Abstract 2967: Preclinical development of a B7-H3-targeting ADC with a novel DNA topoisomerase I inhibitor for solid tumors

Abstract

Abstract Introduction: B7-H3 (CD276) is an immunomodulatory protein of the B7 superfamily molecules, it is overexpressed in a wide range of solid tumors. B7-H3 overexpression often correlates with poor survival and higher tumor grade, it has become an attractive target for the development of novel cancer therapies recently. B7-H3 targeting antibody-drug conjugates (ADCs), such as MGC018 and DS7300a, have shown preliminary clinical efficacy. DB-1311 is a B7-H3 targeting ADC comprised of a humanized B7-H3 antibody conjugated to a novel DNA topoisomerase I inhibitor P1021 via a cleavable linker. We herein report preclinical efficacy and safety data of DB-1311 and its differentiation from DS7300a. Methods: The binding of anti-B7-H3 to other B7 family members were evaluated via ELISA and SPR. Anti-B7-H3 antibody was conjugated to P1021 with different Drug-Antibody-Ratio (DAR) values. The efficacy of B7-H3 ADCs with different DAR values was tested in vivo, pharmacokinetics and safety profile were evaluated in cynomolgus monkeys. Based on potency and toxicity analysis, DB-1311, an ADC with DAR6, was selected for preclinical development. In vitro and in vivo studies were then conducted with DB-1311 to further investigate its pharmacological effects. Results: B7-H3 antibody with DAR6 demonstrated higher efficacy than its DAR4 counterpart in lung cancer (Calu6), glioma(U87MG) and prostate cancer (PC-3) models. In monkeys, the DAR6 ADC showed good stability and dose-proportionally increased exposure. Additionally, it was well tolerated with repeat dose administration up to 80 mg/kg and didn’t show significantly worse toxicities than DAR4 counterpart. In preclinical study, DB-1311 demonstrated specific, dose-dependent cytotoxicity toward B7-H3-positive tumor cell lines in vitro and potent antitumor activity in vivo but minimum tumor growth inhibition activity in a B7-H3 negative xenograft model. Moreover, DB-1311 showed more potent antitumor activity than DS7300a analogue in vitro and in vivo. Conclusions: DB-1311, a preclinical B7-H3 ADC candidate, with a DAR value of approximately 6, exhibited potent cytotoxicity in vitro and antitumor activity in vivo toward a range of B7-H3-expressing tumor cell lines representing several cancer types and was well tolerated in cynomolgus monkeys with promising pharmacokinetics characteristics. The preclinical antitumor activity and safety profile warrants further development of DB-1311 to evaluate its efficacy and safety in clinical studies. Citation Format: Chenggang Li, Jun Yao, Chen Qu, Bing Li, Yu Zhang, Rong Shi, Yang Qiu, Haiqing Hua. Preclinical development of a B7-H3-targeting ADC with a novel DNA topoisomerase I inhibitor for solid tumors [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 2967.