New chemical tools for the design of next generation antibody drug conjugates

About This Grant

Project summary Over the past decade, the clinical and societal impact of antibody-drug conjugate (ADC) technology has grown rapidly, with a notable increase in approved drugs and sales. ADCs utilize an antibody "delivery system" to bind to specific cells, releasing a cytotoxic payload upon lysosomal degradation. However, the field faces many significant challenges, including a lack of diverse linker technologies for payloads without an amine handle, few useful payloads beyond traditional cytotoxic agents, and the lack of chemistry that can rapidly explore dual-payload ADC designs. Our team has had a significant impact in these areas over the past 5 years, and is poised to have an even greater impact over the next 5 years. Herein, we propose three primary focus areas. In focus area #1, we will design new self-immolative spacers that allow the release of payloads that do not contain amine handles. Building on our recently published “GlyPro” self- immolative spacer, we will generate linkers that spontaneously release sulfonamides, ureas, carbamates, and hydroxamates. In focus area #2, we will build on our recently patented “dual payload ADC” designs to systematically look for synergistic combinations of payloads that impart unexpected activity. Our 2-step approach for the preparation of dual payload ADCs allows us to rapidly “mix and match” payloads in order to identify unexpected (or hypothesized) combinations that impart unique properties that either payload alone is incapable of achieving. Finally, in focus area #3, instead of delivering a traditional cytotoxic payload, we will design ADCs that deliver an organic-metallic catalyst. We envision a next generation of ADCs that do not deliver a “payload”, but rather deliver a new function to antigen-expressing cells. These “mechanized antibodies” may be useful for diverse applications including detoxification, anti- inflammatory therapeutics, antibody-directed prodrug activation, and even biomaterials. Together, advancements in these three focus areas will result in new ADC designs that will have a broad impact on targeted therapeutic agents in a variety of disease states.