Abstract 5468: A novel kinase degrader antibody conjugate for the treatment of mCRPC

Abstract Antibody Drug Conjugates (ADCs) represent an efficacious therapeutic modality. However, the classical payloads currently employed are limited in diversity, targeting mostly DNA, topoisomerases or tubulin and are sensitive to developing resistance. The high off-tumor toxicity observed with these payloads furthermore leads to a narrow therapeutic window. To overcome these challenges there is an urgent need for novel payloads that have a different mechanism of action and a more benign free-payload toxicity profile. Kinases play an essential role in the development and growth of many different cancers and thus form a target class of particular interest for novel payloads. To date, over 80 kinase inhibitors have been developed as therapeutic agents. The vast majority, however, lacks the potency required for an ADC payload. One of the main reasons for this is their inability to abrogate the scaffolding function of kinases, which is known to contribute to their oncogenic signaling. For this reason, heterobifunctional kinase degraders have gained interest. These are small molecules that mediate the degradation of a kinase-of-interest by the proteasome. Their catalytic functionality endows them with high potency. An ADC with a degrader-based payload is generally referred to as a Degrader Antibody Conjugate (DAC). We selected a cell cycle kinase that is known to be a tumor driver in many types of cancer. Knocking down this kinase using CRISPR technology is cytotoxic to many cancer cell lines representing major tumor indications (DepMap database). Using libraries of kinase ligands, spacers and E3 ligase ligands we identified degraders that rapidly and deeply degrade the kinase target and have potent antiproliferative activity in cancer cell lines, including those resistant to classical payloads. Degrader payloads were further selected for high microsomal lability, predicting rapid liver clearance, contributing to a more benign free payload toxicity profile. Mechanistic studies show that our lead degrader has a unique mode of action that results in complete cell cycle disruption, leading to DNA damage and potent immunogenic cell death. Our lead degrader was coupled to various maleimide-based hydrophilic linkers and conjugated to clinically validated antibodies to generate DACs. The high hydrophilicity of the linker-degrader combination allows for the generation of DACs up to DAR8 while retaining good monomericity and stability. Active DACs for various indications were generated, showing the wide applicability of our cell cycle kinase degrader-based payload. Our lead DAC for the treatment of metastatic castrate resistant prostate cancer (mCRPC) shows sub-nanomolar cytotoxic activity, potent target degradation, and effective bystander kill. The lead DAC was tested in a therapeutic in vivo xenograft model for prostate cancer and is currently progressing towards clinical development for mCRPC. Citation Format: Joost C. Uitdehaag, Jos de Man, Freek van Cauter, Sander P. van Gemert, Yvonne G.T. van Mil, Milan J. Hoffmann, Daphne Montizaan, Winfried R. Mulder, Michelle Muller, Martine B. Prinsen, Jan Gerard Sterrenburg, Diep Vu, Joeri J. de Wit, Erik Ensing, Rogier C. Buijsman. A novel kinase degrader antibody conjugate for the treatment of mCRPC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5468.