CHIMERIC CD4/IMMUNOGLOBULIN ANTIBODIES FOR AIDS

ONE OF THE MOST URGENT CHALLENGES FACING THE MEDICAL COMMUNITY IS THE DEVELOPMENT OF EFFECTIVE THERAPEUTIC AGENTSFOR VICTIMS OF THE WORLDWIDE AIDS EPIDEMIC. BECAUSE OF THEIR HIGH DEGREE OF SPECIFICITY AND HIGHLY SPECIALIZED EFFECTOR FUNCTIONS, MONOCLONAL ANTI-HIV ENVELOPE PROTEIN ANTIBODIES ARE CONSIDERED TO BE PROMISING CANDIDATES FOR MEETING THIS CHALLENGE. AS THE EXACT AMINO ACID SEQUENCE OF THE ENVELOPE PROTEIN (GP160) ON HIV TYPES CAN VARY GREATLY, THE OVERALL SUCCESS OF SUCH AN APPROACH WILL DEPEND ON THE IDENTIFICATION OF VIRUS-NEUTRALIZING MONOCLONAL ANTIBODIES (MOAB'S) THAT CAN RECOGNIZE HIGHLY CONSERVED FEATURES OF THE ENVELOPE. THIS PROJECT PRESENTS A PROCEDURE FOR THE PREPARATION OF A NOVEL ANTIBODY CHIMERA THAT MAY FULFILL THESE CRITERIA. THOUGH ESSENTIALLY A HUMAN GAMMA 1 KAPPA ANTIBODY, THE AMINO ACID SEQUENCE OF ONE OR BOTH PAIRS OF VARIABLE REGIONS(V REGIONS) IN THIS CHIMERA WILL BE REPLACED WITH THE SEQUENCE OF A SINGLE-PROTEIN DOMAIN (E1 DOMAIN) OF THE CD4 MOLECULE. CD4 IS THE CELLULAR RECEPTOR FOR HIV. THE E1DOMAIN OF CD4 IS PROBABLY SUFFICIENT TO EXPRESS FULL VIRUS BINDING. IT SHARES SIGNIFICANT STRUCTURAL HOMOLOGY WITH IMMUNOGLOBULIN V DOMAINS. BECAUSE ALL HIV TYPES SEEM TO USECD4 AS THEIR CELLULAR RECEPTOR, THIS CD4/AB CHIMERA (E1/AB) MAY PROVIDE A CONVENIENT ROUTE TO A GROUP-SPECIFIC THERAPEUTIC AGENT.