A Human FcγRI/CD64 Transgenic Model for In Vivo Analysis of (Bispecific) Antibody Therapeutics

The human high-affinity IgG receptor, hFcγRI (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 hFcγRI in immunity, we developed a novel transgenic mouse model. The human FcγRIA gene, with endogenous regulatory sequences, was used to generate two lines of transgenic FVB/N mice. Immunohistochemical and flow cytometric studies showed that hFcγRI expression was restricted to myeloid cells. Monocytes, macrophages, and polymorphonuclear neutrophils (PMN) expressed physiologic hFcγRI levels, whereas lymphocytes and mast cells lacked expression. Human FcγRI expression was regulated in vivo by the cytokines IFN-γ (exactly as in humans) and IL-10. The transgenic receptor proved functional and bound human tumor cells via anti-hFcγRI-based bispecific antibodies. hFcγRI could, furthermore, be efficiently targeted in vivo by CD64 antibodies. These data demonstrate that the hFcγRI 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.