Abstract Therapeutic applications for Antibody Drug Conjugates (ADCs) continue to expand, and it is expected that they will become a mainstay therapy in many cancer indications. Most ADCs in clinical development however utilize a limited selection of payloads. These are potent and efficacious but are also known to induce problematic off-tumor related toxicities. Moreover, this widespread use of a limited set of topoisomerase or tubulin binding payloads increasingly causes clinical resistance to entire classes of ADC-based therapies that are all based on the same payload. Expanding the limited payload arsenal with novel payloads is therefore urgently needed. Kinases play an essential role in the development and growth of many different cancers, and form an interesting target class for novel payloads. We have identified PLK1 kinase as a particular vulnerability in many types of cancer. High PLK1 expression often correlates with poor patient survival, and many cancer cells are highly sensitive to inhibition or knockout of PLK1. We generated a novel heterobifunctional PLK1 degrader with an average sub-nanomolar IC50 in a large in vitro cancer cell line proliferation panel. Our PLK1 degrader has all characteristics needed for a functional payload and because of its unique mechanism of action compared to classic ADC payloads, it can potently kill cancer cell lines that are resistant or refractory to classical payloads like DXd or MMAE. The PLK1 degrader payload is designed in such a way that it is rapidly removed from circulation once it diffuses out of the tumor into the vascular system. This reduces the risk of off-tumor related toxicity. PLK1 Degrader Antibody Conjugates (DACs) can be manufactured up to DAR8 without stability issues and have antibody-like pharmacokinetic properties. PLK1 DACs degrade all intracellular PLK1 within 48 hours and disrupt mitosis and the pre-replication complex, leading to severe DNA damage and apoptosis, which is consistent with the mechanism reported for PLK1 knockdown. The promise of our DAC technology was confirmed in vivo in a therapeutic triple negative breast cancer (MDA-MB-468) model where rapid tumor regression was achieved. Our PLK1 degrader-based DAC technology is broadly applicable and offers new treatment opportunities to cancer patients who are resistant or refractory to ADCs that carry classical payloads. Citation Format: Joost C. Uitdehaag, Jos de Man, Freek van Cauter, Sander P. van Gemert, Yvonne G. van Mil, Daphne Montizaan, Winfried R. Mulder, Michelle Muller, Martine B. Prinsen, Joost A. Rens, Jan-Gerard Sterrenburg, Diep Vu, Joeri J. de Wit, Erik Ensing, Rogier C. Buijsman. In vivo characterization of a PLK1 degrader antibody conjugate for treatment of DXd and MMAE refractory tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4394.
Uitdehaag et al. (2026) studied this question.