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  Methods for treatment of diabetes using peptide analogues of insulinUSPTO Application #: 20060040863Title: Methods for treatment of diabetes using peptide analogues of insulin Abstract: The present invention is directed toward peptide analogues of insulin B chain that are generally derived from peptides comprising residues 9 to 23 of the native B chain sequence. The analogues are altered from the native sequence at position 12, 13, 15 and/or 16, and may be additionally be altered at position 19 and/or other positions. Pharmaceutical compositions containing these peptide analogues are provided. The peptide analogues are useful for treating and inhibiting the development of diabetes. (end of abstract) Agent: Seed Intellectual Property Law Group PLLC - Seattle, WA, US Inventors: Amitabh Gaur, Nicholas Ling, Paul J. Conlon USPTO Applicaton #: 20060040863 - Class: 514012000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 25 Or More Peptide Repeating Units In Known Peptide Chain Structure The Patent Description & Claims data below is from USPTO Patent Application 20060040863. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. patent application Ser. No. 10/339,160, filed Jan. 8, 2003, now U.S. Pat. No. 6,933,274, which application is a continuation of Ser. No. 09/787,140, filed Jun. 7, 2001, now U.S. Pat. No. 6,562,942, which is a National Stage Application of PCT/US99/03915 (35 U.S.C. 371), international filing date of Feb. 23, 1999, which claims foreign priority benefits under 35 U.S.C. 119 from U.S. application Ser. No. 09/028,156, filed Feb. 23, 1998, now abandoned, all of which are incorporated herein by reference in their entirety. BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention relates generally to peptide analogues of insulin, and more specifically to methods for treating diabetes using peptide analogues derived from residues 9-23 of human insulin B chain. [0004] 2. Description of the Related Art [0005] Insulin dependent diabetes mellitus (IDDM) is an organ specific aautoimmune disease affecting close to a million people in different age groups in the United States. The disease is characterized by extensive destruction of the insulin producing beta cells in the pancreatic islets and dysregulation of glucose metabolism leading to frank diabetes. The defining feature of IDDM is the lymphocytic infiltration of the islets. Among the invading cells, T cells appear to be one of the major mediators of autoimmune destruction. [0006] Type I diabetes is further characterized by increased levels of antibodies to various islet associated antigens, including insulin, GAD65, GAD67 and ICA512. These antibodies can be detected much before frank disease, and an immune response to such antigens can be used as a predictor for impending diabetes in patients with susceptible genetic (HLA) haplotypes. [0007] Currently, patients are dependent on insulin injections to maintain normoglycemia. Insulin is a polypeptide hormone consisting of two disulfide-linked chains, an A chain consisting of 21 amino acid residues and a B chain of 30 residues. While administration of insulin provides significant benefits to patients suffering from diabetes, the short serum half-life of insulin creates difficulties for maintaining proper dosage. The use of insulin also can result in a variety of hypoglycemic side-effects and the generation of neutralizing antibodies. [0008] In view of the problems associated with existing treatments of diabetes, there is a compelling need for improved treatments that are more effective and are not associated with such disadvantages. The present invention exploits the use of peptide analogues which antagonize a T cell response to insulin to effectively treat diabetes, while further providing other related advantages. BRIEF SUMMARY OF THE INVENTION [0009] The present invention provides compounds and methods for treating and preventing diabetes. Within certain aspects, the present invention provides peptide analogues comprising residues 9 to 23 of human insulin B chain (SEQ ID NO:2), wherein the peptide analogue differs in sequence from native human insulin B chain residues 9 to 23 due to substitutions at between 1 and 4 amino acid positions. Such substitutions may be made at one or more residues selected from the group consisting of residues 12, 13, 15 and 16, with or without additional substitutions at other residues. Within certain preferred embodiments, such substitutions may occur at two or three amino acid residues within residues 9 to 23 of insulin B chain. Substitutions may also occur at residue 19. Substitutions are preferably non-conservative, and analogues wherein residue 12, 13, 15, 16 and/or 19 are altered (to, for example, alanine) are preferred. Analogues further comprising residue 24 of insulin B chain are also preferred. In certain other embodiments, the peptide analogues comprise no more than 18 residues, no more than 16 residues or no more than 15 residues of human insulin B chain. [0010] Within further embodiments, the peptide analogues consist essentially of residues 9 to 23 or 9 to 24 of human insulin B chain (SEQ ID NO:2), wherein the peptide analogue differs in sequence from native human insulin B chain residues 9 to 23 due to substitutions at between 1 and 4 amino acid positions, and wherein at least one substitution occurs at a residue selected from the group consisting of residues 12, 13, 15 and 16. [0011] Within further aspects, pharmaceutical compositions are provided, comprising a peptide analogue as described above in combination with a physiologically acceptable carrier or diluent. [0012] The present invention further provides methods for treating and/or inhibiting the development of diabetes, comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition as described above. [0013] These and other aspects of the invention will become evident upon reference to the following detailed description and attached drawings. In addition, various references are set forth below which describe in more detail certain procedures or compositions. These references are incorporated herein by reference in their entirety as if each were individually noted for incorporation. BRIEF DESCRIPTION OF THE DRAWINGS [0014] FIG. 1 depicts the amino acid sequence of residues 9-23 of insulin B chain (SEQ ID NO:2). [0015] FIG. 2 is a graph showing the proliferative response (measured in cpm) of a NOD mouse T cell clone to a native insulin B chain (9-23) peptide in the presence of varying amounts of representative peptide analogues, in which different residues are substituted with alanine, as indicated. [0016] FIG. 3 is a graph showing the proliferative response (measured in cpm) of a NOD mouse T cell clone to a native insulin B chain (9-23) peptide in the presence of varying amounts of the representative peptide analogue in which amino acids at positions 16 and 19 are substituted with alanine (NBI-6024; indicated by squares). For comparison the proliferative response in the presence of an unrelated control peptide derived from myelin basic protein (NBI-5096; indicated by circles) is also shown. The response is shown as mean CPM.+-.SEM of triplicate cultures. [0017] FIGS. 4-6 are histograms illustrating the proliferative response (measured in cpm) of T cell lines from different diabetic patients to the native B chain (9-23) peptide or to representative peptide analogues. Peripheral blood mononuclear cells were isolated from diabetic patients and cultured in the presence of insulin B chain (9-23) peptide. After three rounds of restimulation with insulin B chain (9-23), 1.times.10.sup.5 T-cells and 7.times.10.sup.4 irradiated autologous PBMCs were added to each well in a round bottom 96-well plate in complete medium. Cells were cultured for 5 days with NBI-6024 (insulin B chain 9-23 with alanine substitutions at positions 16 and 19), insulin B chain (9-23) or medium only. On day 4, the cells were pulsed with .sup.3H-thymidine and re-cultured for an additional 18 hours. The cultures were then harvested, counted using liquid scintillation, and the data was expressed as the mean counts per minute (cpm) of replicate samples.+-.standard error of the mean (sem). [0018] FIG. 7 is a histogram illustrating the proliferative response (measured in cpm) of a T cell line from a diabetic patient to the native B chain (9-23) peptide or to representative peptide analogues containing alanine substitutions as indicated. Peripheral blood mononuclear cells were isolated from diabetic patients and cultured in the presence of insulin B chain (9-23) peptide. After three rounds of restimulation with insulin B chain (9-23), 1.times.10.sup.5 T-cells and 7.times.10.sup.4 irradiated autologous PBMCs were added to each well in a round bottom 96-well plate in complete medium. Cells were cultured for 5 days with analogue, insulin B chain (9-23) or medium only (BKG), as indicated. On day 4, the cells were pulsed with .sup.3H-thymidine and re-cultured for an additional 18 hours. The cultures were then harvested, counted using liquid scintillation, and the data was expressed as the mean counts per minute (cpm) of replicate samples.+-.standard error of the mean (sem). [0019] FIG. 8 is a graph showing the percent of female NOD mice that were diabetic following nine weekly treatments with representative peptide analogues. Ten mice each were treated subcutaneously beginning on day 24 with peptide analogues of the B chain (9-23) containing alanine substitutions at residue 12 (open triangles), 13 (squares) or 16 (solid triangles). All of the mice treated with a control peptide, neurotensin (circles), became diabetic. [0020] FIG. 9 is a graph showing the same data as in FIG. 8, but contrasting only the A13 analogue-treated group with the control peptide (neurotensin)-treated group. Continue reading... Full patent description for Methods for treatment of diabetes using peptide analogues of insulin Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Methods for treatment of diabetes using peptide analogues of insulin patent application. Patent Applications in related categories: 20080167221 - Heterocarpine, a plant-derived protein with anti-cancer properties - The invention relates to a plant-derived protein with anti-cancer properties which binds the human growth hormone-releasing hormone (hGHRH). Said protein, which is obtained from the Pilocarpus Heterophyllus plant, is particularly adapted for preparing a medicament that is intended for the treatment of cancers for which growth is dependant on the ... ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. 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