Monoclonal antibody 197 (anti-Fc gamma RI) infusion in a patient with immune thrombocytopenia purpura (ITP) results in down-modulation of Fc gamma RI on circulating monocytes.
A 44-year old woman with refractory immune thrombocytopenia purpura was treated with the murine monoclonal antibody 197 in a phase 1 trial. It vitro studies have demonstrated that the monoclonal antibody 197 (subclass IgG2a) binds to two distinct epitopes of Fc gamma RI, with the constant domain binding to the Fc-binding portion of the Fc gamma RI and the variable domain binding to a different epitope, resulting in crosslinking and modulation of this receptor. The monoclonal antibody 197 was administered on days 1, 3 and 5 at doses of 0.25 mg/kg, 0.35 mg/kg and 0.45 mg/kg, respectively. The fusions were well tolerated with transient facial flushing, and wheal-and-flare rash during the first infusion, which resolved with a slower infusion rate and the administration of diphenhydramine and acetaminophen. Although a marked clinical improvement did occur with resolution of oral ecchymoses and epistaxis after the first mAb infusion, the initial platelet count of 6 x 10(9)/I did not change appreciable over the 5 d course of monoclonal antibody treatment. Binding of fluorescein-labelled monoclonal antibody 197 to peripheral monocytes showed a rapid and persistently decreased mean fluorescein intensity, indicated binding of administered 197 to the monocytes in vivo. Indirect staining for FcgammaRI using fluorescein-labelled goat anti-mouse immunoglobulin was also decreased, suggesting modulation of the receptor. The patient experienced monocytopenia which persisted throughout the 5 d of monoclonal antibody 197 therapy, but reversed following institution of intravenous IgG. These data indicate that intravenous monoclonal antibody 197 induces specific down-modulation of Fc gamma RI expression on monocytes.
Ericson
S G
SG
Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA.
Coleman
K D
KD
Wardwell
K
K
Baker
S
S
Fanger
M W
MW
Guyre
P M
PM
Ely
P
P
D000328:Adult; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D001792:Blood Platelets / Q000276:immunology; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology*; D016130:Immunophenotyping; D016131:Lymphocyte Subsets; D010976:Platelet Count; D011696:Purpura, Thrombocytopenic / Q000276:immunology / Q000628:therapy*; D017452:Receptors, IgG / Q000276:immunology
D000911:Antibodies, Monoclonal; D007141:Immunoglobulin Fc Fragments; D017452:Receptors, IgG