Abstract 6341: Preclinical development of a monoclonal antibody targeting CD70 as cancer immunotherapy

Abstract

Abstract CD70 is a novel immune checkpoint highly expressed on cancers of kidney, blood and lymphoid tissues, mesothelium and gastrointestinal system. High expression of CD70 is a prognostic marker for poor survival in patients with ovarian carcinoma, pancreatic cancer and mesothelioma, etc. Several CD70 antibodies are under early stages of clinical trials for oncology indications. We have developed IMM40H, a humanized IgG1 antibody that differentially induces phagocytosis and cytotoxicity in CD70-expressing cancer cells. Results of in vitro study have demonstrated that, in comparison with cusatuzumab, IMM40H possesses better CD70 binding (kD= 3.22E-11M) and functional inhibition ability, as well as more potent activities of ADCC (antibody-dependent cellular cytotoxicity, EC50 = 0.5 -2.0ng/ml) and CDC (complement-dependent cytotoxicity, EC50 = 170 ng/mL) against certain cancer cells. IMM40H also induces strong ADCP (antibody-dependent cellular phagocytosis) activity (EC50 = 0.02nM). At doses between 0.3 mg/kg to 10mg/kg, IMM40H significantly reduced tumor volume in mouse models of multiple myeloma, lymphoma and kidney cancer. Notably, in a U266 multiple myeloma model, IMM40H, at the dose of 0.3 mg/kg, completely inhibited tumor growth in a way that therapeutic effects appeared significantly earlier than that of cusatuzumab at a higher dose of 1 mg/kg. Therapeutic effects of IMM40H at the dose of 3 mg/kg also appeared earlier than that of bortezomib at the dose of 0.5 mg/kg. Interestingly, combination of IMM40H and IMM01 (a SIRPα-IgG1 Fc fusion protein targeting CD47) generated significant therapeutic synergy in models of A498 kidney cancer and Raji lymphoma. Importantly, maximum tolerated dose of IMM40H exceeds 100 mg/kg (IV, single dose) in cynomolgus monkeys and no significant adverse reaction was observed at a dose range of 3 to 30 mg/kg (IV, QW, 5 times) in monkeys. Taken together, our data show that targeting CD70 on tumor cells using IMM40H antibody may serve as a potent immunotherapy for multiple cancer indications. IND of IMM40H has been approved in China and US. This antibody is now in a phase 1 study in patients with advanced malignancies expressing CD70. Citation Format: Wenzhi Tian, Song Li, Dianze Chen, Dandan Liu, Huiqin Guo, Chunmei Yang, Li Zhang, Wei Zhang, Xiaoping Tu, Liang Peng, Gui Zhao, Ruliang Zhang, Fan Zhang, Frank X. Gan. Preclinical development of a monoclonal antibody targeting CD70 as cancer immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6341.