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FcRs Modulate Cytotoxicity of Anti-Fas Antibodies: Implications for Agonistic Antibody-Based Therapeutics¹

Yuanyuan Xu^2,*, Alexander J. Szalai^*, Tong Zhou^*, Kurt R. Zinn, Tandra R. Chaudhuri, Xiaoli Li^*, William J. Koopman^* and Robert P. Kimberly^*

^* Division of Clinical Immunology and Rheumatology, Department of Medicine and Laboratory for MultiModality Imaging Assessment, Department of Radiology, University of Alabama, Birmingham, AL 35294

Development of anti-Fas Abs to treat diseases with insufficient Fas-mediated apoptosis has been limited by concern about hepatotoxicity. We report here that hepatotoxicity elicited by anti-Fas Ab Jo2 is dependent on FcRIIB. Thus, following Jo2 treatment, all FcRIIB^-/- mice survived while 80% of wild-type and all FcR-^-/- mice died from acute liver failure. Microscopic examination suggests that FcRIIB deficiency protects the hepatic sinusoidal endothelium, a cell type that normally coexpresses Fas and FcRIIB. In vitro studies showed that FcRIIB, but not FcRI and FcRIII, on neighboring macrophages substantially enhanced Jo2 mediated apoptosis of Fas expressing target cells. However, FcRI and FcRIII appeared essential for apoptosis-inducing activity of a non-hepatotoxic anti-Fas mAb HFE7A. These findings imply that by interacting with the Fc region of agonistic Abs, FcRs can modulate both the desired and undesired consequences of Ab-based therapy. Recognizing this fact should facilitate development of safer and more efficacious agonistic Abs.

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