MANUFACTURING CONCEPTS FOR ANTIBODY–DRUG CONJUGATES

The current targeting agent of choice for most antibody–drug conjugates is an intact antibody. Several structural aspects of the antibody can be used to form a stable chemical bond with cytotoxic agents. Currently, the preferred modalities for the random conjugation of small-molecule cytotoxins are primary amines or free sulfhydryl groups resident in the primary structure of the antibody. Several technologies have been used to achieve site-specific conjugation, including the introduction of additional cysteine residues into the antibody primary sequence and the introduction of unnatural amino acids with orthogonal chemical reactivity compared to the 20 main genetically encoded amino acids. Bispecific antibody–drug conjugates are innovative therapeutics designed to exploit the enhanced selectivity of two antigen targets. Following target identification and the development of an antibody with suitable binding affinity, it is necessary to select an appropriate chemical linker with which to attach the toxin.