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Clinical Pharmacology

A Mechanistic Perspective of Monoclonal Antibodies in Cancer Therapy Beyond Target-Related Effects

^aDepartment of Otorhinolaryngology, Head and Neck Surgery, ^bMarlene & Stuart Greenbaum Cancer Center, and ^cDepartment of Pathology, Division of Immunogenetics, University of Maryland School of Medicine, Baltimore, Maryland, USA

Key Words. Cancer • Monoclonal antibodies • Antibody-dependent cellular cytotoxicity • Complement-dependent cytotoxicity

Correspondence: Scott E. Strome, M.D., F.A.C.S., Department of Otorhinolaryngology—Head and Neck Surgery, 16 South Eutaw Street, Suite 500, Baltimore, Maryland 21201-1619, USA. Telephone: 410-328-2378; Fax: 410-328-6192; e-mail: sstrome{at}smail.umaryland.edu

Disclosure: S.E.S. owns stock in Gliknik, has acted as a consultant for Accuitive Medical Ventures, has performed contract work for GTC Biotherapeutics, and receives licensing revenue from IP agreements between Mayo Clinic and various third parties (as an inventor).

Several monoclonal antibodies are now in clinical use for cancer therapy, and many others are currently undergoing clinical evaluation. These agents offer unique specificity against key molecular targets on tumor cells or in the tumor microenvironment. The clinical efficacy of monoclonal antibodies is generally attributed to target-specific mechanisms resulting from neutralizing or inhibiting a growth factor or receptor that drives cell proliferation and tumor growth. Several targets, including CD20, human epidermal growth factor receptor 2, vascular endothelial growth factor, and epidermal growth factor receptor, have been validated in specific malignancies on the basis of monoclonal antibody efficacy. However, monoclonal antibodies also have the potential to activate immune-mediated effector functions, including antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. These functions result from interactions involving the Fc domain of the antibody, and, consequently, may vary by antibody, isotype, and Fc modification, such as changes in glycosylation. Accordingly, all monoclonal antibodies directed against a given target should not be considered equivalent in their ability to stimulate immune-mediated effector functions.

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