Abstract 751: A controlled affinity-guided ADC-linker (MAGNET) technology

Abstract

Abstract Antibody-drug conjugates (ADCs) have emerged as a powerful technology in cancer therapy. However, challenges with current linker technologies have limited the repertoire of ADCs. Currently-used linkers result in a heterogeneous mixture, unstable conjugates and/or involve complex processes such as genetic modification of the antibodies. Here, for the first time, we have explored high affinity non-covalent interactions between antibody and affinity ligands to design novel linkers that overcome the above challenges. The affinity ligands-based linkers coupled with payload, enable strong non-covalent association with the antibodies owing to their high specificity and affinity for antibodies without the need for any chemical reaction with the antibody. With a prototype affinity ligand, we demonstrated that the affinity ligand is able to guide the payload to six precise locations on the antibody conferring site-specificity to the resulting ADCs. Significantly, despite non-covalent interactions, the conjugates were found to be stable in presence of albumin and in human plasma. The ADC exhibited excellent antigen-specific internalization and nanomolar potency in vitro and were effective in suppressing tumor growth in a lung adenocarcinoma xenograft model with minimal systemic toxicity. This novel technology, which we term MAGNET (multivalent, affinity-guided antibody-empowerment technology) overcomes the existing limitations of ADC engineering by imparting trinity of (1) site-specificity, (2) stability and (3) homogeneity, while simplifying the ADC synthesis process. The self-assembled MAGNET ADCs pave the way for exploration of non-covalent conjugation of payloads to any biomolecule, and heralds a new paradigm for ADC generation. Citation Format: Nimish Gupta, Goutam Biswas, Aniruddha Sengupta, Monideepa Roy, Sudip Roy, Shiladitya Sengupta. A controlled affinity-guided ADC-linker (MAGNET) technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 751.