Click chemistry has found wide application in bioconjugation, enabling control over the site of modification in biomolecules. Demonstrations of this chemistry to construct chemically defined antibody-drug conjugates (ADCs) have increased in recent years, following studies that support benefits of homogeneity and site-specificity of drug placement on the antibody. In this chapter, a brief history of early applications of this chemistry in ADCs is presented. Examples of click chemistries that are utilized for ADC synthesis, including those currently undergoing clinical investigations, are enumerated. Protocols for two common conjugation methods based on carbonyl-aminooxy coupling and strain-promoted azide-alkyne cycloaddition are described.
Keywords: Aldehyde; Antibody–drug conjugates (ADCs); Bioconjugation; Click chemistry; Oxime; Site-specific; Strain-promoted azide–alkyne cycloaddition (SPAAC).