Multicomponent Synthetic Conjugation: Redefining Chemical Bioconjugation for the Accelerated Production of Next-Generation Antibody-Drug Conjugates in Oncology

Objective

Cancer remains one of the leading causes of death worldwide and in Europe in particular. In the continuous fight against this disease, the recent emergence of antibody-drug conjugates (ADCs) has unveiled tremendous hope for the patients. Composed of an antibody that binds cancer cells selectively, ADCs are capable of delivering a cytotoxic drug into tumors selectively, resulting in targeted cell death. Even though a dozen ADCs has already been marketed, they are still extremely expensive and time-consuming to produce. Besides, their development still lacks guiding principles to maximize their efficacy and increase their safety. At the moment, ADCs share the same structural canvas and are produced through the one- or two-step conjugation of antibodies, using a narrow set of linkers and drugs. These limitations represent a major barrier to innovation and to breakthroughs in this yet booming field, preventing the emergence of next-generation ADCs. My proposal to address these challenges is to focus on the bioconjugation step and use it as a chemical step toward the synthesis of valuable motifs. Using a novel chemical approach coined Multicomponent Synthetic Conjugation (MuSyC), I propose to use multicomponent reactions to construct and conjugate valuable motifs at the same time on antibodies, and expand the chemical space of bioconjugation. I will apply this strategy to selected cytotoxic drugs and peptide linkers, in order to streamline the development of the next generation of toxic immunoconjugates. In addition, I will also develop DNA-based tools to guide the discovery of site-selective conjugation reactions. This project will lead to next generations of toxic antibody conjugates, augment the current limited repertoire of approved drugs and linkers, while providing a better understanding of their key structural features.