One target, different effects: a comparison of distinct therapeutic antibodies against the same targets

Abstract

To date, more than 30 antibodies have been approved worldwide for therapeutic use. While the monoclonal antibody market is rapidly growing, the clinical use of therapeutic antibodies is mostly limited to treatment of cancers and immunological disorders. Moreover, antibodies against only five targets (TNF-α, HER2, CD20, EGFR, and VEGF) account for more than 80 percent of the worldwide market of therapeutic antibodies. The shortage of novel, clinically proven targets has resulted in the development of many distinct therapeutic antibodies against a small number of proven targets, based on the premise that different antibody molecules against the same target antigen have distinct biological and clinical effects from one another. For example, four antibodies against TNF-α have been approved by the FDA -- infliximab, adalimumab, golimumab, and certolizumab pegol -- with many more in clinical and preclinical development. The situation is similar for HER2, CD20, EGFR, and VEGF, each having one or more approved antibodies and many more under development. This review discusses the different binding characteristics, mechanisms of action, and biological and clinical activities of multiple monoclonal antibodies against TNF-α, HER-2, CD20, and EGFR and provides insights into the development of therapeutic antibodies.

Figure 1

Mechanisms of action for therapeutic antibodies. Antibodies against soluble ligands, such as anti-TNF-α antibodies infliximab, adalimumab, golimumab and certolizumab pegol, interfere with ligand-receptor interaction (A). Anti-EGFR antibodies cetuximab, panitumumab and nimotuzumab inhibit ligand binding to the receptor (A) and thus stabilize the inactive conformation of EGFR (B). HER2 is in a constitutively active conformation, and anti-HER2 antibodies trastuzumab and pertuzumab block homo- and heterodimerization of HER2 with ErbB recetors (C). For antibodies targeting CD20, which does not have a known ligand and probably is not a receptor, the major mechanisms of action is Fc-mediated effector functions (D). Most of other antibodies, especially of IgG1 subtype, that bind a cell surface antigen can also mediate ADCC/CDC for effective cell killing. See text for various other possible mechanisms not shown in this figure, such as receptor internalization and sensitization of the target cells.