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US-20260125484-A1 - ANTIBODY CAPABLE OF SPECIFICALLY BINDING TO HUMAN ENDOTHELIN RECEPTOR, AND USE THEREOF IN TREATMENT OF DIABETIC NEPHROPATHY AND CHRONIC NEPHROPATHY

US20260125484A1US 20260125484 A1US20260125484 A1US 20260125484A1US-20260125484-A1

Abstract

Provided herein are an ET A R antibody and a pharmaceutical composition thereof, also provided herein is a method for treating, preventing or ameliorating one or more symptoms of diabetic nephropathy and one or more symptoms of chronic nephropathy.

Inventors

  • Cheng Zhang
  • Shuqian Jing

Assignees

  • GMAX BIOPHARM LLC

Dates

Publication Date
20260507
Application Date
20220330
Priority Date
20210331

Claims (20)

  1. 1 . An antibody capable of specifically binding to ET A R, wherein the antibody comprises one, two, three, four, five or six amino acid sequences, wherein each amino acid sequence is independently selected from the amino acid sequences listed below: a. light chain CDR1 amino acid sequences: SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, and SEQ ID NO: 30; b. light chain CDR2 amino acid sequences: SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, and SEQ ID NO: 48; c. light chain CDR3 amino acid sequences: SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, and SEQ ID NO: 68; d. heavy chain CDR1 amino acid sequences: SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, and SEQ ID NO: 90; e. heavy chain CDR2 amino acid sequences: SEQ ID NO: 92, SEQ ID NO: 94, SEQ ID NO: 96, SEQ ID NO: 98, SEQ ID NO: 100, SEQ ID NO: 102, SEQ ID NO: 104, SEQ ID NO: 106, SEQ ID NO: 108, SEQ ID NO: 110, SEQ ID NO: 112, and SEQ ID NO: 114; and f. heavy chain CDR3 amino acid sequences: SEQ ID NO: 116, SEQ ID NO: 118, SEQ ID NO: 120, SEQ ID NO: 122, SEQ ID NO: 124, SEQ ID NO: 126, SEQ ID NO: 128, SEQ ID NO: 130, SEQ ID NO: 132, SEQ ID NO: 134, and SEQ ID NO: 136.
  2. 2 . The antibody of claim 1 capable of specifically binding to ET A R, wherein the antibody comprises one or two amino acid sequences, wherein each amino acid sequence is independently selected from the amino acid sequences listed below: a. light chain CDR1 amino acid sequences: SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, and SEQ ID NO: 30; and b. heavy chain CDR1 amino acid sequences: SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, and SEQ ID NO: 90.
  3. 3 . The antibody of claim 1 capable of specifically binding to ET A R, wherein the antibody comprises one or two amino acid sequences, wherein each amino acid sequence is independently selected from the amino acid sequences listed below: a. light chain CDR2 amino acid sequences: SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, and SEQ ID NO: 48; and b. heavy chain CDR2 amino acid sequences: SEQ ID NO: 92, SEQ ID NO: 94, SEQ ID NO: 96, SEQ ID NO: 98, SEQ ID NO: 100, SEQ ID NO: 102, SEQ ID NO: 104, SEQ ID NO: 106, SEQ ID NO: 108, SEQ ID NO: 110, SEQ ID NO: 112, and SEQ ID NO: 114.
  4. 4 . The antibody of claim 1 capable of specifically binding to ET A R, wherein the antibody comprises one or two amino acid sequences, wherein each amino acid sequence is independently selected from the amino acid sequences listed below: a. light chain CDR3 amino acid sequences: SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, and SEQ ID NO: 68; and b. heavy chain CDR3 amino acid sequences: SEQ ID NO: 116, SEQ ID NO: 118, SEQ ID NO: 120, SEQ ID NO: 122, SEQ ID NO: 124, SEQ ID NO: 126, SEQ ID NO: 128, SEQ ID NO: 130, SEQ ID NO: 132, SEQ ID NO: 134, and SEQ ID NO: 136.
  5. 5 . (canceled)
  6. 6 . (canceled)
  7. 7 . (canceled)
  8. 8 . The antibody of claim 1 capable of specifically binding to ET A R, wherein the antibody comprises one or two amino acid sequences, wherein each amino acid sequence is independently selected from the amino acid sequences listed below: a. light chain variable domain amino acid sequences: SEQ ID NO: 138, SEQ ID NO: 140, SEQ ID NO: 142, SEQ ID NO: 144, SEQ ID NO: 146, SEQ ID NO: 148, SEQ ID NO: 150, SEQ ID NO: 152, SEQ ID NO: 154, SEQ ID NO: 156, SEQ ID NO: 158, SEQ ID NO: 160, SEQ ID NO: 162, and SEQ ID NO: 164; and b. heavy chain variable domain amino acid sequences: SEQ ID NO: 166, SEQ ID NO: 168, SEQ ID NO: 170, SEQ ID NO: 172, SEQ ID NO: 174, SEQ ID NO: 176, SEQ ID NO: 178, SEQ ID NO: 180, SEQ ID NO: 182, SEQ ID NO: 184, SEQ ID NO: 186, SEQ ID NO: 188, SEQ ID NO: 190, and SEQ ID NO: 192.
  9. 9 . (canceled)
  10. 10 . The antibody of claim 1 capable of specifically binding to ET A R, wherein the antibody comprises a combination of amino acid sequences independently selected from the list below: SEQ ID NO: 138 and SEQ ID NO: 166, SEQ ID NO: 140 and SEQ ID NO: 168, SEQ ID NO: 142 and SEQ ID NO: 170, SEQ ID NO: 144 and SEQ ID NO: 172, SEQ ID NO: 146 and SEQ ID NO: 174, SEQ ID NO: 148 and SEQ ID NO: 176, SEQ ID NO: 150 and SEQ ID NO: 178, SEQ ID NO: 152 and SEQ ID NO: 180, SEQ ID NO: 154 and SEQ ID NO: 182, SEQ ID NO: 156 And SEQ ID NO: 184, SEQ ID NO: 158 and SEQ ID NO: 186, SEQ ID NO: 160 and SEQ ID NO: 188, SEQ ID NO: 162 and SEQ ID NO: 190, and SEQ ID NO: 164 and SEQ ID NO: 192.
  11. 11 . (canceled)
  12. 12 . (canceled)
  13. 13 . (canceled)
  14. 14 . (canceled)
  15. 15 . The antibody of claim 1 capable of specifically binding to ET A R, wherein the antibody comprises a combination of amino acid sequences SEQ ID NO: 162 and SEQ ID NO: 190.
  16. 16 . The antibody of claim 1 capable of specifically binding to ET A R, wherein the antibody comprises one or two amino acid sequences, wherein each amino acid sequence is independently selected from the amino acid sequences listed below: a. light chain constant region amino acid sequences: SEQ ID NO: 194 and SEQ ID NO: 196; and b. a heavy chain constant region amino acid sequence: SEQ ID NO: 198.
  17. 17 . The antibody of claim 1 capable of specifically binding to ET A R, wherein the antibody comprises a murine antibody or a humanized antibody, or the antibody comprises a monoclonal antibody.
  18. 18 . (canceled)
  19. 19 . (canceled)
  20. 20 . The antibody of claim 1 capable of specifically binding to ET A R, wherein the antibody has an IC 50 value of approximately 1 nM to 200 nM or 10 nM to 100 nM in reducing human endothelin signaling.

Description

SEQUENCE LISTING This application incorporates by reference in its entirety the Computer Readable Form of a Sequence Listing in ASCII text format submitted via EFS-Web. The Sequence Listing text file submitted via EFS-Web entitled “087222-8005US01 SeqL_ST25_v2”, was created on Dec. 23, 2025 and is 93,983 bytes in size. TECHNICAL FIELD Provided herein are an ETAR antibody and a pharmaceutical composition thereof. Also provided herein is a method for treating, preventing or ameliorating one or more symptoms of diabetic nephropathy and one or more symptoms of chronic nephropathy. BACKGROUND ART Endothelin is a polypeptide consisting of 21 amino acids with a molecular weight of 2,400 Da, the N-terminus comprises cysteines at positions 1-15 and 3-11 which are linked by two disulfide bonds, and the C-terminus comprises some hydrophobic amino acid residues. The N-terminal structure determines the affinity of endothelin to a receptor, while the C-terminal structure determines the position where endothelin binds to the receptor. There are three subtypes of endothelin (ET), namely ET-1, ET-2, and ET-3. Endothelin receptors (ETRs) include two types: ETAR and ETBR, which belong to G-protein coupled receptors (GPCRs). ET and receptors thereof are widely distributed in human tissues and organs, including cardiovascular system, lungs, renal system, brain, nerve tissues, etc. Renal medulla contains the highest level of ET-1 in the body (Kitamura et al., 1989, BiochemBiophys Res Commun 161: 348-352). Compared with other organs, kidneys are more sensitive to ET-1 (Speed and Pollock, 2013, Hypertension 61: 1142-1145). ET and receptors thereof may be involved in renal injury caused by obesity, hypertension, diabetes, etc., and generally mediated by ETAR. With the development of global economy and the improvement of living standards, the incidence and prevalence of diabetes increase progressively, so that diabetes has become a significant public health problem. Diabetic nephropathy is one of the most important complications of diabetes, affecting 15-25% of patients with type I diabetes and 30-40% of patients with type II diabetes (Schernthaner and Schernthaner, 2013, J Nephrol 26:975-985). SUMMARY OF THE INVENTION Provided herein are an ETAR antibody and a pharmaceutical composition thereof. Also provided herein is a method for treating, preventing or ameliorating one or more symptoms of diabetic nephropathy and one or more symptoms of chronic nephropathy. Provided herein are an ETAR antibody, which comprises one, two, three, four, five or six amino acid sequences, wherein each amino acid sequence is independently selected from the amino acid sequences listed below: a. light chain CDR1 amino acid sequences: SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, and SEQ ID NO: 30;b. light chain CDR2 amino acid sequences: SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, and SEQ ID NO: 48;c. light chain CDR3 amino acid sequences: SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, and SEQ ID NO: 68;d. heavy chain CDR1 amino acid sequences: SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, and SEQ ID NO: 90;e. heavy chain CDR2 amino acid sequences: SEQ ID NO: 92, SEQ ID NO: 94, SEQ ID NO: 96, SEQ ID NO: 98, SEQ ID NO: 100, SEQ ID NO: 102, SEQ ID NO: 104, SEQ ID NO: 106, SEQ ID NO: 108, SEQ ID NO: 110, SEQ ID NO: 112, and SEQ ID NO: 114; andf. heavy chain CDR3 amino acid sequences: SEQ ID NO: 116, SEQ ID NO: 118, SEQ ID NO: 120, SEQ ID NO: 122, SEQ ID NO: 124, SEQ ID NO: 126, SEQ ID NO: 128, SEQ ID NO: 130, SEQ ID NO: 132, SEQ ID NO: 134, and SEQ ID NO: 136. In one embodiment, the ETAR antibody provided herein comprises: a. a light chain CDR1 amino acid sequence: SEQ ID NO: 8b. a light chain CDR2 amino acid sequence: SEQ ID NO: 32c. a light chain CDR3 amino acid sequence: SEQ ID NO: 50d. a heavy chain CDR1 amino acid sequence: SEQ ID NO: 70e. a heavy chain CDR2 amino acid sequence: SEQ ID NO: 92f. a heavy chain CDR3 amino acid sequence: SEQ ID NO: 116. In one embodiment, the ETAR antibody provided herein comprises: a. a light chain CDR1 amino acid sequence: SEQ ID NO: 10b. a light chain CDR2 amino acid sequence: SEQ ID NO: 34c. a light chain CDR3 amino acid sequence: SEQ ID NO: 52d. a heavy chain CDR1 amino acid sequence: SEQ ID NO: 72e. a heavy chain CDR2 amino acid sequence: SEQ ID NO: 94f. a heavy chain CDR3 amino acid sequence: SEQ ID NO: 118. In one embodiment, the ETAR antibody provided herein comprises: a. a light chain CDR1 amino acid sequence: SEQ ID NO: 12b. a light chain CDR2 amino acid sequence: SEQ ID NO: 36c. a light chain CDR3 amino acid sequence: SEQ ID NO: 54d