Abstract 7018: Antibody-degrader conjugates unlock the therapeutic potential of heterobifunctional degraders through antibody-like pharmacokinetics and excellent in vivo efficacy

Abstract Heterobifunctional small molecules recruiting the proteasomal machinery enable the targeted protein degradation (TPD) of selected proteins and considerably broaden the druggable space for therapeutic use. Many such molecules have seen fantastic success in preclinical and clinical developments, e.g., for targeted degradation of specific oncoproteins that were previously inaccessible for cancer therapy. Even though early hits are quickly generated by adapting the modular concept of bifunctional degraders, most of such molecules are against the central rules of a “drug-like” molecule: they are usually larger in size (800-1500 Da) and often lack sufficient solubility. These early bifunctional degraders hits require exhaustive structure optimization in each case to optimize pharmacokinetics (PK) profiles and bioavailability. Here, we report Tubulis’ antibody-degrader conjugates that exploit bifunctional degraders as high-potency bioactive payloads to be released specifically inside cells that are targeted by the antibody. Our linker technology ensures high degrader-to-antibody ratios (DARs) and excellent linker stability in blood plasma. Moreover, we liberate the degrader after receptor-mediated uptake of the ADC and show high efficiencies in target protein degradation. Most importantly, our conjugates exhibit antibody-like PK properties that ensure long-lasting plasma circulation of high DAR constructs over weeks, even when bifunctional degraders are employed that have not been optimized for PK properties. Taken together, these factors allow impressive in vivo efficacy of the conjugates after single dose application in preclinical animal models. Citation Format: Jan G. Felber, Anil P. Jagtap, Philipp Ochtrop, Saskia Schmitt, Isabelle Mai, Sarah Herterich, Paul Machui, Dietmar König, Dominik simon vogt, Schumacher, Jonas Helma-Smets, Annette Vogl, Marc-André Kasper. Antibody-degrader conjugates unlock the therapeutic potential of heterobifunctional degraders through antibody-like pharmacokinetics and excellent in vivo efficacy [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 7018.