Antibody Directed Delivery for Treatment of Cancer: Antibody Drug Conjugates and Immunotoxins

Chapter
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

A major goal in the development of cancer therapeutics is to identify agents that will effectively eradicate tumors while having minimal effects on cells of normal tissues. Unfortunately, the majority of anticancer agents developed to date have substantial side effect profiles and a narrow therapeutic index. One means to improve the selectivity and efficacy of cancer therapy is by choosing therapeutic targets with altered levels of expression on malignant versus normal cells. Following the introduction of monoclonal antibody (MAb) technology by Kohler and Milstein (Nature 256:495–497, 1975), the potential to utilize the antigen-selectivity of MAbs to deliver toxic agents initiated an extensive effort to design antibody-targeted therapeutics. The clinical utility of MAb-based therapeutics was substantially improved by both the chimerization and humanization of murine MAbs, both of which substantially reduced immunogenicity and improved MAb half-life. The ability to obtain fully human MAbs from transgenic mice and by phage display has further enhanced the clinical potential of these approaches (Nat Rev Immunol 6:343–357, 2006; Expert Opin Investig Drugs 7:607–614, 1998; Nat Biotechnol 23:1117–1125, 2005). Monoclonal antibodies and fragments of MAbs have been used to effectively deliver radionuclides (Hosp Pract (Minneap) 38:82–93, 2010; Clin Cancer Res 17:6406–6416, 2011), cytokines (Integr Biol (Camb) 3:468–478, 2011; Int J Cancer 102:109–116, 2002), plant and bacterial toxins (FEBS J 278:4683–4700, 2011; Expert Opin Drug Deliv 8:605–621, 2011; Drug Discov Today 16:495–503, 2011), and a variety of cytotoxic drugs (Nat Biotechnol 21:778–784, 2003; Cancer Res 53:3336–3342, 1993; Expert Opin Investig Drugs 6:169–172, 1997; Science 261:212–215, 1993). Although simple in concept, the design of effective targeting agents has required substantial investigation and modification in the selection of MAbs and their targets, the types of linkers used, and the potency of the toxic agents that are delivered. This chapter focuses on MAb-directed delivery of plant and bacterial toxins (immunotoxins) and MAb-directed delivery of cytotoxic drugs (antibody–drug conjugates: ADCs).

Keywords

Toxicity Lymphoma Radionuclide Methotrexate Disulfide 

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Regeneron Pharmaceuticals Inc.New YorkUSA

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