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JP-2026076162-A - Cannabinoid receptor type 1 (CB1) binding protein and its use

JP2026076162AJP 2026076162 AJP2026076162 AJP 2026076162AJP-2026076162-A

Abstract

[Problem] To provide antibodies and their antigen-binding fragments, which are binding proteins that bind to the cannabinoid type 1 receptor (CB1), and which are useful in the treatment and diagnosis of diseases. [Solution] This disclosure provides an isolated, modified CB1-binding protein that does not exist in nature, comprising an anti-CB1 antibody or its antigen-binding fragment. The CB1-binding protein has utility in the treatment and diagnosis of CB1-mediated conditions, diseases, and disorders. [Selection Diagram] None

Inventors

  • バナジー，アンタラ
  • ファンジュール，アンドレア
  • ホーイ，ロバート，ジェイ．
  • サッヘン，ケイシー
  • スースロフ，ニコライ

Assignees

  • 武田薬品工業株式会社

Dates

Publication Date
20260511
Application Date
20251224
Priority Date
20180430

Claims (20)

  1. An isolated antibody or its antigen-binding fragment that binds to the human cannabinoid type 1 receptor (CB1) (SEQ ID NO: 1), wherein the binding protein comprises six complementarity-determining regions (CDRs): CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, in which case, CDR-H1 has the amino acid sequence G-Y-T-F-T-D-Y-W (residues 26-33 of SEQ ID NO: 329) or a modified form of the amino acid sequence by substitution of at least one amino acid residue, wherein the substitution of G at position 1 is S; the substitution of T at position 3 is E; the substitution of T at position 5 is S or N; the substitution of D at position 6 is R or Y; the substitution of Y at position 7 is H; and the substitution of W at position 8 is A or N; CDR-H2 has the amino acid sequence I-Y-P-Y-D-G-D-T (residues 51-58 of SEQ ID NO: 329) or a modified form of the amino acid sequence by substitution of at least one amino acid residue, wherein the substitution of I at position 1 is F; the substitution of Y at position 2 is D, S, or T; the substitution of P at position 3 is T; the substitution of Y at position 4 is G, D, or S; the substitution of D at position 5 is Y or S; the substitution of G at position 6 is S; the substitution of D at position 7 is E, G, or R; and the substitution of T at position 8 is A, S, or I; CDR-H3 has the amino acid sequence A-R-G- X1 - X2 - X3 - X4 - X5 - X6 - X7 - X8 - X9 -W- X10 - X11 -Y (residues 98-113 of SEQ ID NO: 329) or a modified form of the above amino acid sequence by substitution of at least one amino acid residue, in which case the substitution of A at position 1 is S; the substitution of G at position 3 is S; X1 at position 4 is Q, Y, K, R, or G, or is absent; X2 at position 5 is E, Y, L, or G, or is absent; X3 at position 6 is Y or P, or is absent; X4 at position 7 is Y, R, or E, or is absent; X5 at position 8 is G, or is absent; X6 at position 9 is T, or is absent; X at position 10 7 is either N or D, or does not exist; X at position 11 8 is either Y, N, A, or G, or does not exist; X at position 12 9 is either N, Y, S, A, or R, or does not exist; the permutation of W at position 13 is Y, A, or P; X at position 14 10 is either L, M, F, or G, or does not exist; X at position 15 11 is either P, D, A, or T, or does not exist; the permutation of Y at position 16 is V; CDR-L1 has the amino acid sequence Q- X1 -I-S-S- X2 -Y (residues 27-33 of SEQ ID NO: 330) or a modified form of the amino acid sequence by substitution of at least one amino acid residue, wherein the substitution of Q at position 1 is S or E; X1 at position 2 is E, S, T, N, G, or R; the substitution of I at position 3 is V; the substitution of S at position 4 is A, R, or G; the substitution of S at position 5 is G, N, or T; X2 at position 6 is S, N, peptide F-R-Y-S, or absent; and the substitution of Y at position 7 is F, D, or N; CDR-L2 has the amino acid sequence: X 1 - T - S (residues 51-53 of SEQ ID NO: 330) or a modified form of the amino acid sequence by substitution of at least one amino acid residue, in which case X 1 at position 1 is A, Y, G, R, D, or S; the substitution of T at position 2 is A; the substitution of S at position 3 is R; and CDR-L3 has the amino acid sequence: Q - Q - Y - X 1 - S - X 2 - P - Y - T (residues 91-99 of SEQ ID NO: 330) or a modified form of the amino acid sequence by substitution of at least one amino acid residue, in which case the substitution of Q at position 1 is L or H; the substitution of Q at position 2 is H; the substitution of Y at position 3 is S or G; X 1 at position 4 is S, W, H, Y, N, or I; the substitution of S at position 5 is E, R, G, T, or N; and X at position 6 The isolated antibody or antigen-binding fragment thereof, wherein 2 is Y, I, S, T, L, or W; and the substitution of Y at position 8 is P, L, F, or absent; and in such case, the said substitution, addition, or deletion of at least one amino acid residue does not inhibit the ability of the antibody or antigen-binding fragment thereof to bind to human CB1.
  2. An isolated antibody or antigen-binding fragment thereof that binds to the human cannabinoid type 1 receptor (CB1) (SEQ ID NO: 1), wherein the antibody comprises a variable weight (VH) domain sequence CDR and a variable light (VL) domain sequence CDR, wherein the VH domain sequence is one of the following: SEQ ID NOs: 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, 24 The isolated antibody or its antigen-binding fragment, selected from the group consisting of 6, 258, 270, 282, 294, 306, and 318, and/or the VL domain selected from the group consisting of SEQ ID NOs: 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, 312, and 324.
  3. An isolated antibody or antigen-binding fragment thereof that binds to the human cannabinoid type 1 receptor (CB1) (SEQ ID NO: 1), wherein the antibody comprises a variable weight (VH) domain sequence and a variable light (VL) domain sequence, and the VH domain sequence is such that SEQ ID NOs: 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, 246, 25 The isolated antibody or its antigen-binding fragment, selected from the group consisting of 8, 270, 282, 294, 306, and 318, and/or the VL domain selected from the group consisting of SEQ ID NOs: 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, 312, and 324.
  4. The isolated antibody or its antigen-binding fragment according to claim 3, comprising a VH/VL pair of heavy chain CDRs and light chain CDRs selected from the group consisting of SEQ ID NOs: 18/24, 30/36, 42/48, 54/60, 66/72, 78/84, 90/96, 102/108, 114/120, 126/132, 138/144, 150/156, 162/168, 174/180, 186/192, 198/204, 210/216, 222/228, 234/240, 246/252, 258/264, 270/276, 282/288, 294/300, 306/312, and 318/324.
  5. The isolated antibody or its antigen-binding fragment according to claim 4, comprising a VH/VL pair selected from the group consisting of SEQ ID NOs: 18/24, 30/36, 42/48, 54/60, 66/72, 78/84, 90/96, 102/108, 114/120, 126/132, 138/144, 150/156, 162/168, 174/180, 186/192, 198/204, 210/216, 222/228, 234/240, 246/252, 258/264, 270/276, 282/288, 294/300, 306/312, and 318/324.
  6. (20, 21, 22); (32, 33, 34); (44, 45, 46); (56, 57, 58); (68, 69, 70); (80, 81, 82); (92, 93, 94); (104, 105, 106); (116, 117, 118); (128, 129, 130); (140, 141, 142); (152, 153, 154); (164, 165, 166); (176, 177, 178); (188, 189, 190); (200, 201, 2 02); (212, 213, 214); (224, 225, 226); (236, 237, 238); (248, 249, 250); (260, 261, 262); (272, 273, 274); (284, 285, 286); (296, 297, 298); (308, 309, 310); and (320, 321, 322) selected from the group consisting of HCDR sets (HCDR1, HCDR2, HCDR3) and (26, 27, 28); (3 8, 39, 40); (50, 51, 52); (62, 63, 64); (74, 75, 76); (86, 87, 88); (98, 99, 100); (110, 111, 112); (122, 123, 124); (134, 135, 136); (146, 147, 148); (158, 159, 160); (170, 171, 172); (182, 183, 184); (194, 195, 196); (206, 207, 208); (218, 219 The isolated antibody or its antigen-binding fragment according to claim 3, comprising an LCDR set (LCDR1, LCDR2, LCDR3) selected from the group consisting of (220); (230, 231, 232); (242, 243, 244); (254, 255, 256); (266, 267, 268); (278, 279, 280); (290, 291, 292); (302, 303, 304); (314, 315, 316); and (326, 327, 328).
  7. Sequence numbers (20, 21, 22/26, 27, 28); (32, 33, 34/38, 39, 40); (44, 45, 46/50, 51, 52); (56, 57, 58/62, 63, 64); (68, 69, 70/74, 75, 76); (80, 81, 82/86, 87, 88); (92, 93, 94/98, 99, 100); (104, 105, 106/110, 111, 112); (11 6, 117, 118/122, 123, 124); (128, 129, 130/134, 135, 136); (140, 141, 142/146, 147, 148); (152, 153, 154/158, 159, 160); (164, 165, 166/170, 171, 172); (176, 177, 178/182, 183, 184); (188, 189, 190/194, 195, 1 96); (200, 201, 202/206, 207, 208); (212, 213, 214/218, 219, 220); (224, 225, 226/230, 231, 232); (236, 237, 238/242, 243, 244); (248, 249, 250/254, 255, 256); (260, 261, 262/266, 267, 268); (272, 273, 274/27 The isolated antibody or its antigen-binding fragment according to claim 6, comprising a (HCDR set/LCDR set) pair selected from the group consisting of (8, 279, 280); (284, 285, 286/290, 291, 292); (296, 297, 298/302, 303, 304); (308, 309, 310/314, 315, 316); and (320, 321, 322/326, 327, 328).
  8. The isolated antibody or its antigen-binding fragment according to claim 7, comprising an HC/LC pair selected from the group consisting of SEQ ID NOs: 17/23, 29/35, 41/47, 53/59, 65/71, 77/83, 89/95, 101/107, 113/119, 125/131, 137/143, 149/155, 161/167, 173/179, 185/191, 197/203, 209/215, 221/227, 233/239, 245/251, 257/263, 269/275, 281/287, 283/289, 305/311, and 317/323.
  9. An isolated antibody or antigen-binding fragment thereof that binds to the human cannabinoid type 1 receptor (CB1) (SEQ ID NO: 1), wherein the antibody comprises a variable weight (VH) domain sequence CDR and a variable light (VL) domain sequence CDR, wherein the VH domain sequence is one of the SEQ ID NOs: 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, 246, 258, 270, 282, 294, 306, and 318 The isolated antibody or its antigen-binding fragment, having at least 95% identity to an amino acid sequence selected from the group consisting of [specific sequences], and/or the VL domain sequence having at least 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, 312, and 324.
  10. The isolated antibody or its antigen-binding fragment according to claim 9, wherein the VH is represented by SEQ ID NO: 114 and the VL is represented by SEQ ID NO: 120.
  11. The isolated antibody or its antigen-binding fragment according to claim 9, wherein the VH is represented by SEQ ID NO: 126 and the VL is represented by SEQ ID NO: 132.
  12. The isolated antibody or its antigen-binding fragment according to claim 9, wherein the VH is represented by SEQ ID NO: 138 and the VL is represented by SEQ ID NO: 144.
  13. The isolated antibody or its antigen-binding fragment according to claim 9, wherein the VH is represented by SEQ ID NO: 150 and the VL is represented by SEQ ID NO: 156.
  14. The isolated antibody or its antigen-binding fragment according to claim 9, wherein the VH is represented by SEQ ID NO: 162 and the VL is represented by SEQ ID NO: 168.
  15. The isolated antibody or its antigen-binding fragment according to claim 9, wherein the VH is represented by SEQ ID NO: 174 and the VL is represented by SEQ ID NO: 180.
  16. The isolated antibody or its antigen-binding fragment according to claim 9, wherein the VH is represented by SEQ ID NO: 186 and the VL is represented by SEQ ID NO: 192.
  17. The isolated antibody or its antigen-binding fragment according to claim 9, wherein the VH is represented by SEQ ID NO: 198 and the VL is represented by SEQ ID NO: 204.
  18. The isolated antibody or its antigen-binding fragment according to claim 9, wherein the VH is represented by SEQ ID NO: 210 and the VL is represented by SEQ ID NO: 216.
  19. The isolated antibody or its antigen-binding fragment according to claim 9, wherein the VH is represented by SEQ ID NO: 222 and the VL is represented by SEQ ID NO: 228.
  20. The isolated antibody or its antigen-binding fragment according to claim 9, wherein the VH is represented by SEQ ID NO: 234 and the VL is represented by SEQ ID NO: 240.

Description

Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 62/664,882 filed April 30, 2018, the entire disclosure of which is incorporated herein by reference. This invention relates to a cannabinoid receptor type 1 (CB1) binding protein and its use. Incorporation by Reference: The contents of all cited references (including references, patents, patent applications, and websites) that may be cited throughout this application are incorporated herein by reference in their entirety for all purposes, as are the cited references. Unless otherwise indicated, this disclosure utilizes the prior art of immunology, molecular biology, cell biology, drug development, and drug delivery. Cannabinoid receptor 1 (CB1) is a seven-transmembrane cell membrane receptor belonging to the G protein-coupled receptor superfamily, primarily expressed in the brain, and also in the periphery, including the lungs, liver, kidneys, and adipose tissue. CB1 is activated by naturally occurring cannabinoids called endocannabinoids (such as eicosinoids), or by cannabinoids introduced into the body (such as cannabis), or by related synthetic compounds. Cannabinoids bind to CB1 reversibly and stereoselectively. Following engagement with CB1, multiple intracellular signaling pathways are activated, resulting in inhibition of adenylyl cyclase and activation of mitogen-activated protein (MAP) kinase, inhibition of presynaptic N-type and P/Q-type calcium channels and D-type outward-facing potassium channels, and inward rectification and activation of A-type outward-facing potassium channels. CB1 expression is thought to regulate neurotransmitter release by preventing excessive neuronal activity, thereby reducing pain and other inflammatory symptoms, and further regulating food intake. Abnormal CB1 activity is associated with several diseases, including obesity and related disorders such as dyslipidemia, diabetes, fibrosis, liver diseases such as fatty liver, kidney diseases, cardiovascular diseases, and cancer. Prader-Willi syndrome (PWS) is a genetic disorder caused by a deletion of a specific paternal gene, characterized by obesity, type 2 diabetes, growth retardation, and muscle weakness. CB-1 has been identified as a target of the inverse agonist limonabant in PWS (Motaghedi et al. (2011) Eur. J. Med. Genet. 54:14-18). Limonabant (SR141716, also known as Acomplaia and Zimulti) is an appetite-suppressing anti-obesity drug developed and marketed by Sanofi-Aventis as an oral central CB1 antagonist. This product is indicated for the treatment of obese and overweight patients with associated risk factors such as type 2 diabetes or dyslipidemia, in conjunction with diet and exercise. In June 2006, this drug was approved by the EMEA for obesity. In 2008, Sanofi-Aventis suspended all development and marketing of the drug for all indications due to the risk of serious psychiatric problems, including suicidal ideation. In January 2009, the EC suspended the drug's marketing authorization. Another inverse agonist, taranabant (MK-0364), was studied by Merck, but its Phase 3 trial was discontinued due to high levels of side effects, including depression and anxiety. Several other CB1 inverse agonists (e.g., AM251, AM1387, and AM4113) and antagonists (e.g., cannabigerol, ibipinabant, otenabant, surinabant, tetrahydrocannabivarin, and virodamine) are being studied, but they are either in the early stages of research or have been downgraded to non-human studies due to CNS side effects. Several CB-1 inverse agonists/antagonists are under development that target CB1, primarily expressed in the periphery, by limiting the ability of CB-1 inverse agonists/antagonists to cross the blood-brain barrier (BBB). For example, TM-38837 is a Phase 1 CB1 inverse agonist/antagonist under development by 7TM Pharma A/S to treat obesity and metabolic disorders. Another peripherally selective silent antagonist not yet in clinical practice is AM6545. Peripherally selective CB-1 antagonistism may be a safer and more effective method for targeting peripheral endocannabinoid activity in several tissues, namely: (1) liver – decreased lipid synthesis, fat storage, and glucose secretion; (2) muscle – increased glucose uptake and oxidation; (3) adipocytes – decreased lipid synthesis and fat storage; decreased adiponectin synthesis; and (4) gastrointestinal tract (GI) – increased satiety, GI transit, and absorption (Kloet and Woods (2009) Endocrinol. 150:2531-2536). Biomolecules such as antibodies and associated binding proteins offer potentially safer and more effective methods for delivering therapeutic agents while avoiding CNS damage and side effects. Generally, only about 0.1% of circulating antibodies exceed the intact blood-brain barrier (BBB) (Poduslo et al. (1994) Proc. Natl. Acad. Sci. USA 91:5705-5709; Yu and Watts (2013) Neurotherapeut. 10:459-472). Therefore, the inherently low exposure of the CNS to functional anti-CB1