Abstract 2660: HMBD-501 - a novel Fc engineered, exatecan-based next generation HER3 targeting antibody drug conjugate shows robust efficacy and tolerability in pre-clinical solid tumor models

Abstract

Abstract HER3 is a member of the epidermal growth factor receptor (ERBB) family of tyrosine kinase receptors overexpressed in a broad range of tumors and is associated with disease progression and poor survival. For example, more than 50% of melanoma, cervical, lung, gastric, colorectal, and ovarian cancers show overexpression of HER3, while in breast, pancreatic and prostate cancers the overexpression ranges between 25-40%. In addition, recent studies show that HER3 expression is significantly induced in tumors during metastasis (in colorectal) and during acquired resistance to tyrosine kinase inhibitors (TKI) in lung cancers. This widespread overexpression of HER3 makes it an ideal target for antibody drug conjugates (ADCs). ADCs are a therapeutic modality that harness an antibody’s target specificity to selectively deliver cytotoxic payloads to tumors. Patritumab-Deruxtecan (U3-1402), a HER3-targeting ADC, showed clinical response in a subset of EGFR mutant and TKI resistant lung cancers in a Phase 1 study, albeit with toxicities including severe interstitial lung disease (ILD) and high grade cytopenias. Mechanistic studies show that these ADC-related toxicities are likely driven by Fc- or micropinocytosis-mediated uptake of ADCs by normal cells. We have developed HMBD-501, a novel anti-HER3 ADC with (i) a high-affinity Fab, which can bind to HER3 in the presence or absence of its ligand NRG1, (ii) an engineered Fc-domain to avoid FcgR binding and potential toxicities, and (iii) site-specific conjugation to a next generation cleavable linker and exatecan-based payload. In our preclinical studies, HMBD-501 demonstrates superior inhibition of tumor growth compared to other exatecan-based anti-HER3 ADCs, in a variety of in vitro and in vivo cancer models with a range of HER3 expression. Additionally, the optimized Fc engineering of HMBD-501 shows enhanced tolerability in vivo indicating a potential reduction in Fc mediated toxicities. Finally, the next generation site-specific conjugation-linker-payload technology of HMBD-501 allows optimal plasma stability and pharmacokinetic profile. In conclusion, HMBD-501 represents a next generation HER3 targeting ADC that has a potentially best-in-class efficacy and tolerability profile. Our findings strongly support the development of HMBD-501 as a promising candidate in the treatment of HER3 expressing solid tumors. Citation Format: Suhail Ahmed Kabeer Rasheed, Dipti Thakkar, Shalini Paliwal, Wen Jie Chin, Akshaya Bansal, Ben Ayers, Che Theng ng, Brendon Hanson, Piers Ingram, Jerome Boyd-Kirkup. HMBD-501 - a novel Fc engineered, exatecan-based next generation HER3 targeting antibody drug conjugate shows robust efficacy and tolerability in pre-clinical solid tumor models [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 2660.