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CN-122011199-A - Anti-CD 137 antibodies and methods of use

CN122011199ACN 122011199 ACN122011199 ACN 122011199ACN-122011199-A

Abstract

The present disclosure provides antibodies or antigen-binding fragments thereof that specifically bind to human CD137, multispecific antibodies and antigen-binding fragments thereof that specifically bind to human GPC3 and CD137, pharmaceutical compositions comprising the antibodies, and uses of the antibodies, multispecific antibodies, or compositions for treating a disease such as cancer.

Inventors

  • QU LIANG
  • XUE LIU
  • JI RUYUE
  • YUAN XI
  • LI ZHUO
  • LI JIE
  • SUN JIAN

Assignees

  • 广州百济神州生物制药有限公司

Dates

Publication Date
20260512
Application Date
20231120
Priority Date
20221121

Claims (6)

  1. 1. A multispecific antibody or antigen-binding fragment thereof comprising a first antigen-binding domain that specifically binds to human glypican 3 (GPC 3) and a second antigen-binding domain that specifically binds to human CD137, wherein the multispecific antibody or antigen-binding fragment comprises a first polypeptide of SEQ ID NO: 25 and a second polypeptide of SEQ ID NO: 23.
  2. 2. A multispecific antibody or antigen-binding fragment thereof comprising a first antigen-binding domain that specifically binds to human glypican 3 (GPC 3) and a second antigen-binding domain that specifically binds to human CD137, wherein the multispecific antibody or antigen-binding fragment comprises a first polypeptide of SEQ ID NO: 21 and a second polypeptide of SEQ ID NO: 23.
  3. 3. A multispecific antibody or antigen-binding fragment thereof comprising a first antigen-binding domain that specifically binds to human glypican 3 (GPC 3) and a second antigen-binding domain that specifically binds to human CD137, wherein the multispecific antibody or antigen-binding fragment comprises a first polypeptide of SEQ ID No. 33 and a second polypeptide of SEQ ID No. 23.
  4. 4. A multispecific antibody or antigen-binding fragment thereof comprising a first antigen-binding domain that specifically binds to human glypican 3 (GPC 3) and a second antigen-binding domain that specifically binds to human CD137, wherein the multispecific antibody or antigen-binding fragment comprises a first polypeptide of SEQ ID NO: 27 and a second polypeptide of SEQ ID NO: 23.
  5. 5. A multispecific antibody or antigen-binding fragment thereof comprising a first antigen-binding domain that specifically binds to human glypican 3 (GPC 3) and a second antigen-binding domain that specifically binds to human CD137, wherein the multispecific antibody or antigen-binding fragment comprises a first polypeptide of SEQ ID No. 29 and a second polypeptide of SEQ ID No. 23.
  6. 6. A multispecific antibody or antigen-binding fragment thereof comprising a first antigen-binding domain that specifically binds to human glypican 3 (GPC 3) and a second antigen-binding domain that specifically binds to human CD137, wherein the multispecific antibody or antigen-binding fragment comprises a first polypeptide of SEQ ID NO: 31 and a second polypeptide of SEQ ID NO: 23.

Description

Anti-CD 137 antibodies and methods of use The application is a divisional application of an application patent application with the application date of 2023, 11-20, chinese application number of 202380079710.5 and the application name of anti-CD 137 antibody and using method. Technical Field Disclosed herein are antibodies that specifically bind to human CD137 (TNF receptor superfamily member 9 (TNFRSF 9)), multispecific antibodies that bind to human CD137, or antigen-binding fragments thereof, compositions comprising the antibodies, and methods or uses for treating cancer. Background Glypican 3 (GPC 3) belongs to the family of Heparan Sulfate Proteoglycans (HSPG), comprising 60-70 kD core proteins linked to the cell membrane surface by glycosyl phosphatidylinositol anchors (GPIs). The carboxyl terminus of GPC3 was modified with a heparan sulfate side chain (Filmus J et al J. Clin. Inv. [ J. Clinical study ] 2001; 108:497-501). Specific expression of GPC3 in tumor cells is of great concern. GPC3 is expressed in hepatocellular carcinoma (HCC), the most common type of liver cancer. Notably, no expression was detected in non-malignant tissues. Overexpression of GPC3 is also reported in hepatoblastomas, lung Squamous Cell Carcinoma (LSCC), and other cancers. Thus, GPC3 is suitable as a tumor antigen for targeted therapy. (Li N et al, trends cancer 2018; 4:741-54; ho M, et al, eur J cancer 2011; 47:333-8; moek et al, am. J Pathol [ J.S. Pathology ]2018; 188 (9): 1973-1981). CD137 (also called TNFRSF9/41 BB) is a costimulatory molecule belonging to the TNFRSF family. It was discovered by T-cytokine selection of mouse helper cells and cytotoxic cells stimulated by concanavalin a. It was identified in 1989 as an inducible gene that is expressed on antigen-primed T cells but not on resting T cells (Kwon et al, proc. Natl. Acad. Sci. USA. [ national academy of sciences USA ] 1989; 86:1963-1967). In addition, it is known to be expressed in Dendritic Cells (DCs), natural killer cells (NK) (Vinay et al mol. Cancer Ther. [ molecular Cancer therapeutics ]2012; 11:1062-1070), activated CD4+ and CD8+ T lymphocytes, eosinophils, natural killer T cells (NKT) and mast cells (Kwon et al, 1989 supra; vinay D., int. J. Hematol. [ International journal of hematology ] 2006; 83:23-28). CD137 maintains and enhances immune effector function by inducing Th1 cytokine production (Bartkowiak et al, front Oncol. [ oncology Front ] 2015:117; shuford et al, J Exp Med. [ journal of Experimental medicine ] 1997; 186:47-55). Upon binding to its sole ligand (CD 137L, 4-1BBL or TNFSF 9), activation of CD137 signaling through the NF-. Kappa.B pathway results in increased expression of pro-survival molecules (Wang et al, immunol Rev. [ Immunol comment ]2009; 229:192-215). Anti-CD 137 antibody Wu Ruilu mab (Urelumab) (BMS-663513) that binds to CRD I of CD137 and Wu Tuolu mab (Utomilumab) (PF-05082566) that binds to CRD III and IV of CD137 show potential as cancer therapeutic agents because of their ability to activate cytotoxic T cells and increase production of interferon gamma (IFN- γ). The mechanism by which these antibodies regress tumors is their potentiation of the cancer immune cell response. In particular, anti-CD 137 antibodies stimulate and activate effector T lymphocytes (e.g., by stimulating cd8+ T lymphocytes to produce infγ), and enhance production of NKT and APC (e.g., macrophages). Wu Ruilu mab shows promising results in preclinical experiments and early clinical studies (Sznol et al, clin. Oncol. [ clinical oncology ] 2008; 26 (journal 15)). However, in later studies Wu Ruilu mab showed liver toxicity, resulting in suspension of development of this antibody until month 2 of 2012 (Segal et al, clin. Cancer Res. [ clinical Cancer study ]2017; 23:1929-1936). Hepatotoxicity is primarily due to tumor and stromal cell secreted S100A4 protein, and limiting the dose of Wu Ruilu mab to 8 mg or 0.1 mg/kg per patient every 3 weeks restored the interest in this antibody (Segal et al Clin. Cancer Res. [ clinical Cancer research ]2017; 23:1929-1936). Compared to Wu Ruilu mab Wu Tuolu showed better safety profile and preliminary studies showed no hepatotoxicity or other dose limiting factors (Segal et al, j. Clin. Oncol. [ journal of clinical oncology ] 2014; 32 (journal 15)). The reported results of the Wu Tuolu mab as phase I trial for monotherapy showed good safety profile (Segal et al, clin. Cancer res. [ clinical Cancer research ]2018; 24:1816-1823). The difference between these two antibodies is presumed to be due to their different binding sites at the CD137 receptor. There is no approved therapeutic antibody against CD137 and the medical need for therapeutic agents targeting CD137 remains unmet. In addition, anti-TAAxCD 137 multispecific antibodies that recruit immune cells to cancers that express tumor-associated antigens (TAAs) can be used to treat cancers. Disclosure of Invention The present disclosure contains antibodies and antigen b