Numerous antibody-drug conjugates (ADC) are being developed for cancer immunotherapy. Although several of these agents have demonstrated considerable clinical efficacy and have won FDA approval, in many instances they have been characterized by adverse side effects (ASE) which can be quite severe in a fraction of treated patients. The key hypothesis in this perspective is that many of the most serious ASE associated with the use of ADC in the treatment of cancer can be most readily explained and understood due to the inappropriate processing of these ADC via pathways normally followed for immune complex clearance, which include phagocytosis and trogocytosis. We review the key published basic science experiments and clinical observations that support this idea. We propose that it is the interaction of the ADC with Fc receptors expressed on off-target cells and tissues that can most readily explain ADC-mediated pathologies which therefore provides a rationale for the design of protocols to minimize ASE. We describe measurements that should help to identify those patients most likely to experience ASE due to ADC and we propose readily available treatments as well as therapies under development for other indications that should substantially reduce ASE associated with ADC. Our focus will be on the following FDA-approved ADC for which there are substantial literatures: gemtuzumab ozogamicin (Mylotarg) and inotuzumab ozogamicin; and trastuzumab emtansine (T-DM1), and trastuzumab deruxtecan (T-DXd).

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