Systemic administration of an Fcgamma-Fc(epsilon)-fusion protein in house dust mite sensitive nonhuman primates.
Crosslinking Fc(epsilon)RI and FcgammaRIIB receptors inhibits mast cell and basophil activation, decreasing mediator release. In this study, a fusion protein incorporating human Fcgamma and Fc(epsilon) domains, hGE2, was shown to inhibit degranulation of human mast cells and basophils, and to exhibit efficacy in a nonhuman primate model of allergic asthma. hGE2 increased the provocative concentration of dust mite aeroallergen that induced an early phase asthmatic response. The treatment effect lasted up to 4 weeks and was associated with reduction in the number of circulating basophils and decreased expression of Fc(epsilon)RI on repopulating basophils. Repeat hGE2 dosing induced production of serum antibodies against human Fcgamma and Fc(epsilon) domains and acute anaphylaxis-like reactions. Immune serum induced histamine release from human IgE or hGE2-treated cord blood-derived mast cells and basophils in vitro. These results indicate that repeat administration with hGE2 induced an antibody response to the human molecule that resulted in activation rather than inhibition of allergic responses.
Van Scott
Michael R
MR
Department of Physiology, East Carolina University, Greenville, NC 27834, USA. vanscottmi@ecu.edu
Mertsching
Elisabeth
E
Negrou
Ella
E
Miles
Jeremy
J
Stallings
Howard W
HW
Graff
Candace
C
Kehry
Marilyn R
MR
D000485:Allergens / Q000276:immunology / Q000378:metabolism; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D001491:Basophils / Q000276:immunology* / Q000378:metabolism; D006636:Histamine Release; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism; D039981:Pyroglyphidae / Q000276:immunology*; D017455:Receptors, IgE / Q000008:administration & dosage* / Q000276:immunology / Q000378:metabolism; D017452:Receptors, IgG / Q000008:administration & dosage* / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics
D000485:Allergens; C499173:FCGR2B protein, human; D017455:Receptors, IgE; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins