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US-12624116-B2 - Methods of treating severe insulin resistance by interfering with glucagon receptor signaling

US12624116B2US 12624116 B2US12624116 B2US 12624116B2US-12624116-B2

Abstract

Provided herein are methods of treating a patient with severe insulin resistance. The methods comprise administering to a patient in need thereof a therapeutic amount of a GCG/GCGR signaling pathway inhibitor, such that blood glucose or beta-hydroxybutyrate levels are lowered or that the severe insulin resistance is mediated, or a condition or disease characterized by severe insulin resistance is mediated, or at least one symptom or complication associated with the condition or disease is alleviated or reduced in severity. The GCG/GCGR signaling pathway inhibitor can be a small molecule inhibitor of the signaling pathway, an antisense inhibitor of the signaling pathway, a GCG neutralizing monoclonal antibody, a GCGR antagonist, a peptide inhibitor of the signaling pathway, a DARPin, a Spiegelmer, an aptamer, engineered Fn type-III domains, etc. The therapeutic methods are useful for treating a human suffering from severe insulin resistance.

Inventors

  • Jesper Gromada
  • Haruka Okamoto
  • Stephen Jaspers
  • Joyce Harp

Assignees

  • REGENERON PHARMACEUTICALS, INC.

Dates

Publication Date
20260512
Application Date
20230605

Claims (18)

  1. 1 . A method for treating a patient having severe insulin resistance, the method comprising administering to the patient a therapeutically effective amount of a composition comprising a glucagon receptor (GCGR) antagonist, wherein the GCGR antagonist lowers blood glucose levels or levels of ketone bodies of the patient, mediates a condition or disease associated with severe insulin resistance, or alleviates or reduces in severity at least one symptom or complication associated with the condition or disease, wherein: the severe insulin resistance is associated with a genetic variant of one or more genes selected from the group consisting of INSR, PSMD6, ADRA2A, AGPAT2, AKT2, APPL1, BBS1, BSCL2, CIDEC, GRB10, IRS2, KLF14, LEP, LEPR, LMNA, MC4R, PCNT, PIK2CA, POLD1, PPARG, PTPRD, PTRF, RASGRP1, TBCID4, and TCF712, and wherein the GCGR antagonist is an isolated human monoclonal antibody or antigen-binding fragment thereof comprising: (a) a heavy chain variable region (HCVR) comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) that are contained within an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 86; and a light chain variable region (LCVR) comprising three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) that are contained within an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 88; or (b) an HCVR comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) that are contained within an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 34; and an LCVR comprising three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) that are contained within an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 42.
  2. 2 . The method of claim 1 , wherein the condition or disease is selected from the group consisting of Donohue syndrome, Rabson-Mendenhall syndrome, Type A insulin resistance, Type B insulin resistance, HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome, pseudoacromegaly, Alstrom syndrome, myotonic dystrophy, Werner's syndrome, lipodystrophy, cirrhosis, monogenic morbid obesity, hyperproinsulinemia, carboxypeptidase E deficiency, defective arginine metabolism, and Bardet-Biedl syndrome.
  3. 3 . The method of claim 1 , wherein insulin degrading protease activity is detected in the patient sera.
  4. 4 . The method of claim 1 , wherein neutralizing anti-insulin antibodies or anti-insulin receptor antibodies are detected in the patient sera.
  5. 5 . The method of claim 1 , wherein the GCGR antagonist is administered concomitantly with insulin.
  6. 6 . The method of claim 1 , wherein the composition is administered to the patient in combination with at least one additional therapeutic agent.
  7. 7 . The method of claim 6 , wherein the at least one additional therapeutic agent is selected from the group consisting of insulin, a biguanide, hIGF1, leptin, pioglitazone, vildagliptin, acarbose, alpha-glycosidase inhibitors, L-arginine, dipeptidyl-peptidase-4 inhibitors, insulin secretagogues, amylin receptor agonists, insulin sensitizers, FGF21, SGLT2 inhibitors, SGLT1 inhibitors, GLP-1 agonists, GLP-1 receptor activators, β3 adrenergic agonists, NPR1 agonists, NPR3 antagonists, tri-iodothyronine, a GCG inhibitor, and a second GCGR antagonist.
  8. 8 . The method of claim 7 , wherein the insulin secretagogues are selected from the group consisting of sulfonylureas, ATP-sensitive K channel antagonists, and meglitinides.
  9. 9 . The method of claim 7 , wherein the insulin sensitizer is thiazolidinedione or rosiglitazone.
  10. 10 . The method of claim 1 , wherein the isolated human antibody or antigen-binding fragment thereof comprises: (a) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 72; an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74; an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76; an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 80; an LCDR2 comprising the amino acid sequence of AAS; and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 84; or (b) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 36; an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38; an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40; an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44; an LCDR2 comprising the amino acid sequence of LGS; and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48.
  11. 11 . The method of claim 1 , wherein the isolated antibody or antigen-binding fragment thereof comprises: (a) an HCVR amino acid sequence as set forth in SEQ ID NO: 86 and an LCVR amino acid sequence as set forth in SEQ ID NO: 88; or (b) an HCVR amino acid sequence as set forth in SEQ ID NO: 34 and an LCVR amino acid sequence as set forth in SEQ ID NO: 42.
  12. 12 . The method of claim 1 , wherein the ketone bodies are beta-hydroxybutyrate.
  13. 13 . The method of claim 1 , wherein the patient exhibits elevated levels of blood glucose.
  14. 14 . The method of claim 1 , wherein the amount and/or dosage of insulin necessary to treat the patient is reduced.
  15. 15 . The method of claim 14 , wherein the GCGR antagonist is administered concomitantly with insulin.
  16. 16 . The method of claim 14 , wherein the amount and/or dosage of insulin may be reduced by about 30% to about 95% when administered concomitantly with the GCGR antagonist.
  17. 17 . The method of claim 14 , wherein the amount and/or dosage of insulin may be reduced by about 90% when administered concomitantly with the GCGR antagonist.
  18. 18 . The method of claim 1 , wherein β-cell mass in the patient is increased relative to the β-cell mass prior to treatment.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation application of U.S. patent application Ser. No. 17/222,236, filed on Apr. 5, 2021, which is a divisional application of U.S. 371 National Phase patent application Ser. No. 16/328,935, filed Feb. 27, 2019, which is the National Stage Application of PCT/US2017/049137, filed Aug. 29, 2017, which claims the benefit under 35 USC § 119 (e) of U.S. Provisional Application No. 62/411,032, filed Oct. 21, 2016, and to U.S. Provisional Application No. 62/381,263, filed Aug. 30, 2016, each of which are incorporated herein by reference. To the extent appropriate, a claim of priority is made to each of the above-disclosed applications. TECHNICAL FIELD The invention relates to methods of using a glucagon (GCG) inhibitor or a glucagon receptor (GCGR) antagonist to treat or to slow the progression of severe insulin resistance, and/or reducing the therapeutic insulin dose in a patient in need thereof. SEQUENCE LISTING An official copy of the sequence listing is submitted concurrently with the specification electronically via Patent Center. The contents of the electronic sequence listing (10282US03_Sequence_Listing_ST26.xml; Size 368,640 bytes; and Date of Creation: Jun. 5, 2023) is part of the specification and is herein incorporated by reference in its entirety. BACKGROUND Glucagon is a 29 residue polypeptide hormone, which in cooperation with insulin, mediates homeostatic regulation of the amount of glucose in the blood. Glucagon primarily acts by stimulating certain cells, for example, liver cells, to release glucose when blood glucose levels fall to maintain normal blood glucose levels. The action of glucagon is opposite to that of insulin, which stimulates cells to take up and store glucose whenever blood glucose levels rise. Glucagon is produced in the alpha cells of the pancreas, whereas insulin is secreted from the neighboring beta cells. It is an imbalance of glucagon and insulin that may play an important role in several diseases, such as diabetes mellitus and diabetic ketoacidosis. In particular, studies have shown that higher basal glucagon levels and lack of suppression of postprandial glucagon secretion contribute to diabetic conditions in humans (Muller et al. (1970), N Eng J Med, 283:109-115). It is believed that glucagon's effects on elevating blood glucose levels are mediated in part by the activation of certain cellular pathways following the binding of glucagon (GCG) to its receptor (designated GCGR). GCGR is a member of the secretin subfamily (family B) of G-protein-coupled receptors and is predominantly expressed in the liver. The binding of glucagon to its receptor triggers a G-protein signal transduction cascade, activating intracellular cyclic AMP and leading to an increase in glucose output through de novo synthesis (gluconeogenesis) and glycogen breakdown (glycogenolysis) (Wakelam et al., (1986) Nature, 323:68-71; Unson et al., (1989) Peptides, 10:1171-1177; and Pittner and Fain, (1991) Biochem. J., 277:371-378). The action of glucagon can be suppressed by providing an antagonist, such as a small molecule inhibitor, a GCG antibody, or a GCGR antibody, as described herein. Anti-GCG antibodies are mentioned, e.g., in U.S. Pat. Nos. 4,206,199; 4,221,777; 4,423,034; 4,272,433; 4,407,965; 5,712,105; and in PCT publications WO2007/124463 and WO2013/081993. Anti-GCGR antibodies are described in U.S. Pat. Nos. 5,770,445, 7,947,809, and 8,545,847; European patent application EP2074149A2; EP patent EP0658200B1; US patent publications 2009/0041784; 2009/0252727; and 2011/0223160; and PCT publication WO2008/036341. Small molecule inhibitors of GCG or GCGR are mentioned, e.g. in WO 07/47676; WO 06/86488; WO 05/123688; WO 05/121097; WO 06/14618; WO 08/42223; WO 08/98244; WO 2010/98948; US20110306624; WO 2010/98994; WO 2010/88061; WO 2010/71750; WO 2010/30722; WO 06/104826; WO 05/65680; WO 06/102067; WO 06/17055; WO 2011/07722; or WO 09/140342. Severe insulin resistance syndromes are rare metabolic disorders in which patients do not respond well to insulin. Current treatments available for severe insulin resistance syndromes include regular feedings and very high doses of insulin in attempt to provide adequate glycemic control. Administration of IGF-I, while effective in the short term, failed to provide long-term glycemic control in patients with severe insulin resistance. Vestergaard et al., (1997) European Journal of Endocrinology, 136:475-482. Administration of recombinant leptin has shown some success in patients with Rabson-Mendenhall syndrome (RMS) by reducing blood glucose levels over several months. Cochran et al., (2004) Journal of Clinical Endocrinology and Metabolism, 89:1548-1554. Given the absence of effective therapies to treat, or to slow the progression of severe insulin resistance disease, i.e., to extend the life and/or improve the quality of life of a patient having severe insulin resistance, there is a need to identify