Abstract: The present invention is in the therapeutic field of drugs for medical conditions relating to diabetes. More specifically the invention relates to insulin analogues of human insulin. The invention provides pharmaceutical compositions comprising such insulin analogues and the uses if the such analogues for the treatment or prevention of medical conditions relating to diabetes.

Abstract: The present disclosure relates generally to compositions of insulin-Fc (e.g., proinsulin-Fc) fusion proteins and their use to treat autoimmune disease, e.g., autoimmune diabetes, e.g., Type 1 diabetes.

Abstract: The present invention relates to insulin derivatives which, in comparison to insulin glulisine and similar derivatives, has a simplified process for synthesis. In particular, the present invention relates to insulin derivatives or physiologically tolerable salts thereof in which the motif Leucine-Proline-X-Threonine appears at the end of the B-chain, where X is any amino acid residue. Due to the nature of the process, the A-chain and B-chain must begin with a Glycine amino acid residue.

Abstract: A two-chain insulin analogue contains a modified A-chain polypeptide and a modified B-chain polypeptide. The A-chain polypeptide comprises one or more of: a His or Glu substitution at position A8, a Glu substitution at position A14; and a Gln or Arg substitution at positon A17. The B-chain polypeptide comprises one or more of: a deletion of the amino acids at position B1, B1-B2, B1-B3, B30 or a combination thereof; an Ala or Glu substitution at position B2; a Glu substitution at position B3. The analogue exhibits thermodynamic stability in a zinc-free solution, decreased self-association, maintains biological potency, and no increased mitogenicity. The analogue exhibits resistance to chemical degradation and physical degradation. A method of treating a patient with diabetes mellitus or obesity comprises administering a physiologically effective amount of the insulin analogue or a physiologically acceptable salt thereof to a patient.

Abstract: Described are a genetically modified microorganism and corresponding methods and products. The genetically modified microorganism may include a first gene that encodes an acyl transferase and a second gene that encodes a peptide or protein. One or both of the first and second gene may be heterologous. The genetically modified microorganism may include a modified acyl-CoA biosynthetic pathway configured for one or more of: inducible biosynthesis of an acyl-CoA and over-accumulation of the acyl-CoA. The genetically modified microorganism may be effective upon fermentation to cause acylation of the peptide or protein by the acyl transferase using the acyl-CoA to provide a N-acylated peptide or protein product.

Abstract: Provided is a method of preparing a physiologically active polypeptide conjugate, in which a physiologically active polypeptide and a non-peptidyl polymer are linked to each other via a covalent bond. The method is to improve an overall yield of the physiologically active polypeptide conjugate by improving a reaction of the non-peptidyl polymer and the physiologically active polypeptide, and particularly, the method is to prepare a physiologically active polypeptide conjugate in a high yield by performing a two-step reaction through selective precipitation. The preparation method of the present invention is used to produce a non-peptidyl polymer-physiologically active polypeptide conjugate and a physiologically active polypeptide-physiologically active carrier conjugate in a high yield, and therefore, the method may be used in the development of long-acting formulations of various peptide drugs which maintain in vivo activity at a relatively high level and have remarkably increased blood half-life.

Abstract: Disclosed herein is a glucose-responsive insulin delivery system based on the interaction between the glucose-modified insulin and glucose transporters (GLUTs) on erythrocytes (or red blood cells, RBCs). After being conjugated with glucose, insulin can efficiently bind to RBC membranes. The binding is reversible in the setting of hyperglycemia, resulting in fast release of insulin and subsequent drop of blood glucose (BG) level in vivo. In some embodiments, the delivery vehicle can include: 1) intravenously injectable polymeric nanoparticles (˜100 nm in diameter) coated with RBC membrane and loaded with glucose-modified insulin and/or 2) painless microneedle (MN) patches loaded with the complex of GLUT and glucose-modified insulin.

Abstract: An improved method of coupling amino acids into peptides or peptidomimetics is disclosed in which the activation and coupling are carried out in the same vessel, in the presence of a carbodiimide in an amount greater than 1 equivalent as compared to the amino acid, in the presence of an activator additive, and at a temperature greater than 30° C.

Abstract: Amylin receptor antagonists capable of binding to the amylin receptor and inhibiting activity of amylin or amyloid-beta protein are provided. The amylin receptor antagonists can be administered in the form of pharmaceutical compositions or the like. Methods for preparing and using the amylin receptor antagonists for treating, preventing, or ameliorating Alzheimer's disease are also provided.

Abstract: Described herein are methods of making targeting peptides conjugated to a recombinant lysosomal enzyme by modifying the amino (N)-terminus and one or more lysine residues on a recombinant human lysosomal enzyme using a first crosslinking agent to give rise to a first crosslinking agent modified recombinant human lysosomal enzyme, modifying a lysine or cysteine within a short extension linker at the carboxyl (C)-terminus on a variant IGF-2 peptide having a short extension linker using a second crosslinking agent to give rise to a second crosslinking agent modified variant IGF-2 peptide, and then conjugating the first crosslinking agent modified recombinant human lysosomal enzyme to the second crosslinking agent modified variant IGF-2 peptide containing a short extension linker. Also described herein are conjugates synthesized using the methods disclosed herein. Also described herein are treatment methods using the disclosed conjugates.

Abstract: The present disclosure relates generally to compositions of insulin-Fc (e.g., proinsulin-Fc) fusion proteins and their use to treat autoimmune disease, e.g., autoimmune diabetes, e.g., Type 1 diabetes.

Abstract: The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules.

Abstract: A facile laboratory-based method and kit for use in accordance with the method is disclosed. The method allows for the localisation of biomolecules comprising a conjugatable sulfhydryl group to be localised to the surface of cells, such as red blood cells, as lipid conjugates. The method obviates the need to purify the lipid-conjugated biomolecule before contacting with the cells.

Abstract: A physiological parameter associated with tissue of a host may be monitored in the tissue to confirm subcutaneous delivery of medication to the host. More particularly, such may involve delivering medication subcutaneously to the host with a medical device which includes a sensor used to measure the physiological parameter, particularly within a predetermined time period after delivery of the medication. Such may also or otherwise involve forming a depot in the tissue with the medication, and using the sensor to measure the physiological parameter while the sensor is at least partially within the depot.

Abstract: A process is described for purifying insulin and insulin analogs that comprises high-pressure liquid chromatography with an acidic cation exchange medium performed under low to moderate pressure at an elevated temperature.

Abstract: The present invention provides a novel process for preparing a cell-binding agent cytotoxic agent conjugate. The process comprises the steps of: (a) reacting a cytotoxic agent with a bifunctional crosslinking reagent represented by the structural formula (I) or a salt thereof, in a buffer solution comprising a buffering agent to provide a first mixture comprising a cytotoxic agent-linker compound, wherein the buffer solution has high buffer capacity; and (b) reacting the first mixture comprising the cytotoxic agent-linker compound from step (a) with a cell-binding agent in a solution having a pH of 4 to 9 to provide a second mixture comprising the cell-binding agent cytotoxic agent conjugate. The cell-binding agent cytotoxic agent conjugates prepared according to the processes described herein are also included in the present invention.

Abstract: Methods for monitoring and adjusting a physiological state of a subject. The methods include (1) providing a subject having one or more physiological parameters defined by one or more biometrics, (2) monitoring a selected biometric analyte associated with a selected biometric to define a state of the selected biometric, (3) based on the results of the monitoring, adjusting the state of the selected biometric by administering to the subject a supplement selected to affect the state of the selected biometric.

Abstract: The present invention relates to glucagon receptor agonists and their medical use, for example in the treatment of severe hypoglycemia.

Abstract: Method of localizing a sulfhydryl (—SH) group containing biomolecule to the surface of a cell membrane by mixing in a volatile reaction buffer a molar excess of the sulfhydryl (—SH) group containing biomolecule with a lipid conjugated maleimide of the structure F-S-L as defined in the specification to provide a reaction mix, incubating the reaction mix for a time and at a temperature sufficient to allow all the lipid conjugated maleimide to have reacted with the sulfhydryl (—SH) group, and freeze-drying the reaction mix to remove the volatile reaction buffer and provide a reaction product. An aqueous solution of the reaction product is contacted with the cell membrane.

Abstract: The invention is directed to a single-step method for rapidly and efficiently preparing protein-polymer conjugates, including an insulin-polymer conjugate. According to the method of the present invention, a protein and hydrophilic polymer are contacted in the presence of at least one organic solvent and at least one metal chelator, under conditions that promote the formation of a conjugate of the protein and polymer. Thus, the invention is directed to the site-specific modification of selected proteins, such as insulin, with poly(ethylene glycol) at residue PheB1. The invention also provides a pharmaceutical formulation for encapsulating the conjugate in a biodegradable polymer.

Abstract: As explained hereinbefore, the C12orf59 gene of the present invention suppresses cancer cell invasion and inhibits cancer cell survivability, and the over expression of C12orf59 protein or a fragment thereof inhibits cancer cell invasion, so that C12orf59 gene or a fragment thereof not only can be effectively used for the pharmaceutical composition for preventing and treating cancer but also can be used as a clinical marker for screening a cancer treatment agent candidate, for diagnosing various cancers or for predicting pathological stage. In addition, the C12orf59 gene or a fragment thereof of the present invention can be used for the method for preventing and treating cancer and for the preparation of a pharmaceutical composition for preventing and treating cancer.

Abstract: The present invention relates to an insulin derivative for the treatment of a condition or disease where administration of insulin will be of benefit, comprising administering, to a patient in need thereof, effective dosages of the insulin derivative, wherein said insulin derivative exhibits a prolonged profile of action and wherein said dosages are administered at intervals longer than 24 hours.

Abstract: The present disclosure provides crystalline insulin-conjugates. The present disclosure also provides formulations, methods of treatment, methods of administering, and methods of making that encompass these crystalline insulin-conjugates.

Abstract: The invention provides processes for obtaining a precursor for insulin, analogs or derivatives thereof having correctly bonded cystine bridges. The process involves solubilizing a precursor of insulin, insulin analog or derivatives in an aqueous solution or a buffer containing cysteine or cysteine hydrochloride and one or more of chaotropic auxiliary. The solubilized precursors are refolded by adding diluent to the solubilized mixture (reverse dilution). Further, the solubilized precursors, wherein the concentration of precursor in reaction mixture is more than 0.65 g/liter can also be refolded by diluting the reaction mixture with a diluent optionally comprising about 5-40% v/v of one or more of alcoholic or aprotic solvents.

Abstract: Insulins to which there is connected an amino acid oligomer have satisfactory properties.

Abstract: The present invention relates to human insulin analogues containing a substituting cysteine, to human insulin derivatives containing a PEGylated substituting cysteine and methods of making such. The compounds of the invention may be useful for the treatment of diabetes.

Abstract: Disclosed is a method for preparing an insulin glargine (GlyA21-ArgB31-AryB32-human insulin) crystal, comprising crystallizing the insulin glargine at pH 7.0-9.0 and in a crystallization solution containing a recombinant insulin glargine, an organic solvent of a 10-30% concentration by volume, a zinc compound, a phenol derivative, a salt and an organic acid.

Abstract: An insulin conjugate is disclosed in which insulin is coupled to a modifying moiety of the formula X—R1—Y-PAG-Z—R2 wherein X, Y, and Z are linking groups, R2 is a capping group, and PAG is a carbon chain that incorporates one or more alkylene glycol moieties.

Abstract: An insulin compound coupled to a modifying moiety having a formula: —X—R1—Y-PAG-Z—R2??(Formula VI) where, X, Y and Z are independently selected linking groups and each is optionally present, and X, when present, is coupled to the insulin compound by a covalent bond, either R1 or R2 is a lower alkyl, optionally including a carbonyl group, and when R1 is a lower alkyl, R2 is a capping group, and PAG is a linear or branched carbon chain incorporating one or more alkalene glycol moieties, and optionally incorporating one or more additional moieties selected from the group consisting of —S—, —O—, —N—, and —C(O)—.

Abstract: Single chain insulin analogs are provided having high potency and specificity for the insulin receptor. As disclosed herein optimally sized linking moieties can be used to link human insulin A and B chains, or analogs or derivatives thereof, wherein the carboxy terminus of the B25 amino acid of the B chain is linked to the amino terminus of the A1 amino acid of the A chain via the intervening linking moiety. In on embodiment the linking moiety comprises a polyethylene glycol of 6-16 monomer units and in an alternative embodiment the linking moiety comprises a non-native amino acid sequence derived form the IGF-1 C-peptide and comprising at least 8 amino acids and no more than 12 amino acid in length. Also disclosed are prodrug and conjugate derivatives of the single chain insulin analogs.

Abstract: This document relates to conjugates of a biologically active molecule or a derivative thereof and functionalized (e.g., mono- or bi-functional) polymers (e.g., polyethylene glycol and related polymers) as well as methods and materials for making and using such conjugates.

Abstract: Acylated insulins wherein an acyl moiety is attached to the parent insulin and wherein said acyl moiety comprises repeating units of alkylene glycol containing amino acids and wherein there is only one lysine residue (K & Lys) in the parent insulin have satisfactory properties when administered pulmonary.

Abstract: The invention concerns a soluble pharmaceutical formulation comprising an insulin derivative wherein the formulation further comprises more than 4 zinc atoms per 6 molecules of the insulin derivative, and a citric acid monohydrate and/or a histidine compound used in an amount sufficient to increase the tendency of the insulin derivative to self-associate into dodecamers. The invention further comprises a process for preparing the soluble pharmaceutical formulation.

Abstract: Acylated insulins wherein an acyl moiety is attached to the parent insulin and wherein the acyl moiety comprises repeating units of alkylene glycol containing amino acids and wherein there is only one lysine residue (K & Lys) in the parent insulin, having satisfactory properties when administered pulmonary.

Abstract: Compositions containing conjugates of heparosan polymer with at least one drug are disclosed, along with methods of production and use thereof.

Abstract: This invention relates to insulin derivatives having long duration of action. The insulin derivatives have been found to be useful for the treatment of diabetes, and in particular for less frequent administration to the diabetic patients, in particular as seldom as about once weekly.

Abstract: Nanoparticles having a core and a corona of ligands covalently linked to the core, wherein differing species of peptides are bound to the nanoparticles and incorporated into various dosage forms.

Abstract: The present invention provides albumin-binding probes capable of reversibly linking to short-lived amino-containing drugs and non-covalently associating with albumin in-vivo, thereby converting said drugs into inactive reactivable prodrugs having prolonged lifetime in-vivo. The invention further provides conjugates of said probes with amino-containing drugs, as well as pharmaceutical compositions and uses thereof.

Abstract: A method treating a patient includes administering a physiologically effective amount of a fibrillation-resistant insulin analogue or a physiologically acceptable salt thereof to the patient. The fibrillation-resistant insulin analogue or a physiologically acceptable salt thereof, contains an insulin A-chain sequence modified at position A8 and an insulin B-chain sequence or an analogue thereof. The fibrillation-resistant insulin analogue may exhibit thermodynamic stability similar to or exceeding that of wild-type human insulin and displays a susceptibility to fibrillation similar to or exceeding that of wild-type human insulin. An insulin analogue may display greater in vitro insulin receptor binding than normal insulin while displaying binding to IGFR less than twice that of normal insulin and less than that of fast-acting insulin analogs.

Abstract: Novel PEGylated insulin analogs exhibiting resistance towards proteases can, effectively, be administered pulmonary or orally. The insulin analogs contain B25H and A14E or A14H. The PEGylation is at B29K.

Abstract: The present disclosure provides POZ derivatives having a range of active functional groups allowing conjugation of POZ derivatives to a variety of target molecules under a wide range of reaction conditions to produce a hydrolytically stable target molecule-POZ conjugate. Furthermore, the present disclosure provides novel methods of synthesis for the disclosed POZ derivatives and hydrolytically stable target molecule-POZ conjugates created using the disclosed terminally activated monofunctional POZ derivatives. In one embodiment, the POZ derivative is a terminally activated monofunctional POZ derivative.

Abstract: Low-copper click chemistry, 1.3-dipolar cycloadditions, and Staudinger ligations for modifying biomolecules is provided. Compositions, methods, and kits relating to low-copper click chemistry, 1.3-dipolar cycloadditions, and Staudinger ligations are also provided.

Abstract: The invention relates to biomolecules conjugated to graphene quantum dots, and in particular, to use of such biomolecule-graphene quantum dot conjugates as fluorophores for imaging applications.

Abstract: Acylated insulins wherein an acyl moiety is attached to the parent insulin and wherein said acyl moiety comprises repeating units of alkylene glycol containing amino acids and wherein there is only one lysine residue (K & Lys) in the parent insulin have satisfactory properties when administered pulmonary.

Abstract: The present invention relates to PEGylated C-peptide derivatives comprising at least one PEG group attached to the N-terminus, which exhibit improved pharmacokinetic and biological activity in vivo.

Abstract: Provided herein are water-soluble carbohydrate polymers which are monoderivatized at their reducing terminus, such that the carbohydrate polymers can be selectively conjugated at a single location. Also provided are methods of preparation and conjugation of the monoderivatized carbohydrate polymers.

Abstract: Novel modified exendins and exendin agonists having an exendin or exendin agonist linked to one or more polyethylene glycol polymers, for example, and related formulations and dosages and methods of administration thereof are provided. These modified exendins and exendin agonists, compositions and methods are useful in treating diabetes and conditions that would be benefited by lowering plasma glucose or delaying and/or slowing gastric emptying or inhibiting food intake.

Abstract: A pharmaceutical composition for treatment for of r afflicted or in risk of becoming of impaired glucose tolerance (IGT) and/or type-2 it comprising an effective amount of relaxin for protecting beta-cells and beta-cell function against the effects of high blood glucose (glucotoxicity). Treatment of persons of disglycaemias, and protection of beta cells of the islets of Langerhans and beta-cell function in patients having type-2 diabetes, is diclosed.

Abstract: Prodrug formulations of insulin and insulin analogs are provided wherein the insulin peptide has been modified by an amide bond linkage of a dipeptide prodrug element. The prodrugs disclosed herein have extended half lives of at least 10 hours, and more typically greater than 2 hours, 20 hours and less than 70 hours, and are converted to the active form at physiological conditions through a non-enzymatic reaction driven by chemical instability.

Abstract: Modified insulin polypeptides and their uses thereof are provided.