IgG Fc domains that bind C1q but not effector Fcγ receptors delineate the importance of complement-mediated effector functions.

Chang-Han Lee (1) , Gabrielle Romain (2) , Wupeng Yan (2) , Makiko Watanabe (1) , Wissam Charab (1) , Biliana Todorova (3) , Jiwon Lee (1) , Kendra Triplett (1) , Moses Donkor (1) , Oana Lungu (1) , Anja Lux (4) , Nicholas Marshall (1) , Margaret Lindorfer (5) , Odile Richard-Le Goff (3) , Bianca Balbino (3, 6) , Tae Hyun Kang (1) , Hidetaka Tanno (1) , George Delidakis (1) , Corrine Alford (1) , Ronald Taylor (7) , Falk Nimmerjahn (4) , Navin Varadarajan (2) , Pierre Bruhns (3) , Yan Jessie Zhang (1) , George Georgiou (1)

1 University of Texas at Austin [Austin]
2 University of Houston
3 Anticorps en Thérapie et Pathologie
4 FAU - Friedrich-Alexander Universität Erlangen-Nürnberg
5 University of Virginia School of Medicine [US]
6 UPMC - Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie
7 xxx - University of Virginia, Department of Biochemistry and Molecular Genetics

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 Fcγ receptor (FcγR). 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 FcγR-dependent effector functions that are much better studied, while they circumvented certain adverse reactions associated with FcγR 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.

Domains: Life Sciences [q-bio]; Immunology

Chang-Han Lee, Gabrielle Romain, Wupeng Yan, Makiko Watanabe, Wissam Charab, et al.. IgG Fc domains that bind C1q but not effector Fcγ receptors delineate the importance of complement-mediated effector functions.. Nature Immunology, 2017, 18 (8), pp.889-898. ⟨10.1038/ni.3770⟩. ⟨pasteur-02510289⟩