Antibody-Drug Conjugates: Can Coupling Cytotoxicity and Specificity Overcome Therapeutic Resistance?

Abstract

As their name implies, antibody-drug conjugates (ADCs) comprise a humanized or fully human IgG coupled to a cytotoxic small molecule payload. The former component provides the ADC with an antibody’s exquisite selectivity for its target antigen, which is typically a cell surface molecule with a tumor-restricted expression pattern. The latter component provides the ADC with a highly potent cytotoxic payload that can efficiently kill targeted cells at low concentrations (sub nM). As relatively recent additions to the armament of anti-cancer drugs, ADCs hold great promise for disease management, particularly with respect to difficult to treat, drug-resistant tumors. Here, we provide an overview of modern approaches to cancer treatment, from first-generation systemically delivered chemotherapeutics, through the contemporary use of molecularly-targeted small molecules and biologics, to the culmination of both of these approaches—the ADC. Next, we detail the particular features of ADCs that relate to their potential for overcoming drug resistance, namely, the cytotoxic small molecule and the linker component. The latter is exceptionally well-suited to modifications that can render cytotoxic payloads poor substrates for multidrug transporter-mediated efflux from the cell. Finally, we touch on the possibility that ADCs might also serve as an effective means to treat tumors that are resistant to unmodified monoclonal antibody therapies (e.g., rituximab and trastuzumab).