Abstract B112: Experimental antibody-drug conjugate combinations for advanced prostate cancer
Authors: Semenova Galina , Coleman Ilsa , Gulati Roman , Morrissey Colm , Haffner Michael , Nelson Peter S , Lee John K 
Published: February 2025

Abstract
An Antibody-Drug Conjugate (ADC) is a monoclonal antibody targeted against an antigen on the cancer cell surface and is conjugated to a cytotoxic drug (payload) via a chemical linker. To date no ADCs were clinically approved for prostate cancer (PCa) therapy due to a lack of efficacy and systemic toxicity. Rational design of ADCs and development of combinatorial ADC-based approaches may enhance the therapeutic window for the effective treatment of PCa. In this work we (1) analyzed the distribution of ADC target antigens in advanced PCa and (2) explored synergistic interactions between ADC payloads to propose new combination therapy with improved efficacy and cancer specificity. Multiplexed immunofluorescent staining of lethal metastatic castration-resistant prostate cancers (mCRPCs) have shown that majority of androgen receptor regulated (AR+) mCRPCs were double-positive for B7-H3 & STEAP1 or B7-H3 & PSMA or PSMA & STEAP1, nominating these antigen pairs as targets for dual ADC therapy. To identify synergistic ADC payloads, we have designed a custom drug screen that included 23 cytotoxic agents from 3 major payload classes and 78 drug combinations. Validation of screening results in prostate cancer cell lines have demonstrated that Bcl-xl inhibitor A-1331852 interacts synergistically with either DNA-damaging payload tested in the screen, and that isolated loss of p53 can induce resistance to proposed combinations. To introduce these synergistic payloads into ADC approach we obtained 3 genotoxic conjugates (B7-H3 - seco-DUBA, PSMA – SG3249, and STEAP1 – DXd) and tested them as single agents and combined with systemic A-1331852 in p53-proficient and p53-deficient prostate cancer cells. Co-administration of B7-H3 – seco-DUBA ADC with A-1331852 was also tried in mCRPC xenografts with different p53 statuses. Although faster and greater responses to ADC/payload combinations were observed in models with intact p53, addition of systemic A-1331852 improved the efficacy of DNA-damaging ADCs in all models tested in vitro and in vivo. These findings suggest that concurrent use of an ADC bearing DNA-damaging payload with an ADC bearing Bcl-xl inhibitor is a promising therapeutic strategy for the treatment of mCRPC. In conclusion, this work addresses challenges associated with ADC monotherapy in mCRPC and explores the potential of rational ADC combinations. We nominate B7-H3, PSMA, and STEAP1 as targets for ADC co-targeting, and we propose to use DNA-damaging agents and Bcl-xl inhibitor A-1331852 as payloads for dual ADC therapy. Because the prototypes of such ADCs have already demonstrated safety in early phase human studies, the data generated in this work enables near-term clinical development of new agents for mCRPC therapy. To our knowledge, described study is the first to propose the use of ADC combinations for the treatment of mCRPCs. This work was supported by PCF Young Investigator Award to GS
Citation Format: Galina Semenova, Ilsa Coleman, Roman Gulati, Colm Morrissey, Michael Haffner, Peter S Nelson, John K Lee. Experimental antibody-drug conjugate combinations for advanced prostate cancer [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B112.