title: Monomeric IgG1 Fc molecules displaying unique Fc receptor interactions that are exploitable to treat inflammation-mediated diseases.
abstract: The IgG1 Fc is a dimeric protein that mediates important antibody effector functions by interacting with Fcγ receptors (FcγRs) and the neonatal Fc receptor (FcRn). Here, we report the discovery of a monomeric IgG1 Fc (mFc) that bound to FcγRI with very high affinity, but not to FcγRIIIa, in contrast to wild-type (dimeric) Fc. The binding of mFc to FcRn was the same as that of dimeric Fc. To test whether the high-affinity binding to FcγRI can be used for targeting of toxins, a fusion protein of mFc with a 38 kDa Pseudomonas exotoxin A fragment (PE38), was generated. This fusion protein killed FcγRI-positive macrophage-like U937 cells but not FcγRI-negative cells, and mFc or PE38 alone had no killing activity. The lack of binding to FcγRIIIa resulted in the absence of Fc-mediated cytotoxicity of a scFv-mFc fusion protein targeting mesothelin. The pharmacokinetics of mFc in mice was very similar to that of dimeric Fc. The mFc's unique FcγRs binding pattern and related functionality, combined with its small size, monovalency and the preservation of FcRn binding which results in relatively long half-life in vivo, suggests that mFc has great potential as a component of therapeutics targeting inflammation mediated by activated macrophages overexpressing FcγRI and related diseases, including cancer.
authors.affiliation: a Key Laboratory of Medical Molecular Virology of Ministries of Education and Health; Shanghai Medical College ; Fudan University ; Shanghai , China.
authors.forename: Tianlei
authors.initials: T
authors.lastname: Ying
authors.forename: Yang
authors.initials: Y
authors.lastname: Feng
authors.forename: Yanping
authors.initials: Y
authors.lastname: Wang
authors.forename: Weizao
authors.initials: W
authors.lastname: Chen
authors.forename: Dimiter S
authors.initials: DS
authors.lastname: Dimitrov
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D001426:Bacterial Proteins / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D057809:HEK293 Cells; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000494:pharmacology; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D000090204:Mesothelin; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding / Q000276:immunology; D011961:Receptors, Fc / Q000276:immunology* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D020298:U937 Cells
chemical_list: D000911:Antibodies, Monoclonal; D001426:Bacterial Proteins; D015395:Histocompatibility Antigens Class I; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; C000715528:Msln protein, mouse; D011961:Receptors, Fc; C111749:pseudomonas exoprotein A protein, Pseudomonas aeruginosa; D000090204:Mesothelin; C100688:Fc receptor, neonatal
keywords: ADCC; FcRn; Fcγ receptors; chronic inflammation; monomeric Fc