Advances in antibody-drug conjugates: A new era of targeted cancer therapy

Abstract

Antibody-drug conjugates (ADCs), a potent class of anticancer therapeutics, comprise a high-affinity antibody (Ab) and cytotoxic payload coupled via a suitable linker for selective tumor cell killing. In the initial phase of their development, two ADCs, Mylotarg^®, and Adcetris^® were approved by the US Food and Drug Administration (FDA) for treating hematological cancer, but the real breakthrough came with the discovery of the breast cancer-targeting ADC, Kadcyla^®. With advances in bioengineering, linker chemistry, and potent cytotoxic payload, ADC technology has become a more powerful tool for targeted cancer therapy. In addition, ADCs with improved safety using humanized Abs with a unified 'drug:antibody ratio' (DAR) have been achieved. Concomitantly, there has been a significant increase in the number of clinical trials with anticancer ADCs with high translation potential.

Figure 1.

(a) Structural characteristics of earlier generation and advanced-generation antibody–drug conjugates (ADCs) [75]. (b) List of targetable tumor antigens: epidermal growth factor receptor (EFGF), platelet-derived growth factor receptor (PDGFR); tyrosine-protein kinase met (C-Met); epithelial cell adhesion molecule (EPCAM); carbonic anhydrase- IX (CA-9); tumor-associated calcium signal transducer 2 (TROP-2); vascular endothelial growth factors receptor-2 (VEGFR-2); prostate specific membrane antigen (PSMA); endothelin receptor-B (ET-B); matrix metallopeptidase-9 (MMP-9); and fibroblast activated protein (FAP) [1].

Figure 2.

Mechanistic pathways of antibody–drug conjugate (ADC) internalization and cancer cell killing [2].

Figure 3.

(a) Schematic representation of fully human (blue), mouse (green), chimeric (fused mouse-originating antigen-binging domain with human constant domain, green-blue) and humanized [fused mouse CDR domain with a human immunoglobulin (Ig)-G backbone] antibody. Fab and Fc are antibody subdomains and Fv is a variable domain. (b) Advances in ADC technologies and representative images of first-generation (i), second-generation (ii) and third-generation (iii) ADCs. Adapted, with permission, from [7] (bi,ii), [76] (biii), [14] (biv) and [66] (bv).