Discovery and Manufacturing Strategies for Novel, Homogeneous ADC Molecules

Several key learnings have emerged through application of rapid re-iterative ADC design using reactive non-natural amino acids to specifically position conjugation sites: Site-specific homogeneous molecules can improve therapeutic index preclinically and have the potential to optimize clinical impact for a given combination of antibody and warhead. Site matters. Homogeneity is required, but not sufficient, for best in class molecules. Finding the optimal site for conjugation is crucial. Beyond antibody stability, PK and attributes that optimize for internalization and cell killing in vitro, certain conjugation sites on the antibody further enhance solid tumor killing efficacy in vivo. The antibody production process has been split into two stages; First the production of the ribosome-rich extract that can now be considered a critical raw material. And secondly, use of that cell-free extract to produce nnAA containing antibodies in 10 hours from DNA. Each stage has been optimized for speed, efficiency and flexibility and now established as a viable manufacturing process: Removal of RF-1 from the extract permits very efficient production of nnAA containing Use of novel nnAAs allows complete conjugation in minutes Extracts that incorporate orthogonal tRNAs and lack RF-1 provide for efficient and flexible manufacturing.