Target Antigen Attributes and Their Contributions to Clinically Approved Antibody-Drug Conjugates (ADCs) in Haematopoietic and Solid Cancers

Abstract

Antibody drug conjugates (ADCs) are powerful anti-cancer therapies comprising an antibody joined to a cytotoxic payload through a chemical linker. ADCs exploit the specificity of antibodies for their target antigens, combined with the potency of cytotoxic drugs, to selectively kill target antigen-expressing tumour cells. The recent rapid advancement of the ADC field has so far yielded twelve and eight ADCs approved by the US and EU regulatory bodies, respectively. These serve as effective targeted treatments for several haematological and solid tumour types. In the development of an ADC, the judicious choice of an antibody target antigen with high expression on malignant cells but restricted expression on normal tissues and immune cells is considered crucial to achieve selectivity and potency while minimising on-target off-tumour toxicities. Aside from this paradigm, the selection of an antigen for an ADC requires consideration of several factors relating to the expression pattern and biological features of the target antigen. In this review, we discuss the attributes of antigens selected as targets for antibodies used in clinically approved ADCs for the treatment of haematological and solid malignancies. We discuss target expression, functions, and cellular kinetics, and we consider how these factors might contribute to ADC efficacy.

Keywords: Fab regions; IgG; antibody-drug conjugates (ADCs); antigen; cancer immunotherapy; checkpoint inhibitors; effector functions; mAb; monoclonal antibodies; target.

Figure 1

ADC Mechanism of Action. (A) Schematic diagram of an ADC, and descriptions of mechanisms of linker cleavage and payload toxicity. (B) Mechanism of action of an internalising ADC: Internalisation of ADC, trafficking to early and late endosomes and lysosomes followed by release of payload. (C) Mechanisms of cell death potentiated by ADC payloads, and relevant examples. (D) Schematic diagram of ADC recycling mediated by the neonatal Fc receptor (FcRn). (E) Mechanism of action of a non-internalising ADC. ADC binding to tumour-proximal extracellular matrix proteins or neovasculature before linker cleavage by proteases and release of cytotoxic payload. Created using Biorender.com. Abbreviations: ADC, Antibody-Drug Conjugate; DM-1, Mertansine DM-1; Dxd, Deruxtecan; ECM, Extracellular Matrix; FcRn, Neonatal Fc Receptor; MMAE/F, Monomethyl Auristatin E/F; PBD, Pyrrrolobenzodiazepine.

Figure 2

ADC Targets for Haematological Malignancies. Schematic diagrams of EMA and FDA-approved ADCs for haematological cancers binding to their target cells. Approximate drug-antibody ratios for each ADC are represented. ADC payloads that function by tubulin inhibition are shown in red, and DNA-interacting payloads are shown in blue. Dashed lines indicate binding. The effect of afucosylation on belantamab mafodotin is shown by a dashed line indicating enhanced binding to CD16 on an NK cell, and induction of NK cell-mediated killing of target cells indicated by a red line. Created using Biorender.com.

Figure 3

ADC Targets for Solid Tumours. Schematic diagrams of EMA and FDA-approved ADCs for solid tumours binding to target cells. Approximate drug-antibody ratios for each ADC are represented. ADC payloads that function by tubulin inhibition are shown in red, and topoisomerase inhibitors are shown in yellow. Dashed lines indicate binding. Created using Biorender.com.

Figure 4

Schematic representation of the proposed effect of antigen shedding on the binding-site barrier and ADC effectiveness. (A) When rates of antigen shedding are low, a greater number of cell surface antigens per cancer cell are available which serve as a ‘binding-site barrier’, depleting the supply of ADC molecules entering the tumour microenvironment close to the vasculature. (B) When rates of antigen shedding are high, a smaller number of cell surface antigens per cancer cell are available, meaning that fewer ADCs bind to each cancer cell and a greater number of ADC molecules are available to bind to more cancer cells distant from the vasculature. Created with Biorender.com.