John C. Byrd, MD
Dr. Byrd indicated no relevant conflicts of interest.
Beurskens FJ, Lindorfer MA, Farooqui M, et al. Exhaustion of cytotoxic effector systems may limit monoclonal antibody-based immunotherapy in cancer patients. J Immunol. 2012;188:3532-3541.
Clinical use of the therapeutic antibody rituximab has favorably affected outcome in most CD20-positive B-cell malignancies. Available data suggests that rituximab mediates tumor cell killing through different mechanisms including antibody-dependent cellmediated phagocytosis (ADCP), antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct killing. Based on these observations, second- and third-generation anti-CD20 antibodies with enhanced capacity to mediate ADCP, ADCC, CDC, and/or direct killing have been developed; however, to date, only ofatumumab is FDA-approved (for treatment of patients with refractory chronic lymphocytic leukemia [CLL]). Ofatumumab binds CD20 close to the plasma membrane and mediates CDC more effectively than rituximab. The dose and schedule recommended for ofatumumab results in patients being treated with a large amount of antibody, and, while effective against CLL, treatment is expensive.
Based on studies from a clinical trial using ofatumumab to treat patients with CLL, Beurskens and colleagues reported the fascinating observation that while the antibody effectively eliminated a portion of the malignant B-cells, complement stores were depleted in the process. Residual circulating CLL cells were found to have both antibody and complement C3d bound, suggesting that they had survived CDC because the initial brisk activation of complement induced by infusion of high-dose ofatumumab exhausted the complement system. Subsequent in vitro studies indicated that the efficacy of ofatumumab could be enhanced by reducing the dose of the drug and altering the treatment schedule. In this way, the ofatumumab would be administered only when complement supplies are sufficient to mediate CDC optimally.
This work is important because it argues that current dosing of anti-CD20 antibodies is suboptimal. Moreover, the results of the in vitro experiments suggest a rational approach to improving the efficacy of ofatumumab by modifying the infusion schedule. Based on those studies, such a schedule would likely involve a pulse-dosing strategy designed to deliver an effective amount of antibody while avoiding excess complement consumption. The optimal amount of antibody for the treatment of CLL could be determined in a clinical trial by analyzing the relationship between the amount of antibody infused and the complement titer. Conceivably, a reduction in cost of treatment could also be realized if a pulse-dosing strategy requires less antibody than that currently recommended. Rational dosing of therapeutic antibodies is important as these agents have become an indispensible component of our therapeutic armamentarium. But completion of carefully designed trials will be required to determine if the findings of Beurskens and colleagues translate into a clinical benefit for patients and a financial gain for our health-care system.
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