Medarex has exclusive license to several monoclonal antibodies (mAb) reactive to the high affinity Fc receptor for IgG (Fc-gamma-Rl) which is expressed on human monocytes and, after IFN-gamma activation, on human PMNs. This receptor is a critical trigger molecule for ADCC by these cells. We propose to determine the feasibility of using the mAb to this receptor in conjunction with mAbs to HIV antigens to kill HIV-infected cells. Studies by consultants to Medarex indicate that this approach pen-nits lysis of tumor cell targets. In this application, we propose studies to demonstrate that bi-specific antibodies composed of mAb to trigger molecules on myeloid cells coupled to antibodies reactive to the HIV gpl2O antigen can mediate killing of cells expressing gpl2O by human monocytes, macrophages and/or granulocytes.
Our specific aims are, therefore, to investigate, using these bi-specific antibodies, whether our anti-Fc-gamma- RI mAbs, when coupled to anti-gp120 mAb, mediate: 1) killing by human monocytes of the cell lines expressing the HIV gpl20; 2) enhanced killing of gpl2O expressing cells if the monocytes are first activated by cytokines; 3) killing of these gp 120 expressing cells by other human myeloid cells, before or after activation by cytokines. We would thus define the receptors and conditions which promote killing by human monocytes or PmNs of cells which model HIV-infected cells. In particular, these studies would focus on the ability of monocytes and PMNs targeted through Fc-gamma-RI to mediate killing of cells expressing the gp 120 antigen as a prelude to studies of cytoxity of HIV and HIV infected cells.