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Nat Immunol. 2017 Aug;18(8):889-898. doi: 10.1038/ni.3770. Epub 2017 Jun 12.

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

Author information

1
Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA.
2
Department of Chemical and Biomolecular Engineering, University of Houston, Houston, Texas, USA.
3
Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, USA.
4
Institut Pasteur, Department of Immunology, Unit of Antibodies in Therapy and Pathology, Paris, France.
5
INSERM, U760, Paris, France.
6
Institute of Genetics, Department of Biology, University of Erlangen-Nürnberg, Erlangen, Germany.
7
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
8
Université Pierre et Marie Curie, Paris, France.
9
Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, USA.
10
Institute for Cell and Molecular Biology, University of Texas at Austin, Austin, Texas, USA.
11
Center for Systems and Synthetic Biology University of Texas at Austin, Austin, Texas, USA.

Abstract

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.

PMID:
28604720
PMCID:
PMC6015732
DOI:
10.1038/ni.3770
[Indexed for MEDLINE]
Free PMC Article

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