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Biological impediments to monoclonal antibody–based cancer immunotherapy

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California

Requests for reprints: Ayyappan K. Rajasekaran, Department of Pathology and Laboratory Medicine, Room 13-344 CHS, University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095. Phone: 310-825-1199; Fax: 310-267-2410. E-mail: arajasekaran{at}mednet.ucla.edu

The ability of antibodies to exploit antigenic differences between normal and malignant tissues and to exact a variety of antitumor responses offers significant advantages to conventional forms of therapy. Several monoclonal antibodies (mAb) have already proved to be relatively well tolerated and effective for the treatment of many different malignant diseases. However, mAbs must overcome substantial obstacles to reach antigens presented on target cells to be of therapeutic value. Intravenously administered antibodies must avoid host immune response and contend with low or heterogeneous expression of antigen on tumor cells. Antibodies must also overcome significant physical barriers en route to a solid tumor mass, including the vascular endothelium, stromal barriers, high interstitial pressure, and epithelial barriers. Here we review the application and evolution of mAbs as effective forms of treatment, with particular attention to the barriers and impediments to successful treatment and discuss strategies to overcome these barriers and improve the efficacy of mAb-based therapy.

Key Words: monoclonal antibody • antibody immunotherapy • epithelial barrier • tight junctions • cancer

Grant support: Department of Defense grant DAMD17-02-1-0661 and NIH grant DK56216.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 1/ 6/04; revised 3/29/04; accepted 5/ 5/04.