A HUMAN ANTIBODY REPERTOIRE IN A TRANSGENIC MOUSE

MONOCLONAL ANTIBODIES HAVE BEEN SHOWN TO REPRESENT, AS A CLASS OF MOLECULES, IMPORTANT THERAPEUTIC PROTEINS WITH APPLICATION IN VARIOUS IMPORTANT DISEASE STATES. THE GOAL OF GENPHARM'S PROGRAM IS TO PROVIDE ACCESS TO THE HUMAN IMMUNOGLOBULIN REPERTOIRE SUCH THAT HUMAN MONOCLONAL ANTIBODIES CAN BE ISOLATED IN AN ANALOGOUS MANNER TO RODENT MONOCLONAL ANTIBODIES. THE GOAL OF PHASE I IS TO GENERATE TRANSGENIC MICE THAT RESPOND TO A BROAD RANGE OF ANTIGENS WITH THE PRODUCTION OF PRIMARY B-CELLS EXPRESSING A HUMAN IGM HEAVY CHAIN. AN IGM MINILOCUS CONSISTING OF UNREARRANGED HUMAN V, B, AND J SEGMENTS WILL BE INSERTED INTO THE MOUSE GERMLINE. THIS MINILOCUS WILL PROVIDE A DIVERSE REPERTOIRE OF HEAVY CHAIN GENES VIA V-D-J JOINING. IN PHASE II, TRANSGENIC MICE WILL BE PRODUCED THAT MAKE HIGH AFFINITY IGG ANTIBODIES CONTAINING HUMAN HEAVY CHAINS. THE TRANSGENE EXPRESSING B-CELLS WILL UNDERGO AFFINITY MATURATION IN RESPONSE TO A WIDE VARIETY OF ANTIGENS. THESE PHASE II MICE WILL THEN BE BRED WITH HUMAN LIGHT CHAIN EXPRESSING TRANSGENIC MICE TO GENERATE A MOUSE THAT CAN BE USED TO MAKE MOUSE HYBRIDOMAS SECRETING FULLY HUMAN MONOCLONAL ANTIBODIES.