ANTIBODIES THAT REVERSIBLY OPEN THE BLOOD-BRAIN BARRIER

THIS RESEARCH PROJECT WILL DEVELOP A MONOCLONAL ANTIBODY-BASED SYSTEM TO REVERSIBLY PERMEABILIZE THE BLOOD-BRAIN BARRIER (BBB) TO BLOOD-BORNE THERAPEUTICS. SUCH ANTIBODIES ALSO MAY SERVE AS CARRIER MOLECULES TO BRING THERAPEUTICS TO THE BBB. TO THIS END A NATURALLY OCCURRING RECEPTOR ON BRAIN ENDOTHELIUM THAT MAY BE INVOLOVED IN LEUKOCYTE MIGRATION INTO THE BRAIN WILL BE EXAMINED. THE PRESENTLY AVAILABLE MONOCLONAL ANTIBODIES CROSS REACT WITH CEREBRAL CAPILLARIES FROM HUMAN, RAT AND RABBIT. PRELIMINARY STUDIES HAVE SHOWN THAT, UPON INTRAVENOUS INJECTION INTO RABBITS, THE ANTIBODIES INDUCE TRANSIENT BBB PERMEABILITY AND BLOCK LEUKOCYTE MIGRATION INTO THE CSF. THIS DEMONSTRATES THE FEASIBILITY OF THIS APPROACH FOR DELIVERY TO THE BRAIN. PHASE I RESEARCH WILL FOCUS ON A MONOCLONAL ANTIBODY THAT RECOGNIZES RAT AND HUMAN CEREBRAL CAPILLARIES. IN RATS, EXPERIMENTS WILL BE DESIGNED TO ADDRESS THE FOLLOWING: (1) TIME AND DOSEINDEPENDENCE OF ANTIBODY LOCALIZATION TO CEREBRAL CAPILLARIES, (2) ANTIBODY-INDUCED TRANSIENT PERMEABILITY OF THE BBB TO BLOOD-BORNE MOLECULES, (3) SPECIFICITY FOR THE CEREBRAL ENDOTHELIUM,(4) DELIVERY OF ANTIBODY-PROTEIN CONJUGATES TO THE BBB AND (5) ACTION OF ANTIBODY FRAGMENTS. ADDITIONALLY, ISOLATION OF THE RAT CEREBRAL CAPILLARY RECEPTOR POLYPEPTIDE(S) WILL BE INITIATED. PHASE II WORK WILL CONCENTRATE ON ISOLATION OF THE HUMAN RECEPTOR AND DEVELOPMENT OF SECOND GENERATION ANTIBODIES THAT MAY SHOW INCREASED EFFICACY.