A new report by leading experts in monoclonal antibody research for oncology offers a conceptual framework for future research in the design of antibody therapies against solid tumors. Writing in the January 15, 2007 issue of CANCER (http://www.interscience.wiley.com/cancer-newsroom), a peer-reviewed journal of the American Cancer Society, the researchers note that 85 percent of cancers involve solid tumors, but only 25 percent of approved antibody therapies are directed at solid tumor targets. The researchers suggest manipulation of the physical properties of a monoclonal antibody as a potentially effective way to improve antibody treatments for solid tumors.
Monoclonal antibodies’ ability to target a single specific protein on cancer cells, has led to their being called a “magic bullet” that targets only cancer cells while minimizing collateral damage to healthy tissue. That damage causes the toxicity associated with chemotherapy and radiation therapy. In the nearly 20 years since scientists were able to create monoclonal antibodies that could be safely used in humans, eight monoclonal antibodies have been approved for use in clinical treatments to trigger immune responses to cancer cells, modulate cancer cell growth, and deliver drugs to cancer cells. Of these, only three are used on solid tumors. However, solid tumors account for 85 percent of all cancers.
According to review lead author Robert A. Beckman, M.D. of the Department of Clinical Hematology and Oncology at Centocor Research & Development, Inc. in Malvern, PA and his co-authors, Louis M. Weiner, M.D. of Fox Chase Cancer Center in Philadelphia and Hugh M. Davis, Ph.D. of the Department of Clinical Pharmacology and Experimental Medicine at Centocor, a major difficulty in developing monoclonal antibody treatments for solid tumors has been their ability to penetrate the tumor. To be effective, the treatment “must gain access to all viable cells within tumors at sufficient concentrations to effect a maximal change in the tumor.” This is affected by several factors, including the characteristics of the tumor, the antibody, and the target. “The complexity of this problem” can be illustrated in the authors’ discussion of antibody affinity. If an antibody binds too tightly to a surface antigen, the antibody will get stuck in the periphery of the tumor and be ineffective except in that location. But if an antibody binds too loosely, it may not stay in the tumor long enough to be effective at all.
The authors reviewed the literature to illustrate that the groundwork has been laid to overcome these barriers. Researchers, including Dr. Weiner, have made significant advances to understand the optimal antibody affinities required for maximum penetration, even taking into account tumor size. Studies have also investigated the optimal antibody size, shape and charge to penetrate certain types of solid tumors. Researchers have also examined how antibodies, including monoclonal therapies, behave in the human body; to understand how and how often therapies should be administered.
Given these advances in our knowledge, the authors write, “an equally large number of antibody construct and therapy variables are available for optimization including size, charge, and valence; constant region type and glycosylation pattern; presence or absence of a radioisotope or a toxic moiety; dose, route, and schedule of administration; and use of a traditional or of a pre-targeting strategy.” They conclude the framework they offer “should facilitate critical choices among antibody constructs in clinical practice, clinical research, and preclinical research.”
Articles: “Antibody Constructs in Cancer Therapy: Protein Engineering Strategies to Improve Exposure in Solid Tumors,” Robert A. Beckman, Louis M. Weiner, Hugh M. Davis, CANCER; Published Online: December 11, 2006 (DOI: 10.1002/cncr.22402); Print Issue Date: January 15, 2007.
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