MONOCLONAL ANTIBODY (MOAB) CONJUGATES FOR THERAPY AND DIAGNO

MONOCLONAL ANTIBODIES SPECIFIC FOR A HUMAN LUNG TUMOR-ASSOCIATED GLYCOPROTEIN ANTIGEN (GP-160) WILL BE USED TO DEVELOP AND TEST A CYTOTOXIC PROGNOSTIC IMMUNOASSAYS. THE GP-160 IS A MEMBRANE-ASSOCIATED GLYCOPROTEIN THAT IS FOUND IN SIGNIFICANT LEVELS ON SEVERAL MAJOR TYPES OF HUMAN LUNG TUMORS INCLUDING SQUAMOUS CELL CARCINOMAS, ADENOCARCINOMAS, AND LARGE CELL TUMORS. THE SPECIFICITY OF A MONOCLONAL ANTIBODY (5E8) FOR THE TUMOR-ASSOCIATED ANTIGEN HAS BEEN ESTABLISHED. THE PROPOSED THERAPEUTIC EXPLOITATION INVOLVES COVALENT COUPLING OF THESE MONOCLONAL ANTIBODIES TO UNILAMELLAR LIPOSOMES THAT ARE FILLED WITH A CYTOTOXIC DRUG. RECENT ADVANCES IN THE PREPARATION OF LIPOSOMES HAVE BEEN MADE AND THE SUCCESSFUL THERAPEUTIC EXPLOITATION OF SUCH IMMUNOSPECIFIC LIPOSOMES HAS BEEN ESTABLISHED IN A MOUSE TUMOR MODEL. PHASE I OF THIS PROPOSAL WILL INCLUDE 2.A TEST OF THE ABILITY OF IMMUNOSPECIFIC LIPOSOMES TO KILL 3.GENERATION AND PURIFICATION OF 25750 GRAMS OF GP-160-SPECIFIC ANTIBODIES, AND 4.ESTABLISHMENT OF SIMPLE AND SENSITIVE IMMUNOASSAYS FOR DETECTING CIRCULATING GP-160 OR ANTI-GP-160 IN LUNG TUMOR PATIENTS. THE ULTIMATE GOAL OF PHASE I IS TO ESTABLISH A RATIONALE FOR TESTING THE IMMUNOSPECIFIC LIPOSOMES FOR THEIR ABILITY TO SELECTIVELY DELIVER DIAGNOSTIC AND/OR CYTOTOXIC AGENTS TO A TUMOR SITE IN THE PATIENT AND TO PRODUCE TUMOR KILLING IN EXCESS OF THAT INDUCED BY EITHER ANTIBODY OR CYTOTOXIC AGENT ALONE. IT IS EXPECTED THAT CLINICAL TRIALS CAN BEGIN AS SOON AS SELECTIVE KILLING WITH THE LIPOSOMES IS ESTABLISHED IN VITRO AND GRAM QUANTITIES OF ANTIBODY ARE AVAILABLE.