Fc gamma RI blockade and modulation for immunotherapy.
Splenectomy and corticosteroids are the treatment of choice for patients with immune thrombocytopenic purpura (ITP). However, for the 10%-15% of patients who do not respond to conventional therapy, high-dose i.v. IgG can induce life-saving transient responses. The benefits of i.v. IgG have been attributed to Fc receptor blockade; however, the involvement of the individual Fc receptors for IgG (Fc gamma R) in ITP remain to be more completely defined. Recently a mAb, designated mAb H22, which recognizes an epitope on Fc gamma RI (CD64) outside the ligand-binding domain, was humanized. Because mAb H22 is a human IgG1 and Fc gamma RI has a high affinity for human IgG1 antibodies, we predicted that mAb H22 would bind to the Fc gamma RI ligand-binding site through its Fc domain and to its external Fc gamma RI epitope through both Fab domains. These studies demonstrate that mAb H22 blocked Fc gamma RI-mediated phagocytosis of opsonized red blood cells more effectively than an irrelevant IgG. Moreover, cross-linking Fc gamma RI with mAb H22 down-modulated Fc gamma RI expression on monocytes, an effect seen within 2 h.
Wallace
P K
PK
Department of Microbiology, Dartmouth Medical School, Lebanon, NH 03756, USA. pkw@dartmouth.edu
Keler
T
T
Guyre
P M
PM
Fanger
M W
MW
D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism / Q000627:therapeutic use; D001667:Binding, Competitive; D001792:Blood Platelets / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes / Q000276:immunology* / Q000378:metabolism; D004912:Erythrocytes / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology* / Q000378:metabolism / Q000627:therapeutic use; D007167:Immunotherapy / Q000379:methods; D009000:Monocytes / Q000276:immunology / Q000502:physiology; D010587:Phagocytosis; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000276:immunology / Q000628:therapy; D017452:Receptors, IgG / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000939:Epitopes; D007074:Immunoglobulin G; D017452:Receptors, IgG