title: Novel human IgG1 and IgG4 Fc-engineered antibodies with completely abolished immune effector functions.
abstract: Recombinant human IgG antibodies (hIgGs) completely devoid of binding to Fcγ receptors (FcγRs) and complement protein C1q, and thus with abolished immune effector functions, are of use for various therapeutic applications in order to reduce FcγR activation and Fc-mediated toxicity. Fc engineering approaches described to date only partially achieve this goal or employ a large number of mutations, which may increase the risk of anti-drug antibody generation. We describe here two new, engineered hIgG Fc domains, hIgG1-P329G LALA and hIgG4-P329G SPLE, with completely abolished FcγR and C1q interactions, containing a limited number of mutations and with unaffected FcRn interactions and Fc stability. Both 'effector-silent' Fc variants are based on a novel Fc mutation, P329G that disrupts the formation of a proline sandwich motif with the FcγRs. As this motif is present in the interface of all IgG Fc/FcγR complexes, its disruption can be applied to all human and most of the other mammalian IgG subclasses in order to create effector silent IgG molecules.
authors: Department of Protein Analytics, Roche Pharmaceutical Research and Early Development, Large Molecules Research, Roche Innovation Center Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany.
authors: Tilman
authors: T
authors: Schlothauer
authors: Roche Pharmaceutical Research and Early Development, Large Molecules Research, Roche Innovation Center Zurich, Wagistrasse 18, CH-8952 Schlieren, Switzerland.
authors: Sylvia
authors: S
authors: Herter
authors: Roche Pharmaceutical Research and Early Development, Large Molecules Research, Roche Innovation Center Zurich, Wagistrasse 18, CH-8952 Schlieren, Switzerland.
authors: Claudia Ferrara
authors: CF
authors: Koller
authors: Roche Pharmaceutical Research and Early Development, Large Molecules Research, Roche Innovation Center Zurich, Wagistrasse 18, CH-8952 Schlieren, Switzerland.
authors: Sandra
authors: S
authors: Grau-Richards
authors: Roche Pharmaceutical Research and Early Development, Large Molecules Research, Roche Innovation Center Zurich, Wagistrasse 18, CH-8952 Schlieren, Switzerland.
authors: Virginie
authors: V
authors: Steinhart
authors: Department of Protein Analytics, Roche Pharmaceutical Research and Early Development, Large Molecules Research, Roche Innovation Center Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany.
authors: Christian
authors: C
authors: Spick
authors: Department of Protein Analytics, Roche Pharmaceutical Research and Early Development, Large Molecules Research, Roche Innovation Center Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany.
authors: Manfred
authors: M
authors: Kubbies
authors: Roche Pharmaceutical Research and Early Development, Large Molecules Research, Roche Innovation Center Zurich, Wagistrasse 18, CH-8952 Schlieren, Switzerland.
authors: Christian
authors: C
authors: Klein
authors: Roche Pharmaceutical Research and Early Development, Large Molecules Research, Roche Innovation Center Zurich, Wagistrasse 18, CH-8952 Schlieren, Switzerland.
authors: Pablo
authors: P
authors: Umaña
authors: Roche Pharmaceutical Research and Early Development, Large Molecules Research, Roche Innovation Center Zurich, Wagistrasse 18, CH-8952 Schlieren, Switzerland.
authors: Ekkehard
authors: E
authors: Mössner
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D017124:Conserved Sequence; D006031:Glycosylation; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D007074:Immunoglobulin G / Q000737:chemistry* / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D010974:Platelet Aggregation / Q000187:drug effects; D011110:Polymorphism, Genetic; D015202:Protein Engineering; D017433:Protein Structure, Secondary; D011951:Receptors, Complement / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism
chemical_list: C496124:FCGR3A protein, human; C080571:Fc gamma receptor IIB; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D011951:Receptors, Complement; D017452:Receptors, IgG; C032402:complement 1q receptor
keywords: ADCC; CDC; Fc Gamma Receptors; effector silent Fc