CELL-SURFACE EXPRESSION OF A HUMAN-IGG FC CHIMERA ACTIVATES MACROPHAGES THROUGH FC-RECEPTORS

Antibody-dependent eel-mediated cytotoxicity plays an important role i n the macrophage-mediated destruction of target cells. While the selec tivity is based on antibody specificity, the lytic attack is triggered by Fc receptor-mediated respiratory burst. To mimic IgG opsonization, a chimeric antibody-like molecule, containing human IgG1 Fc, was expr essed on the surface of mammalian cells. The transmembrane domain of t he human transferrin receptor was fused in-frame to the N-terminus of the second and third domains of human IgG1 heavy-chain constant region . This fusion molecule was designed to take advantage of the type II m embrane anchor property of the transferrin receptor to express the Fc portion of the molecule in a reverse orientation, such that the Fc por tion projected away from the cell surface. This is in contrast to the conventional cell surface IgG, which is anchored by a C-terminal type I transmembrane domain. The cell surface expressed reverse Fc no longe r activated complement, but retained Fc receptor-binding capability an d activated superoxide production by macrophages. This activity was co mpletely blocked by an Fc gamma R I-specific monoclonal antibody.