Novel linkers and connections for antibody-drug conjugates to treat cancer and infectious disease.

Antibody-drug conjugates (ADCs) are an exciting therapeutic, combining the extreme potency of a small molecule cytotoxic drug with the exquisite selectivity of a monoclonal antibody. Despite the promising concept and many decades of research and clinical experiments, only two ADCs are approved for human use. Among the lessons learned, have been the need for highly stable and potentially releasable linkers and the empirical nature of therapeutic index supporting the testing of many diverse cytotoxics, many requiring new linker connections for the drug's available functional groups. This article will focus on our efforts at Genentech to develop a new disulfide linker as well as our discovery of a novel quaternary ammonium salt linker connection and the application to ADCs for cancer and infectious disease.