Bispecific antibodies: design, therapy, perspectives

Abstract

Antibodies (Abs) containing two different antigen-binding sites in one molecule are called bispecific. Bispecific Abs (BsAbs) were first described in the 1960s, the first monoclonal BsAbs were generated in the 1980s by hybridoma technology, and the first article describing the therapeutic use of BsAbs was published in 1992, but the number of papers devoted to BsAbs has increased significantly in the last 10 years. Particular interest in BsAbs is due to their therapeutic use. In the last decade, two BsAbs - catumaxomab in 2009 and blinatumomab in 2014, were approved for therapeutic use. Papers published in recent years have been devoted to various methods of BsAb generation by genetic engineering and chemical conjugation, and describe preclinical and clinical trials of these drugs in a variety of diseases. This review considers diverse BsAb-production methods, describes features of therapeutic BsAbs approved for medical use, and summarizes the prospects of practical application of promising new BsAbs.

Keywords: bispecific antibodies; monoclonal antibodies; therapeutic antibodies.

Figure 1

Mechanism of blinatumomab therapeutic action: recruitment of T cells to tumors through binding of tumor-cell-surface antigens to immune cells. Abbreviation: mAb, monoclonal antibody.

Figure 2

Mechanism of action: catumaxomab is a trifunctional antibody that accelerates the recognition and destruction of tumor cells by different immune cells. Notes: Catumaxomab binds the EpCAM on the surface of a cancer cell, CD3 on T lymphocytes, and Fc on Fcγ-receptor positive accessory cell. Immunoeffector cells interact with each other, leading to the elimination of tumor cells by the mechanisms of T-cell cytotoxicity, cytokine cytotoxicity, phagocytosis, or antibody-dependent cellular toxicity. Adapted by permission from Macmillan Publishers Ltd: Nat Biotechnol. Walsh G. Biopharmaceutical benchmarks 2010. 2010;28(9):917–924. Copyright 2010 Nature Publishing Group. Available from: https://www.nature.com/nbt/. Abbreviations: EpCAM, epithelial cell adhesion molecule; Fc, fragment crystallizable region.

Figure 3

Architecture of common BsAbs formats. Notes: Adapted from Kontermann RE, Brinkmann U. Bispecific antibodies. Drug Discov Today. 2015;20(7):838–847. Copyright^© 2015 The Authors. Published by Elsevier Ltd. Available from: https://www.sciencedirect.com/science/article/pii/S135964461500077X. Creative Commons license: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode. Abbreviations: scFv, single-chain variable fragment; DART, dual-affinity retargeting; BsAbs, bispecific antibodies.