IL-12 P40 Monomer, Monoclonal Antibody Against P40 Homodimer and the Combination of the Two for Autoimmune Disease Treatment
A novel approach to discover new drugs against MS and other autoimmune diseases is disclosed. The p40 family of cytokines has four members which include interleukin-12 (IL-12), the p40 monomer (p40), the p40 homodimer (p402), and the IL-23. To facilitate the studies on p402 and p40, neutralizing monoclonal antibodies (mAb) against mouse p402 and p40 were generated for the first time. MS and other autoimmune disease drug therapies including recombinant p40 and/or monoclonal antibody against p402 (mAb-p402 a3-1d) are disclosed.
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1. Technical Field:
This disclosure relates to new drugs for the treatment of autoimmune diseases such as multiple sclerosis (MS), systemic lupus erythematosus (lupus), thyrioditis, rheumatoid arthritis, Sjogren's syndrome, Addison's disease etc.
2. Description of the Related Art:
Multiple sclerosis (MS) is the most common human demyelinating disease of the central nervous system (CNS). Despite intense investigations, no effective therapy is available to stop its onset or halt its progression. MS is one of many autoimmune diseases and is a chronic human demyelinating disorder of the CNS of unknown etiology. From a clinical standpoint, MS is characterized by recurrent attacks of neurologic dysfunction. Pathologically, it can be identified by the presence of diffuse, discrete demyelinated areas, called plaques. MS is now widely viewed as an autoimmune disease that develops early in life (between the young ages of 20 and 40), perhaps after an unknown infection that initiates a T-cell mediated immune response.
Despite extensive research to develop pharmacotherapeutic agents to ameliorate exacerbations and to reduce the number of exacerbations and subsequent progression of neurologic disability in MS, only a few therapies are available, which are not very efficient. There is also a lack of effective therapies for other autoimmune diseases such as systemic lupus erythematosus (lupus), thyrioditis, rheumatoid arthritis, Sjogren's syndrome, Addison's disease etc., as well.
SUMMARY OF THE DISCLOSUREA novel approach to discover new drugs against autoimmune diseases is disclosed.
The p40 family of cytokines has four members which include (1) interleukin-12 (IL-12), (2) the p40 monomer (p40), (3) the p40 homodimer (p402), and (4) the IL-23. Previously, with the knowledge that the heterodimers rule and the homodimers remain as mere spectators, those skilled in the art thought that only IL-23 and IL-12 were endowed with biological functions. Both p402 and p40 were considered as inactive molecules with unknown functions. To facilitate the studies on p402 and p40, neutralizing monoclonal antibodies (mAb) against mouse p402 and p40 were generated for the first time.
With experimental allergic encephalomyelitis (EAE) as the established animal model for MS, IL-12 p40 homodimer (p402) and p40 monomer (p40) were considered as inactive or inhibitory molecules and functions of these molecules were poorly understood.
After neutralizing mAb against mouse p40 and p402, the effect of p402, p40, mAb-p402, and mAb-p40 was tested on the disease process of EAE. While the recombinant p40 ameliorated clinical symptoms and disease progression of EAE, the mAb-p40 aggravated the disease process of EAE. On the other hand, the mAb-p402 protected mice from EAE and the recombinant p402 worsened the disease process of EAE. Furthermore, a combination of recombinant p40 and mAb-p402 strongly inhibited clinical symptoms of EAE. Taken together, our exciting results suggest the following new treatment options for MS patients: recombinant p40; monoclonal antibody against p402 (mAb-p402); and combinations of recombinant p40 and mAb-p402.
Therefore, in one aspect, a treatment for autoimmune diseases is disclosed which includes recombinant space p40.
In another aspect, a treatment for autoimmune diseases is disclosed which includes at least one monoclonal antibody against p402 (mAb-p402 a3-1d).
In yet another aspect, a treatment for autoimmune diseases is disclosed which includes a combination of recombinant p40 and at least one monoclonal antibody against p402 (mAb-p402 a3-1d).
In any one or more of the embodiments described above, the autoimmune disease may be selected from the group consisting of multiple sclerosis, lupus, thyrioditis, rheumatoid arthritis, Sjogren's syndrome, Addison's disease and combinations thereof.
In another aspect, a method for treating an autoimmune disease in a mammal is disclosed which includes administering recombinant p40 to the mammal.
In yet another aspect, a method for treating an autoimmune disease in a mammal is disclosed which includes administering at least one monoclonal antibody against p402 (mAb-p402 a3-1d) to the mammal.
In yet another aspect, a method for treating an autoimmune disease in a mammal includes administering a combination of recombinant p40 and at least one monoclonal antibody against p402 (mAb-p402 a3-1d).
Other advantages and features will be apparent from the following detailed description when read in conjunction with the attached drawings.
IL-12p70 on demyelination in the spinal cord and the cerebellum of EAE mice.
SJL/J mice by p402 and mAb against p402.
While the example below is directed towards MS, this disclosure applies to other autoimmune diseases such as systemic lupus erythematosus (lupus), thyrioditis, rheumatoid arthritis, Sjogren's syndrome, Addison's disease etc., as well.
Experimental allergic encephalomyelitis (EAE) is an experimentally induced autoimmune disease of the CNS, and serves as an animal model for MS. When the effect of recombinant p402 and p40 and neutralizing mAbs against p402 and p40 in EAE was tested, the following was observed.
IL-12 p40 monomer prevents MS-like autoimmune demyelination in mice
IL-12 and IL-23 are known to aggravate the disease process of EAE. To understand the role of p40 monomer in the disease process of EAE, first, the level of p40 in the spleen (the most important immune organ) of EAE mice was monitored at different phases of the disease. Surprisingly, the level of p40 was significantly lower in spleen of EAE mice at the acute phase compared with control (
To understand the effect of p40 on disease progression, mice with established disease received weekly intraperitoneal injection of p40 monomer from different phases of the disease. When administered from the onset of acute phase (8 days post transfer), p40 markedly suppressed clinical symptoms (
Histological and blood-brain bather (BBB) and blood-spinal cord barrier (BSB) permeability studies reveal that p40 effectively inhibited the infiltration of mononuclear cells into brain and spinal cord (
In
In
Therefore, p40 monomer may be beneficial for MS and other autoimmune disease patients.
Functional Blocking Monoclonal Antibodies (a3-1d) Against p402 Inhibit the Disease Process of EAE in Mice
To understand the role of p402 in the disease process of EAE, the level of p402 in the serum and spleen of EAE mice at different phases of the disease was monitored. The level of p402 was significantly higher in serum of EAE mice at the onset of acute phase and the acute phase compared with control (
In
Within 4 days of injection, significant reduction in EAE clinical symptoms was found and, interestingly, just one injection kept disease symptoms markedly low throughout the duration of the study (
In
On the other hand, recombinant mouse p402 cytokine aggravated the disease process of EAE (
Combination of p40 Monomer and p402 mAb a3-1d Strongly Suppresses the Disease Process of EAE
Since both p40 and mAb p402 inhibited the disease process of EAE, the combination of the two were investigated to see if they show better efficacy. Therefore, mice and with established disease received one injection of p402mAb a3-1d and a weekly injection of p40 monomer. As shown in
In
Therefore, this combination may be a strong blocker of MS symptoms in patients.
Taken together, these novel results suggest the following three new treatment options for MS and other autoimmune disease patients: recombinant p40; monoclonal antibody against p402 (mAb-p402 a3-1d); and a combination of recombinant p40 and mAb-p402 (a3-1d).
While only certain embodiments have been set forth, alternatives and modifications will be apparent from the above description to those skilled in the art. These and other alternatives are considered equivalents and within the spirit and scope of this disclosure and the appended claims.
Claims
1. A composition for the treatment of autoimmune diseases, the composition comprising:
- a recombinant p4 monomer if Interleukin 12 (IL-12) and at least one monoclonal antibody against p402 homodimer of IL-12.
2. The composition of claim 1 wherein the autoimmune diseases are selected from the group consisting of multiple sclerosis, lupus, thyrioditis, rheumatoid arthritis, Sjogren's syndrome, Addison's disease and combinations thereof.
3-8. (canceled)
9. A method for treating an autoimmune disease in a mammal comprising administering a combination of a recombinant p40 monomer of IL-12 and at least one monoclonal antibody against p402 homodimer of IL-12 to the mammal for treating an autoimmune disease in the mammal.
10. The method of claim 9, wherein the recombinant p40 monomer of IL-12 is administered in a plurality doses.
11. The method of claim 9, wherein the at least one monoclonal antibody against p402 homodimer of IL-12 is administered in a single dose.
12. The method of claim 9, wherein the recombinant p40 monomer of IL-12 is administered in a plurality doses and the at least one monoclonal antibody against p402 homodimer of IL-12 is administered in a single dose.
13. The method of claim 9, wherein the administration ameliorates one or more of symptoms of the autoimmune disease, the one or more symptoms comprising demyelination, blood-brain barrier permeability, blood-spinal cord barrier permeability and combinations thereof.
14. The method of claim 9, wherein the administration ameliorates one or more of the autoimmune diseases selected from the group consisting of multiple sclerosis, lupus, thyrioditis, rheumatoid arthritis, Sjogren's syndrome, Addison's disease and combinations thereof.
15. The method of claim 9, wherein the at least one monoclonal antibody against the p402 homodimer of IL-12 comprises mAb-p402 a3-1d.
Type: Application
Filed: May 21, 2012
Publication Date: Oct 23, 2014
Applicant: RUSH UNIVERSITY MEDICAL CENTER (Chicago, IL)
Inventor: Kalipada Pahan (Skokie, IL)
Application Number: 14/118,698
International Classification: A61K 39/395 (20060101); A61K 38/20 (20060101);