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

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

doi:10.1038/ni.3770

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

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

Authors

Chang-Han Lee¹, Gabrielle Romain², Wupeng Yan³, Makiko Watanabe¹, Wissam Charab¹, Biliana Todorova^{4

5}, Jiwon Lee¹, Kendra Triplett³, Moses Donkor¹, Oana I Lungu¹, Anja Lux⁶, Nicholas Marshall¹, Margaret A Lindorfer⁷, Odile Richard-Le Goff^{4

5}, Bianca Balbino^{4

5

8}, Tae Hyun Kang¹, Hidetaka Tanno¹, George Delidakis¹, Corrine Alford⁹, Ronald P Taylor⁷, Falk Nimmerjahn⁶, Navin Varadarajan², Pierre Bruhns^{4

5}, Yan Jessie Zhang^{3

10}, George Georgiou^{1

3

9

10

11}

Affiliations

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.

PMID: 28604720
PMCID: PMC6015732
DOI: 10.1038/ni.3770

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.

MeSH terms

Animals
Antibodies, Monoclonal
Burkitt Lymphoma / drug therapy
Burkitt Lymphoma / immunology
Cell Line, Tumor
Chromatography, Gel
Chromatography, Liquid
Complement C1q / immunology*
Complement C1q / metabolism
Crystallization
Crystallography, X-Ray
Cytotoxicity, Immunologic / immunology*
Enzyme-Linked Immunosorbent Assay
Humans
Immunoglobulin Fc Fragments / immunology*
Immunoglobulin Fc Fragments / metabolism
Immunoglobulin G / immunology*
Immunoglobulin G / metabolism
Immunotherapy*
In Vitro Techniques
Lymphoma, B-Cell / drug therapy
Lymphoma, B-Cell / immunology
Lymphoma, Large B-Cell, Diffuse / drug therapy
Lymphoma, Large B-Cell, Diffuse / immunology
Mass Spectrometry
Mice
Neoplasms / drug therapy*
Neoplasms / immunology
Phagocytosis / immunology*
Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma / immunology
Receptors, IgG / immunology*
Receptors, IgG / metabolism
Surface Plasmon Resonance
Tandem Mass Spectrometry

Substances

Antibodies, Monoclonal
Immunoglobulin Fc Fragments
Immunoglobulin G
Receptors, IgG
Complement C1q

Abstract

MeSH terms

Substances

Grants and funding