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CN-122029202-A - GUCY2C antibodies and uses thereof

CN122029202ACN 122029202 ACN122029202 ACN 122029202ACN-122029202-A

Abstract

Disclosed herein are antibodies or antigen-binding fragments thereof that bind guanylate cyclase C (GUCY 2C), multispecific antibodies comprising the same, and methods of treating cancer using the same.

Inventors

  • J.He
  • L. BAKER
  • LUO JINQUAN
  • E. Prinzlo
  • A. Zvorak
  • C. Tilerenova

Assignees

  • 詹森生物科技公司

Dates

Publication Date
20260512
Application Date
20240806
Priority Date
20230807

Claims (20)

  1. 1. An isolated antibody or antigen binding fragment thereof comprising a first binding domain, wherein the first binding domain binds guanylate cyclase C (GUCY 2C), and wherein the first binding domain comprises a first heavy chain complementarity determining region (HCDR) 1 of the first heavy chain variable region (VH 1) of SEQ ID No. 7, a first HCDR2 and a first HCDR3, and a first light chain complementarity determining region (LCDR) 1 of the first light chain variable region (VL 1) of SEQ ID No. 8, a first LCDR2 and a first LCDR3, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 amino acid sequences are preferably according to Kabat numbering system, chothia numbering system, abM numbering system, act numbering system or IMGT numbering system or a combination thereof, preferably according to Kabat numbering system, chothia numbering system, abM numbering system, contact numbering system or IMGT.
  2. 2. The isolated antibody or antigen-binding fragment thereof of claim 1, which specifically binds to GUCY2C.
  3. 3. The isolated antibody or antigen-binding fragment thereof of claim 1 or 2, wherein the first binding domain comprises the first HCDR1, the first HCDR2, the first HCDR3, the first LCDR1, the first LCDR2, and the first LCDR3 of: a. SEQ ID NO 1,2, 3, 4, 5, 6; b. SEQ ID NOs 23, 24, 3, 4, 5 and 6, respectively; c. 25, 26, 3, 4, 5 and 6 respectively, or D. SEQ ID NOS 27, 28, 79, 29, 30 and 32, respectively.
  4. 4. The isolated antibody or antigen-binding fragment thereof of any one of claims 1 to 3, wherein the VH1 comprises an amino acid sequence with at least 90%, or at least 95%, or at least 98%, at least 99%, or 100% identity to SEQ ID No. 7.
  5. 5. The isolated antibody or antigen-binding fragment thereof of any one of claims 1 to 4, wherein the VL1 comprises an amino acid sequence having at least 90%, or at least 95%, or at least 98%, or at least 99% or 100% identity to SEQ ID No. 8.
  6. 6. The isolated antibody or antigen-binding fragment thereof of any one of claims 1 to 5, wherein the VH1 comprises the amino acid sequence of SEQ ID No. 7, and the VL1 comprises the amino acid sequence of SEQ ID No. 8.
  7. 7. The isolated antibody or antigen-binding fragment thereof of any one of claims 1 to 6, wherein the first binding domain is or comprises an antibody fragment selected from the group consisting of Fv fragment, single chain fragment (scFv), (scFv) 2 , single chain disulfide stabilizing fragment, stapled scFv fragment (spFv), fab, F (ab') 2 , dAb, VHH, and single chain antibody.
  8. 8. The isolated antibody or antigen-binding fragment thereof of any one of claims 1 to 7, wherein the first binding domain is or comprises a Fab.
  9. 9. The isolated antibody or antigen-binding fragment thereof of any one of claims 1 to 8, which is monospecific.
  10. 10. The isolated antibody or antigen-binding fragment thereof of any one of claims 1 to 8, which is multispecific.
  11. 11. The isolated antibody or antigen-binding fragment thereof of claim 10, which is bispecific.
  12. 12. The isolated antibody or antigen-binding fragment thereof of claim 10, which is trispecific.
  13. 13. The isolated antibody or antigen-binding fragment thereof of any one of claims 10 to 12, further comprising a second binding domain that binds an antigen on a lymphocyte.
  14. 14. The isolated antibody or antigen-binding fragment thereof of claim 13, wherein the lymphocyte is a T cell.
  15. 15. The isolated antibody or antigen-binding fragment thereof of claim 14, wherein the T cell is a CD8 + T cell.
  16. 16. The isolated antibody or antigen-binding fragment thereof of claim 13, wherein the lymphocyte is a Natural Killer (NK) cell.
  17. 17. The isolated antibody or antigen-binding fragment thereof of claim 13, wherein the antigen on the lymphocyte is CD3, CD8, BTNL3, CD186, BTNL8, PD-1, or CD195.
  18. 18. The isolated antibody or antigen-binding fragment thereof of claim 13, wherein the antigen on the lymphocyte is KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, or NKG2C.
  19. 19. The isolated antibody or antigen-binding fragment thereof of any one of claims 13 to 15 and 17, wherein the second binding domain binds to CD3 epsilon (CD 3 epsilon).
  20. 20. The isolated antibody or antigen-binding fragment thereof of any one of claims 13 to 15, 17 and 19, which binds or specifically binds to GUCY2C and CD3 epsilon.

Description

GUCY2C antibodies and uses thereof Cross Reference to Related Applications The present application claims priority from U.S. provisional application No. 63/518,041 filed 8/7 of 2023 and U.S. provisional application No. 63/612,000 filed 12/19 of 2023, the disclosures of each of which are incorporated herein by reference in their entirety. Sequence listing The present application encompasses a sequence table that has been electronically submitted in XML format and is hereby incorporated by reference in its entirety. This XML copy was created at 2024, 7, 23, named JBI6829PCT1.XML and was 85KB in size. Technical Field Antibodies or antigen binding fragments thereof that bind guanylate cyclase 2C (GUCY 2C), multispecific antibodies comprising the same, and methods of treating cancer using the same are provided. Background Gastroesophageal and pancreatic Cancer are one of the malignant tumors with the highest unmet medical need (Devesa SS. et al, cancer 1988; 83:2049-53). Gastric cancer is the second leading cause of cancer death worldwide (Karami P, cancer Epidemiol Biomarkers prev.2014, 23 (5): 700-713). The incidence of esophageal cancer has increased in recent decades. In 2002, about 4,000,000 people worldwide have had gastroesophageal cancer, and 1,100,000 people die (Kamangar, F. Et al, J Clin Oncol 2006; 24 (14): 2137-50). Despite the aggressiveness of established standard treatments, associated with a large number of side effects, the overall 5-year survival rate of gastroesophageal cancer is 20% to 25% (Sahin U, CLIN CANCER RES 2008:2008 (23), 7624-7634). For pancreatic cancer, the medical need is even greater. The prognosis is extremely poor due to the advanced status of the disease at diagnosis, median survival time is less than 6 months, and 5 year survival rate <5.5%. Due to the lack of cancer specific targets, solid tumors have become a challenge for antibody-mediated T cell reorientation, leading to toxicity at sub-effective doses. Thus, the unmet need for solid tumors remains high in terms of extending and improving patient outcome and overall treatment duration. Today, even if the best treatment options are available, the prognosis of advanced gastric cancer is poor. Only 68% of patients receive first-line therapy for their disease. Efforts to stratify Gastroesophageal (GEJ) patients have been attempted, but the resulting impact is less than desired. There remains a high need for more improved treatments and effective therapies for patients with gastric/GEJ cancers. Colorectal cancer (CRC) is the fourth leading cause of cancer and the second leading cause of cancer-related death in the united states and world. Although surgical excision of the primary tumor may be curative, particularly at an early stage of the disease, about 50% of colorectal cancer patients eventually die from distant metastasis. Although chemotherapy, radiation therapy and targeted therapies extend survival to about 24 months, less than 15% of metastatic CRC patients survive for more than 5 years, highlighting the unmet need for a new therapeutic paradigm for this disease. Guanylate cyclase 2C (GUCY 2C) (also known as guanylate cyclase C (GC-C)), enteroguanylate cyclase, guanylate cyclase-C receptor or thermostable enterotoxin receptor (hSTAR) are enzymes found in the luminal surface of the intestinal epithelium and dopamine neurons in the brain (GenBank accession No. NM-004963 and GenPept accession No. NP-004954). The receptor has an extracellular ligand binding domain, a single transmembrane region, a region having a sequence similar to that of a protein kinase, and a C-terminal guanylate cyclase domain. Cell surface expression of GUCY2C is limited to the apical surface of intestinal epithelial cells and shows limited expression in human and mouse extra-intestinal tissues. Importantly, GUCY2C is a cancer mucosal antigen that is ubiquitously overexpressed by primary and metastatic human colorectal cancers and ectopically expressed in esophageal and gastric cancers associated with intestinal dysplasia. Furthermore, anatomical separation of the GUCY2C on the luminal surface of the intestinal epithelium limits access to the globally delivered GUCY2C targeting molecule, allowing diagnostic imaging and monoclonal antibody-based therapies for colorectal cancer metastasis without recognizing the intestinal epithelium. Disclosure of Invention Provided herein is an isolated antibody or antigen binding fragment thereof that binds to GUCY2C comprising heavy chain complementarity determining region 1 (HCDR 1), HCDR2 and HCDR3 of VH1 comprising the amino acid sequence of SEQ ID NO: 7, and heavy chain complementarity determining region 1 (LCDR 1), LCDR2 and LCDR3 of VL1 comprising the amino acid sequence of SEQ ID NO: 8, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 amino acid sequences are preferably according to Kabat numbering system, chothia numbering system, abM numbering system, IMGT numbering system or Contact numbering sy