Abstract 1538: Revisiting the dogma of antibody drug conjugates (ADCs): Emerging data challenge the benefit of linker stability and the primacy of payload delivery

Antibody drug conjugates (ADCs) are an effective class of cancer therapeutics which have become more prominent after eight FDA approvals in the past three years. ADCs are envisioned to enable the selective delivery of a potent drug to cells that express the antibody target while sparing normal tissues, and thus to improve the therapeutic window by both increasing the maximum tolerated dose (MTD) and decreasing the minimum efficacious dose (MED) of the conjugated drug. Mounting clinical evidence does not support this simplified paradigm [1]. Herein we focus on three prominent issues in ADC development: 1. Alternative mechanisms over and above direct tumor targeting are likely to contribute to ADC therapeutic benefits in the clinic [2]. The responses to certain ADCs in patients with different levels of target antigen expression reveal some target-independent antitumor effects, suggesting the possibility that circulating payload may contribute to efficacy. 2. The preclinical optimization of ADCs is based on efficacy and tolerability in non-human animal studies. Fundamental differences in biology and translatability between species potentially overemphasize the importance of linker stability. 3. Clinical data, although limited, does not support the idea that increased ADC stability drives substantial therapeutic benefit. None of the 13 approved ADCs are completely ‘stable’ in circulation, and more stable drug-linkers have been associated with alternative toxicity profiles and no significant improvement in MTD. Novel meta-analyses and case studies assembled and integrated from >40 approved or clinically active ADCs and >70 discontinued ADCs will be presented in support of these three perspectives. The ADCs included in the analysis differ in terms of payload class, linker type, conjugation chemistry, drug-to-antibody ratio, and antibody target. Gaining a better understanding of the mechanism(s) of action of effective ADCs and the interrelationship between ADC structural components and their pharmacokinetics and pharmacodynamics is critical to inform the next generation of ADCs. References: [1] Colombo, R.; Rich, J. R., The therapeutic window of antibody drug conjugates: A dogma in need of revision. Cancer Cell 2022, 40, 1255-1263. [2] Tarcsa, E.; Guffroy, M. R.; Falahatpisheh, H.; Phipps, C.; Kalvass, J. C., Antibody-drug conjugates as targeted therapies: Are we there yet? A critical review of the current clinical landscape. Drug Discovery Today: Technologies 20