IgG Fc Domains that Bind C1q but not Effector Fc? Receptors Delineate the Significance of Complement- Mediated Cell Cytotoxicity and Phagocytosis in Antibody Function


Engineered crystallizable fragment (Fc) regions of antibody domains, which assume a unique and unprecedented asymmetric structure within the homodimeric Fc polypeptide, enable completely selective binding to the complement component C1q and activation of complement via the classical pathway without any concomitant engagement of the Fc? receptor (Fc?R). We used the engineered Fc domains to demonstrate in vitro and in mouse models that for therapeutic antibodies, complement-dependent cell-mediated cytotoxicity (CDCC) and complement-dependent cell-mediated phagocytosis (CDCP) by immunological effector molecules mediated the clearance of target cells with kinetics and efficacy comparable to those of the Fc?R-dependent effector functions that are much better studied, while they circumvented certain adverse reactions associated with Fc?R engagement. Collectively, our data highlight the importance of CDCC and CDCP in monoclonal-antibody function and provide an experimental approach for delineating the effect of complement-dependent effector-cell engagement in various therapeutic settings.




Copyright 2017 Nature Immunol. This is a post-print version of a published paper that is available at: https://www.nature.com/articles/ni.3770. Recommended citation: Lee, Chang-Han, Gabrielle Romain, Wupeng Yan, Makiko Watanabe, Wissam Charab, Biliana Todorova, Jiwon Lee et al. "IgG Fc domains that bind C1q but not effector Fc? receptors delineate the importance of complement-mediated effector functions." Nature immunology 18, no. 8 (2017): 889. doi: 10.1038/ni.3770. This iterm has been deposited in accordance with publisher copyright and licensing terms and with the author's permission.