Development of Antibody-Drug Conjugates (ADCs)

The potential of antibody–drug conjugate (ADC) drugs has long been appreciated. In 1957, Pressman et al. described the key quality characteristics of conjugated antibodies—the bond or linker as we know it today, as well as the payload and the problem of average ligand-to-antibody ratio versus the distribution of different numbers of radioligands per antibody. Today, this is known as the drug-to-antibody ratio, and it is under much better control than that almost a century ago thanks to advances in site-specific conjugation. The complications of intra-tumor pharmacokinetics have long been appreciated. For instance, ADCs can accumulate in tumors due to higher tumor capillary permeability rather than specific target binding. This chapter reviews details on the antibody and antigen, payload, and linker constituents of an ADC, as well as a range of ADC design aspects, including antigen selection, possibilities of epitope masking to prevent off-tumor binding, the selection of the class of IgG, and engineering of the Fc portion of the Ab.