Opportunities and Challenges in Antibody–Drug Conjugates for Cancer Therapy: A New Era for Cancer Treatment

The antibody, linker, and payload moieties all play a significant role in giving the ADC its unique therapeutic potential. The antibody subclass employed in ADCs is determined based on relative individual receptor affinities and pharmacokinetics. Meanwhile, the linker used in an ADC can either be cleavable or non-cleavable. ADC therapy comprises antibody-dependent mechanisms in addition to the direct cytotoxic effects of the payload. These include antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis, as well as the “bystander effect”, which refers to the diffusion of a portion of the cytotoxic molecules out of the target cell, exerting its cytotoxic effect on the adjacent cells. Target antigens of ADCs are expected to be expressed on the membranes of the cancer cells facing the external matrix, although new approaches utilize antigens regarding tumor-associated cells, the tumor microenvironment, or the tumor vasculature. These target antigens of ADCs not only determine the efficacy of these agents but also impact the off-targets and related adverse effects. The majority of ADC-related toxicities are associated with off-targets. The proposed mechanisms of ADC resistance include disrupted intracellular drug trafficking, dysfunctional lysosomal processing, and the efflux of the cytotoxic molecule via ATP-binding cassette (ABC) transporters. The latter mechanism is especially prominent for multi-drug-resistant tumors. An important limitation of ADCs is the penetration of the conjugate into the tumor microenvironment and their delivery to target cancer cells. Cancerous tissues’ vascular profile and the steric “binding site barrier” formed around the peripheral vessels of tumors stand as potential challenges of ADC therapy for solid tumors. As research efforts focus on reducing toxicities, overcoming resistance, and improving pharmacokinetics, ADC options for cancer therapy are expected to continue to diversify, including standalone approaches and combination therapies.