Cysteine-Selective Reactions for Antibody Conjugation

摘要

The unique targeting ability of antibodies has triggered burgeoning interest in the attachment of potent cytotoxic drugs onto these biomolecules to create antibody-drug conjugates (ADCs) which are able to spare healthy tissue by releasing its cargo only upon specific cancer-cell antigen recognition. Despite their conceptual simplicity, the individual components of ADCs must have specific/precise properties to elicit therapeutic benefit. The antibody should have high affinity and specificity for the defined and abundant antigens in tumours and its pharmacokinetic properties should be unaffected upon conjugation with the drug. The cytotoxic molecule should be highly potent, thereby minimizing the number of payload molecules necessary to induce effective cell death. Finally, the conjugation strategy must permit chemical installation of the drug onto the antibody at a pre-determined site(s), and ensure stability of the conjugate whilst in circulation in vivo. Efforts in this field have led to the recent approval of two ADCs as drugs: Adcetris (brentux-imab-vedotin), for the treatment of refractory Hodgkin lymphoma and anaplastic large-cell lymphoma, and Kadcyla (trastuzumab-emtansine), for the treatment of metastatic Her2 + breast cancer.