2016 • Physical and LIfe Sciences
Functionalization of Therapeutic Antibodies Using Continuous Flow Microreactor Technology
Lead Presenter: Jacob Ganley
PI: Katie Dioli
As targeted therapeutics, Antibody-Drug Conjugates (ADCs) have shown great promise in the field of cancer treatment. The ability of a monoclonal antibody to selectively and reliably deliver a cytotoxic payload to a particular cancer cell-surface antigen has proven advantageous in the reduction of both of bystander toxicity and the quantity of drug required for treatment. A critical component of an ADC is the covalent linker, which tethers the cytotoxic agent to the antibody. This linker must bind the drug to the antibody, maintain stability in circulation, and release the drug upon uptake by the target cell; intense research into novel linker structures and conjugation methodologies has been a priority of both academic and biopharmaceutical research groups alike.
One of the main challenges associated with the production of ADC’s is the heterogenecity of conjugates generated. By conventional methods, a variable number of amino acid residues can conjugate to linkers, resulting in a distribution of the drug-to-antibody ratio (DAR). Two of the primary methods of conjugation are Michael-type addition by reduced disulfide bridges (with a DAR in multiples of 2) and nucleophilic substitution by lysine residues. In this investigation, a variety of proteins commercially available antibodies have been functionalized using continuous flow microreactor technology in the hopes of controlling the DAR through more precise and predictable conjugation, in addition to providing a methodological platform for the scale up of continuous manufacturing of antibody-drug conjugates. In addition, novel synthetic approaches to synthesizing commercially utilized linkers are currently being explored.