Abstract 1884: DB-1310, a novel Her3 targeting antibody-drug conjugate, exhibits therapeutic efficacy for solid tumors

Abstract

Abstract Background: HER3 (ErbB3), a member of the human epidermal growth factor receptor family, is frequently overexpressed in various cancers. Its high expression is associated with poor prognosis in several solid tumors. Many anti-Her3 antibodies have been developed for cancer therapy. To date, only patritumab deruxtecan (U3-1402) showed clinical efficacy in both NSCLC and breast cancer among all Her3-targeting therapies. DB-1310 is a HER3 ADC composed of a novel humanized anti-Her3 immunoglobulin G1 (IgG1) monoclonal antibody, covalently linked to a proprietary DNA topoisomerase I inhibitor payload via a maleimide tetrapeptide-based cleavable linker with a drug antibody ratio (DAR) of approximately eight. In the present study, we aim to evaluate the efficacy and safety of DB-1310 in preclinical models. Methods: The binding of DB-1310 to Her3 and other HER families was measured by ELISA and SPR. The competition of binding epitope for DB-1310 and patritumab was tested by FACS. The sensitivity of breast cancer and lung cancer cell lines to DB-1310 was evaluated by in vitro cell killing assay. In vivo growth inhibition study evaluated the sensitivity of DB-1310 to Her3-positive breast cancer and lung cancer xenograft models. In addition, the efficacy of DB-1310 was compared to that of patritumab deruxtecan in tumor xenograft models. The pharmacokinetics and safety profile were also measured in cynomolgus monkey. Results: In this study, DB-1310 showed high affinity to both Human and Cyno Her3 without cross reacting with Her2, Her4 or EGFR. DB-1310 binds Her3 using a different epitope from patritumab. DB-1310 has high internalization capability and translocates into lysosomes after internalization. In vitro, DB-1310 exhibited cytotoxicity in a panel of Her3- expression human breast cancer and lung cancer cell lines. It also showed dose-dependent antitumor killing activity in a HER3-positive breast cancer HCC1569 xenograft model and a lung cancer NCI-H441 xenograft model. Tumor regression was observed in a NSCLC patient-derived xenograft model with EGFR mutation under DB-1310 treatment. Moreover, DB-1310 showed stronger tumor growth inhibition than that of patritumab deruxtecan at the same dose. The systemic exposure AUC0-last and Cmax of DB-1310 and total antibody increased dose proportionally from 1 mg/kg to 10 mg/kg with low released payload in serum. The DB-1310 also showed good safety profile with highest non-severely toxic dose (HNSTD) above 30mg/kg. Conclusions: DB-1310 exhibited its efficacy in tumor models both in vitro and in vivo. These studies suggest that DB-1310 as a novel HER3-targeting ADC showed antitumor efficacy for HER3 positive tumors with good safety profile. Citation Format: Xi Li, Jun Yao, Chen Qu, Luo Lan, Bing Li, Yu Zhang, Rong Shi, Haiqing Hua, Yang Qiu. DB-1310, a novel Her3 targeting antibody-drug conjugate, exhibits therapeutic efficacy 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 1884.