Abstract 743: Using a novel NextGen linker system to generate a conditionally active biologic (CAB) anti-nectin4-ADC demonstrates improved efficacy in pancreatic PDX cancer models and improved tolerability and toxicity profile in non-human primates

Abstract Antibody-drug conjugates (ADCs) are a promising treatment for various forms of cancer. The treatment efficacy is often limited by on-target/off-tumor toxicity caused by the antigen expression in healthy tissue and by unwanted payload release outside the tumor caused by cleavage of the linker via circulating proteases. Our conditionally active biologics (CAB) technology addresses the on-target/off-tumor toxicity and assists in reducing the off-target/off-tumor toxicity by reducing binding to the target under normal physiological conditions (1). To eliminate the remaining off-target/off-tumor toxicity, we developed a novel linker with superior serum stability, solubility, and tumor-specific payload release. Conjugation can be accomplished using regular IgG backbones without the need for sequence modification. Here we report the in vitro and in vivo characterization of a NextGen linker system to generate a CAB anti-Nectin4-ADC that combines the advantages of CAB antibody pH selectivity with the new linker technology. In vivo efficacy data demonstrated complete tumor regression in several cell line derived xenograft models as well as superior efficacy to an enfortumab vedotin analogue in a patient derived pancreatic cancer model. PK and tox data from a toxicology study in non-human primates will be presented. In addition, data demonstrating the influence of linker technology on specific cancer models will also be presented. In conclusion, the NextGen Nectin4 CAB ADC represents a potentially more effective treatment with increased safety in the clinic. (1) Chang HW, Frey G, Liu H, Xing C, Steinman L, Boyle WJ, and Short JM Generating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches. Proc Natl Acad Sci U S A 2021;118 Citation Format: Jing Wang, Jian Chen, Gerhard Frey, Haizhen Liu, Charles Xing, Kathryn Woodard, Hwai Chang, William J. Boyle, Jay M. Short. Using a novel NextGen linker system to generate a conditionally active biologic (CAB) anti-nectin4-ADC demonstrates improved efficacy in pancreatic PDX cancer models and improved tolerability and toxicity profile in non-human primates abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 743.