Application of humanized FcRn mouse model for in vivo testing of therapeutic antibodies (131.37)

Abstract

Abstract IgG antibodies modified for high binding affinity for their receptor FcRn have emerged as a major treatment for a wide array of both neoplastic and autoimmune diseases. The goal of this study was to analyze the effect of human IgG1 antibodies with enhanced in vitro binding to FcRn on their in vivo half-life in mice deficient in mouse FcRn and expressing human FcRn. Two mutants (N434A and T307A/E380A/N434A) of the humanized monoclonal antibody Hu4D5, directed against epidermal growth factor receptor 2 (p185 HER2), show increased pH-dependent binding to human FcRn in vitro. They also have an extended half-life in vivo compared to wild-type antibody in FcRn transgenic mice but not in mice expressing endogenous mouse FcRn. When injected into FcRn-humanized mice at a concentration sufficient to partially saturate human FcRn, the mutants with an extended serum half-life were most effective in reducing the half-life of a tracer antibody. Finally, we use a serum-transfer model of arthritis and FcRn-humanized mice to test whether mutant antibodies could have enhanced therapeutic potential by promoting accelerated clearance of arthritogenic antibodies. Results indicate that the engineered mutant T307A/E380A/N434A is most effective in vivo in ameliorating the inflammatory arthritic lesions. In summary, FcRn-humanized mice are a promising animal model for human IgG therapeutic development.