by intramuscular injection of recombinant super-compound interferon (rSIFN-co) in combination with radiotherapy.
Patient 2.
Non-small-cell lung adenocarcinoma with systemic metastases on body parts including bilateral lungs, liver and lymph nodes/Intramuscular injection and aerosol inhalation of rSIFN-co combined with chemotherapy (GP regimen) and administration of recombinant human endostatin (Endostar). After treatment, the primary lesions in the lungs evidently became reduced in size and the metastatic lesions disappeared in the liver and in many of the lymph nodes.
Patient 3.
Non-small-cell lung cancer with brain metastases/Intramuscular injection and aerosol inhalation of rSIFN-co combined with Gamma knife treatment. After the treatment, primary lesions on right lung and brain metastatic lesions were cleared up.
Patient 4.
Small-cell lung cancer with metastases in the mediastinal lymph nodes and clavicles/Intramuscular injection and aerosol inhalation of rSIFN-co combined with chemotherapy (aerosol inhalation of Cisplatin and EP regimen) and interventional therapy for supraclavicular lesions. After the treatment, primary lesions in the right lung and metastases in mediastinal lymph nodes and clavicles cleared up.
Patient 5.
Non-small-cell lung cancer with metastases to the right humerus, after surgeries/Intramuscular injection and aerosol inhalation of rSIFN-co combined with chemotherapy (aerosol inhalation of Cisplatin). After treatment, the metastatic lesions in right lung hilum, paratracheal lymph nodes and several sites of spinal metastases disappeared.
Patient 6.
Non-small-cell lung cancer with multiple lymph node metastases in mediastinum, left segment of neck, right and root segment of neck, left supraclavicular fossa; left-sided pleural effusion; multiple bone metastases in vertebral column, bilateral ribs, right clavicle joint, sternum and left sacrum, and obvious generalized pain/Intramuscular injection, aerosol inhalation and local spraying of rSIFN-co combined with chemotherapy (GP regimen) and Gefinitib (Iressa) therapy. After the treatment, primary lesions on left lung disappeared and metastatic lesions around the body shrank. Further, generalized pain was relieved.
Patient 7.
Non-small-cell lung cancer with metastases in both lungs, both livers and bones of whole body/Intramuscular injection and aerosol inhalation of rSIFN-co combined with administration of Gefinitib (Iressa). After treatment, metastases disappeared or shrank in lungs and several bones, and metastatic lesions of lymph nodes disappeared in liver and mediastinum.
Patient 8.
Non-small-cell lung cancer with bone metastases/Intramuscular injection and aerosol inhalation of rSIFN-co combined with administration of Gefinitib (Iressa). After treatment, the metastatic lesions in the lungs disappeared and the primary lesions in right lung shrank evidently.
Patient 9.
Non-small-cell lung squamous cell carcinoma/Aerosol inhalation of rSIFN-co combined with chemotherapy (GP regimen) and administration of recombinant human endostatin (Endostar). After treatment, masses of soft tissue at hilum of lower lobe of right lung evidently shrank and enlarged lymph nodes at right lung hilum disappeared.
Patient 10.
Non-small-cell lung cancer with metastases in lung and pleura; pleural effusion/Intramuscular injection of rSIFN-co alone or intrapleural perfusion of rSIFN-co alone. After treatment, primary lesions on the apical segment of upper lobe of left lung were cleared up and metastatic lesions on lingual segment of left lung shrank.
Patient 11.
Non-hodgkin lymphoma/Aerosol inhalation (though nasopharynx and Oral Cavity) of rSIFN-co and local injection into enlarged lymph nodes at neck combined with radiotherapy. After local administration, lesions in the nasal cavity, oropharynx, neck and submaxillary region disappeared or shrank.
Patient 12.
Non-small-cell lung cancer with metastasis in pleura/Intramuscular injection of rSIFN-co. After treatment, lesions on lower lobe of right lung evidently shrank.
Patient 13.
Non-small-cell lung cancer, after surgeries/Intramuscular injection of rSIFN-co alone. After the treatment, no tumor recurrence or metastasis was found in right lung and the whole body.
Patient 14.
Non-small-cell lung adenocarcinoma, after surgery/Intramuscular injection of rSIFN-co alone. After the treatment, no tumor recurrence and metastasis was found.
Patient 15.
Non-small-cell lung cancer with systemic metastases, local injection of rSIFN-co into enlarged lymph nodes in groin. After local injections, metastatic lesions in the lymph nodes in pelvic cavity and inguinal area were cleared up or shrank.
Patient 16.
Rectal cancer, after a surgery/Intramuscular injection of rSIFN-co alone. After the treatment, no tumor recurrence or metastasis was found.
Patient 17.
In situ cervical cancer in situ/Intramuscular injection of rSIFN-co alone or uterine perfusion of rSIFN-co alone. After treatment, cervical tumor was basically inhibited and test of high-risk HPV became negative. Also, no tumor cells were found in cervical smear.
Patient 18.
Prostatic cancer/Intramuscular injection of rSIFN-co and local spraying (to skin surface where prostate biopsy was done) of rSIFN-co combined with local radiotherapy. After treatment, the prostate tumor and two lymph nodes in right-sided ischiorectal fossa were eliminated; the posterior wall of fundus of urinary bladder, bilateral seminal vesicles and anterior rectal wall infected by lesions recovered; and the level of tumor marker (PSA) become normal.
Patient 19.
Melanoma of nose (after a surgery) combined with bone metastases at bilateral hip joints, bilateral femurs, bilateral humeri, ribs and bilateral shoulder joints/Intramuscular injection of rSIFN-co and local spraying of rSIFN-co on lesions. After treatment, multiple enlarged lymph nodes at bilateral shoulder joints and subaxillary were cleared up as well as recurrence and metastases at bilateral hip joints, upper femur, residual right paranasal sinuses and nasal cavity after surgery.
- {circle around (1)} Standard for cancer staging, refer to AJCC Cancer Staging Manual (6th Edition)/Edited by F. L. Greene, D. L. Page and I. D. Fleming etc. Shenyang: Liaoning Science and Technology Press, 2005.8;
- {circle around (2)} Standard for effect evaluation of antitumor drags, refer to Practical Therapeutics of Antitumor Drμgs/Edited by Liu Xinchun etc. (Beijing: People's Medication Publishing House, 2002) p 1100-1101;
- {circle around (3)} Radiotherapy of lung cancer, refer to Modern Lung Cancer Pathology and Clinical Practice/Edited by Xiong Min and Wu Yilong, (Beijing: Science Press, 2003.6), p 324-365;
- {circle around (4)} TC regimen, refer to Modern Lung Cancer Pathology and Clinical Practice/Edited by Xiong Min and Wu Yilong, (Beijing: Science Press, 2003.6), p 386;
- {circle around (5)} “Endostar”, refer to Chemotherapy and Targeted Therapy of Lung Cancer/Edited by Liao Meilin, (Beijing: People's Medication Publishing House, 2009.8), p 261;
- {circle around (6)} “Pemetrexed”, refer to Chemotherapy and Targeted Therapy of Lung Cancer/Edited by Liao Meilin, (Beijing: People's Medication Publishing House, 2009.8), p 94;
- {circle around (7)} EP regimen, refer to Modern Lung Cancer Pathology and Clinical Practice/Edited by Xiong Min and Wu Yilong, (Beijing: Science Press, 2003.6), p 386;
- {circle around (8)} DP regimen, refer to Modern Lung Cancer Pathology and Clinical Practice/Edited by Xiong Min and Wu Yilong, (Beijing: Science Press, 2003.6), p 386;
- {circle around (9)} GP chemotherapy, refer to Chemotherapy and Targeted Therapy of Lung Cancer/Edited by Liao Meilin, (Beijing: People's Medication Publishing House, 2009.8), p 222-230;
- {circle around (10)} “Gefitinib”, refer to Chemotherapy and Targeted Therapy of Lung Cancer/Edited by Liao Meilin, (Beijing: People's Medication Publishing House, 2009.8), p 222-230;
- {circle around (11)} CHOP chemotherapy, refer to Practical Therapeutics of Antitumor Drugs/Edited by Liu Xinchun etc. (Beijing: People's Medication Publishing House, 2002), p 931;
- {circle around (12)} Radiotherapy of prostatic cancer, refer to Advance in Clinical Oncology/Edited by Sun Yan and Zhao Ping, (Beijing: Peking Union Medical College Press, 2005.9ISBN7-81072-711-7), p 1009-1010.
In the following tables, the number listed before the brackets represents the number of patients conforming to the condition described in that row and column; the number between each pair of parenthesis represents the number as a percentage of all the patients listed in either that column or that row; finally, II/III/IV between parentheses represent cancer staging. The cancer staging was made in accordance with AJCC Cancer Staging Manual (6th Edition)/Edited by F. L. Greene, D. L. Page and I. D. Fleming etc. Shenyang: Liaoning Science and Technology Press, 2005.8.
Claims
1-507. (canceled)
508. A method for eliminating or reducing the malignant pleural effusion, malignant ascites, and/or malignant pericardial effusion in a subject with tumor, comprising administering to the subject a recombinant interferon encoded by SEQ ID NO: 2, wherein the recombinant interferon is administered in an amount in a range of about 30 μg to about 2000 μg by one administration.
509. The method of claim 508, wherein the tumor is a solid tumor.
510. The method of claim 508, wherein the recombinant interferon is administered to the subject by an administration route, the administration route comprises one or more of: infiltration administration, intrapleural administration, abdominal administration, pericardial administration, thoracic administration and intraperitoneal administration.
511. The method of claim 510, wherein the recombinant interferon is additionally administered to the subject by systemic administration.
512. The method of claim 508, wherein the subject is administered with at least one other anti-cancer drug.
513. The method of claim 512, wherein said other anti-cancer drug is selected from the group consisting of chemotherapeutic drug, targeted drug, and biological drug.
514. A method for preventing tumor recurrence or metastasis, or prolonging or maintaining a tumor-free status in a subject with a tumor, comprising administering to said subject a recombinant interferon encoded by the nucleotide sequence SEQ ID NO: 2, wherein said subject has been treated with at least one anti-cancer therapy before the administration of said recombinant interferon.
515. The method of claim 514, wherein said anti-cancer therapy is selected from the group consisting of chemotherapy, radiotherapy, surgical therapy, interventional therapy, biotherapy, gene therapy, ablation therapy, immunotherapy, targeted therapy, and traditional Chinese medicine therapy.
516. The method of claim 514, wherein the recombinant interferon is administered to the subject by at least one of: systemic administration, local administration, and topical administration.
517. The method of claim 516, wherein said recombinant interferon is administered to said subject in a single dose of the range of about 2 μg to about 2000 μg.
518. A method for treating tumor in a subject, comprising topically or locally administering to the tumor lesions of the subject a recombinant interferon encoded by SEQ ID NO: 2.
519. The method of claim 518, wherein the tumor lesions comprise metastatic tumor lesions.
520. The method of claim 518, wherein the tumor lesions comprise at least one of: bone lesions, muscular lesions, subcutaneous tissue lesions, prostatic lesions and lymph node lesions.
521. The method of claim 519, the tumor metastatic lesions comprise at least one of: bone metastatic lesions, muscular metastatic lesions, subcutaneous tissue metastatic lesions, prostatic metastatic lesions, and lymph node metastatic lesions.
522. The method of claim 518, wherein the recombinant interferon is administered to the lesion by an administration route, the administration route comprises at least one of: infiltration administration, percutaneous administration, transdermal administration, epidermal administration and transmucosal administration.
523. The method of claim 518, wherein the recombinant interferon is administered topically.
524. The method of claim 518, wherein the recombinant interferon is administered by spraying.
525. The method of claim 518, wherein the recombinant interferon is further administered systemically.
526. The method of claim 518, wherein the subject is administered at least one other anti-cancer therapy.
527. The method of claim 526, wherein said anti-cancer therapy is selected from the group consisting of chemotherapy, radiotherapy, surgical therapy, interventional therapy, biotherapy, gene therapy, ablation therapy, immunotherapy, targeted therapy, and traditional Chinese medicine therapy.
Type: Application
Filed: Jul 18, 2018
Publication Date: Nov 15, 2018
Inventor: Guangwen Wei (Chengdu)
Application Number: 16/038,704
