BI-SPECIFIC ANTIBODY-DIRECTED KILLING IN HIV THERAPY

MEDAREX, INC., HAS EXCLUSIVE LICENSE TO SEVERAL MONOCLONAL ANTIBODIES (MABS) REACTIVE TO THE HIGH-AFFINITY FC RECEPTOR FOR IGG (FC RI), WHICH IS EXPRESSED ON HUMAN MONOCYTES AND, AFTER IFN ACTIVATION, ON HUMAN PMNS. THIS RECEPTOR IS A CRITICAL TRIGGER MOLECULE FOR ADCC BY THESE CELLS. THIS RESEARCH WILL DETERMINE THE FEASIBILITY OF USING THE MAB TO THIS RECEPTOR IN CONJUNCTIONWITH MABS TO HIV ANTIGENS TO KILL HIV-INFECTED CELLS. STUDIES HAVE INDICATED THAT THIS APPROACH PERMITS LYSIS OF TUMOR CELL TARGETS. IN THIS PROJECT, STUDIES WILL DEMONSTRATE THAT BI-SPECIFIC ANTIBODIES COMPOSED OF MAB TO TRIGGER MOLECULES ON MYELOID CELLS COUPLED TO ANTIBODIES REACTIVE TO THE HIV GP120 ANTIGEN CAN MEDIATE KILLING OF CELLS EXPRESSING GP120 BY HUMAN MONOCYTES, MACROPHAGES, AND/OR GRANULOCYTES. THE SPECIFIC AIMS ARE TO INVESTIGATE, USING THESE BI-SPECIFIC ANTIBODIES, WHETHER ANTI-FC RI MABS, WHEN COUPLED TO ANTI-GP120 MAB, MEDIATE: (1) KILLING BY HUMAN MONOCYTES OF THE CELL LINES EXPRESSING THE HIV GP120; (2) ENHANCED KILLING OF GP120-EXPRESSING CELLS IF THE MONOCYTES ARE FIRSTACTIVATED BY CYTOKINES; AND (3) KILLING OF THESE GP120-EXPRESSING CELLS BY OTHER HUMAN MYELOID CELLS, BEFORE OR AFTER ACTIVATION BY CYTOKINES. THE STUDIES WILL FOCUS ON THE ABILITY OF MONOCYTES AND PMNS TARGETED THROUGH FC RI TO MEDIATE KILLING OF CELLS EXPRESSING THE GP120 ANTIGEN AS A PRELUDE TO STUDIES OF CYTOTOXICITY OF HIVAND HIV-INFECTED CELLS.