Antibody-Drug Conjugates in Solid Tumor Oncology: An Effectiveness Payday with a Targeted Payload

Abstract

Antibody-drug conjugates (ADCs) are at the forefront of the drug development revolution occurring in oncology. Formed from three main components-an antibody, a linker molecule, and a cytotoxic agent ("payload"), ADCs have the unique ability to deliver cytotoxic agents to cells expressing a specific antigen, a great leap forward from traditional chemotherapeutic approaches that cause widespread effects without specificity. A variety of payloads can be used, including most frequently microtubular inhibitors (auristatins and maytansinoids), as well as topoisomerase inhibitors and alkylating agents. Finally, linkers play a critical role in the ADCs' effect, as cleavable moieties that serve as linkers impact site-specific activation as well as bystander killing effects, an upshot that is especially important in solid tumors that often express a variety of antigens. While ADCs were initially used in hematologic malignancies, their utility has been demonstrated in multiple solid tumor malignancies, including breast, gastrointestinal, lung, cervical, ovarian, and urothelial cancers. Currently, six ADCs are FDA-approved for the treatment of solid tumors: ado-trastuzumab emtansine and trastuzumab deruxtecan, both anti-HER2; enfortumab-vedotin, targeting nectin-4; sacituzuzmab govitecan, targeting Trop2; tisotumab vedotin, targeting tissue factor; and mirvetuximab soravtansine, targeting folate receptor-alpha. Although they demonstrate utility and tolerable safety profiles, ADCs may become ineffective as tumor cells undergo evolution to avoid expressing the specific antigen being targeted. Furthermore, the current cost of ADCs can be limiting their reach. Here, we review the structure and functions of ADCs, as well as ongoing clinical investigations into novel ADCs and their potential as treatments of solid malignancies.

Keywords: agnostic targets; antibody–drug conjugates; novel therapeutics; precision oncology; solid tumors; targeted therapy.

Figure 1

Schematic diagram of commonly used antibody drug-conjugate. Figure Legend: This diagram shows a common monoclonal antibody with the necessary pieces to conjugate it to a cytotoxic agent. In this schematic, there includes a linker piece to a cleavage site that can be cleaved and allow delivery of the payload.

Figure 2

Schematic diagram of payload delivery and its mechanism of action. Figure Legend: When the antibody engages with the antigen of the target cell, the ADC enters the cell and through the intracellular lysosome is cleaved, which then releases the cytotoxic payload to induce cellular death via various mechanisms.

Figure 3

IC50 (nM) for ADC payloads vs. common chemotherapeutic agents. Figure Legend: IC50 is a measure of the potency of a drug and represents the concentration of the drug required to inhibit the growth of 50% of the cells in vitro. The lower the IC50 value, the more potent the drug. The IC50 values listed in this table are representative values and vary depending on the cell line (tumor/tissue type) used and the experimental conditions (drug concentration, exposure time, environment). Abbreviations: 5-FU—5 fluorouracil, MMAE—monomethyl auristatin E.

Figure 4

Schematic diagram of bystander effect. Figure Legend: Only one type of cells (gray) is concentrating ADC, but after the cellular death, the payload gets released into the local microenvironment, and the drug diffuses into neighboring cells and causes cell death to them as well.