Peptide‐Directed Attachment of Hydroxylamines to Specific Lysines of IgG Antibodies for Bioconjugations with Acylboronates

The role of monoclonal antibodies as vehicles to deliver payloads has evolved as a powerful tool in cancer therapy in recent years. The clinical development of therapeutic antibody‐conjugates with precise payloads holds great promise for targeted therapeutic interventions. The use of affinity‐peptide mediated functionalization of native off‐the‐shelf antibodies offers an effective approach to selectively modify IgG antibodies with a drug antibody ratio (DAR) of 2. Here, we report the traceless, peptide‐directed attachment of two hydroxylamines to native IgGs followed by chemoselective potassium acyltrifluboroborate (KA) ligation with quinolinium acyltrifluoroborates (QATs), which provide enhanced ligation rates with hydroxylamines under physiological conditions. By applying KAT ligation to the modified antibodies, conjugation of small molecules, proteins, and oligonucleotides to off‐the‐shelf IgGs proceeds efficiently, in good yields, and with simultaneous cleavage of the affinity peptide‐directing moiety.