A human Fc gamma RI/CD64 transgenic model for in vivo analysis of (bispecific) antibody therapeutics.
The human high-affinity IgG receptor, hFc gamma RI (CD64), is exclusively expressed on myeloid cells, where it serves an important role as a (cytotoxic) trigger molecule. To establish an in vivo model for analysis of the role of hFc gamma RI in immunity, we developed a novel transgenic mouse model. The human Fc gamma RIA gene, with endogenous regulatory sequences, was used to generate two lines of transgenic FVB/N mice. Immunohistochemical and flow cytometric studies showed that hFc gamma RI expression was restricted to myeloid cells. Monocytes, macrophages, and polymorphonuclear neutrophils (PMN) expressed physiologic hFc gamma RI levels, whereas lymphocytes and mast cells lacked expression. Human Fc gamma RI expression was regulated in vivo by the cytokines IFN-gamma (exactly as in humans) and IL-10. The transgenic receptor proved functional and bound human tumor cells via anti-hFc gamma RI-based bispecific antibodies. hFc gamma RI could, furthermore, be efficiently targeted in vivo by CD64 antibodies. These data demonstrate that the hFc gamma RI transgenic mouse model closely parallels the situation in humans. This mouse model seems useful for in vivo evaluation of the therapeutic potential of novel bispecific reagents in tumor and infection models.
Heijnen
I A
IA
Department of Immunology, University Hospital Utrecht, The Netherlands.
Van de Winkel
J G
JG
D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000276:immunology; D000920:Antibody-Dependent Cell Cytotoxicity; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology; D016753:Interleukin-10 / Q000502:physiology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D017452:Receptors, IgG / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D016753:Interleukin-10; D007371:Interferon-gamma