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

Lee, Chang-Han; Romain, Gabrielle; Yan, Wupeng; Watanabe, Makiko; Charab, Wissam; Todorova, Biliana; Lee, Jiwon; Triplett, Kendra; Donkor, Moses; Lungu, Oana I.; Lux, Anja; Marshall, Nicholas; Lindorfer, Margaret A.; Goff, Odile Richard-Le; Balbino, Bianca; Kang, Tae Hyun; Tanno, Hidetaka; Delidakis, George; Alford, Corrine; Taylor, Ronald P.; Nimmerjahn, Falk; Varadarajan, Navin; Bruhns, Pierre; Zhang, Yan Jessie; Georgiou, George

doi:10.1038/ni.3770

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

Journal Article · Mon Jun 12 00:00:00 EDT 2017 · Nature Immunology

DOI:https://doi.org/10.1038/ni.3770· OSTI ID:1433698

^[1]; Romain, Gabrielle ^[2]; ^[1]; Watanabe, Makiko ^[1]; Charab, Wissam ^[1]; Todorova, Biliana ^[3]; Lee, Jiwon ^[1]; Triplett, Kendra ^[1]; Donkor, Moses ^[4]; Lungu, Oana I. ^[1]; Lux, Anja ^[5]; Marshall, Nicholas ^[6]; Lindorfer, Margaret A. ^[7]; Goff, Odile Richard-Le ^[3]; Balbino, Bianca ^[8]; Kang, Tae Hyun ^[1]; Tanno, Hidetaka ^[1]; Delidakis, George ^[1]; Alford, Corrine ^[1]; ^[9] more »

Univ. of Texas, Austin, TX (United States)
Univ. of Houston, TX (United States)
Inst. Pasteur, Paris (France)
MedImmune, Gaithersburg, MD (United States); Univ. of Texas, Austin, TX (United States)
Univ. of Erlangen-Nürnberg (Germany)
Dept. of Biochemical Engineering and Structure, Merck, NJ (United States); Univ. of Texas, Austin, TX (United States)
Univ. of Virginia of Medicine, Charlottesville, VA (United States)
Inst. Pasteur, Paris (France); INSERM, Paris (France); Univ. Pierre et Marie Curie, Paris (France)
Univ. of Virginia School of Medicine, Charlottesville, VA (United States)

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. Here, 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Inst. of Health; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1433698

Journal Information:: Nature Immunology, Journal Name: Nature Immunology Journal Issue: 8 Vol. 18; ISSN 1529-2908

Publisher:: Nature Research, Springer NatureCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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