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

Hyunbo Shim

doi:10.3858/emm.2011.43.10.063

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.

Highlights

The therapeutic potential of monoclonal antibodies had been well recognized by the pharmaceutical industry, and just one decade after the development of hybridoma technology by Milstein and Köhler (Köhler and Milstein, 1975), the first therapeutic monoclonal antibody was approved for clinical use in 1986
Bacterial cell display-based screening of human epidermal growth factor receptor 2 (HER2) peptides revealed several new epitopes that can be targeted by antibodies to inhibit cell growth and proliferation (Rockberg et al, 2008, 2009). While it remains unclear whether or not antibodies against those epitopes really are different from trastuzumab or pertuzumab in terms of mechanism of action, the multistep activation mechanisms of receptor tyrosine kinase (RTK) such as HER2 and Epidermal growth factor receptor (EGFR) can be exploited to develop neutralizing antibodies with unique biochemical and clinical properties
The existence of multiple functional epitopes that drive different cellular responses upon antibody binding, on an antigen with relatively small extracellular domains, illustrates the point that antibodies with novel mechanisms of action and improved efficacies can be developed against an established target antigen

Summary

Introduction

The therapeutic potential of monoclonal antibodies had been well recognized by the pharmaceutical industry, and just one decade after the development of hybridoma technology by Milstein and Köhler (Köhler and Milstein, 1975), the first therapeutic monoclonal antibody (muromonab, Orthoclone OKT3) was approved for clinical use in 1986. Only a handful of therapeutically relevant antigens, including cell-surface proteins HER2, CD20 and EGFR, and soluble ligands TNF-α and VEGF, have been targeted by multiple antibodies, 540 Exp. Mol. Another humanized anti-HER2 antibody, pertuzumab, binds to an epitope in domain II of HER2-ECD with a Kd of ~2.2 nM and inhibits the ligand-dependent heterodimerization of HER2 with other ErbB receptors such as EGFR and HER3 (Persson et al, 2005).

Results

Conclusion