title: Humanized mAb H22 binds the human high affinity Fc receptor for IgG (FcgammaRI), blocks phagocytosis, and modulates receptor expression.
abstract: About 10-15% of patients with immune thrombocytopenic purpura (ITP) cannot be controlled by corticosteroid therapy and splenectomy. For these patients treatment with high-dose IVIgG induces partial or complete responses. The clinical benefits of IVIgG could be due to blockade of Fc receptors for IgG (FcgammaR), because several model systems clearly show that functional FcgammaR are essential for establishment of ITP and related diseases. However, the specific contributions of the three individual classes of FcgammaR remain to be more completely defined. Recently monoclonal antibody (mAb) H22, which recognizes an epitope on FcgammaRI (CD64) outside the ligand binding domain, was humanized by grafting its complementarity determining regions onto human IgG1 constant domains. Because FcgammaRI has a high affinity for human IgG1 antibodies, we predicted mAb H22 would also bind to FcgammaRI through its Fc domain and block FcgammaRI-mediated phagocytosis. These studies demonstrate that mAb H22 blocked phagocytosis of opsonized red blood cells 1000 times more effectively than an irrelevant IgG. Moreover, cross-linking FcgammaRI with mAb H22 rapidly down-modulated FcgammaRI expression on monocytes without affecting other surface antigens. We conclude that because mAb H22 is a humanized mAb that blocks the FcgammaRI ligand binding domain and down-modulates FcgammaRI expression, it is a particularly good candidate for evaluating the role of FcgammaRI in patients with ITP.
authors.affiliation: Department of Microbiology, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
authors.forename: P K
authors.initials: PK
authors.lastname: Wallace
authors.forename: T
authors.initials: T
authors.lastname: Keler
authors.forename: K
authors.initials: K
authors.lastname: Coleman
authors.forename: J
authors.initials: J
authors.lastname: Fisher
authors.forename: L
authors.initials: L
authors.lastname: Vitale
authors.forename: R F
authors.initials: RF
authors.lastname: Graziano
authors.forename: P M
authors.initials: PM
authors.lastname: Guyre
authors.forename: M W
authors.initials: MW
authors.lastname: Fanger
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000096:biosynthesis; D002478:Cells, Cultured; D000939:Epitopes / Q000032:analysis; D004912:Erythrocytes / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D007127:Immunoglobulin Constant Regions; D007074:Immunoglobulin G; D007700:Kinetics; D051379:Mice; D018448:Models, Immunological; D009000:Monocytes / Q000276:immunology*; D010587:Phagocytosis; D017452:Receptors, IgG / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000939:Epitopes; D007127:Immunoglobulin Constant Regions; D007074:Immunoglobulin G; D017452:Receptors, IgG