P01HL183482

PLANB2CUREHIV (THE 'PLANB' CONSORTIUM) - PROJECT SUMMARY ANTIBODIES CAPABLE OF NEUTRALIZING THE GLOBAL DIVERSITY OF HIV STRAINS ARE DIFFICULT TO ELICIT IN HUMANS. THIS IS BECAUSE SUCH ANTIBODIES REQUIRE UNUSUAL FEATURES DERIVING FROM RARE PRECURSOR B CELLS THAT MUST UNDERGO EXTENSIVE AFFINITY MATURATION. TO DATE, ONLY A SMALL NUMBER OF POTENT BROADLY NEUTRALIZING ANTIBODIES (BNABS) HAVE BEEN ISOLATED AFTER SCREENING THOUSANDS OF PATIENTS RESPONDING TO UNSUPPRESSED INFECTION. PASSIVE IMMUNIZATION WITH RECOMBINANT MONOCLONAL HIV BNABS HOWEVER, CAN MAINTAIN SUPPRESSION OF VIREMIA IN PATIENTS AFTER ANTI-RETROVIRAL TREATMENT (ART) INTERRUPTION FOR AS LONG AS SERUM TITERS REMAIN ABOVE THRESHOLD EFFECTIVE SERUM CONCENTRATIONS. THIS SUGGESTS THAT ESTABLISHING DURABLE BNAB TITERS ABOVE THESE THRESHOLDS COULD RESULT IN AN HIV FUNCTIONAL CURE, DEFINED AS LIFE-LONG SUPPRESSION OF VIREMIA. SINCE HIV BNABS CANNOT BE ELICITED THROUGH VACCINATION, GENE THERAPIES ARE BEING CONSIDERED AS AN APPROACH TO DELIVER SUCH LONG- LASTING BNAB TITERS IN VIVO. OF THESE, GENOME-EDITED B CELLS ARE A NOVEL AND PROMISING APPROACH THAT MAY HOLD SEVERAL KEY ADVANTAGES. PRIMARY B CELL ANTIGEN RECEPTORS (BCRS) CAN BE REPROGRAMMED TO EXPRESS NOVEL SPECIFICITIES BY INSERTING ANTIBODY TRANSGENE CASSETTES INTO THE IGH-LOCUS DOWNSTREAM OF ENDOGENOUS HEAVY CHAIN (HC) IMMUNOGLOBULIN (IG) VARIABLE REGION EXONS. THESE MODIFIED CELLS CAN BE EXPANDED AND DIFFERENTIATED IN VIVO BY VACCINATION INTO MEMORY AND LONG-LIVED PLASMA CELLS THAT CAN DURABLY SECRETE THE NEW ANTIBODY SPECIFICITY IN WILD TYPE IMMUNOCOMPETENT MICE BY INDEPENDENT RESEARCH GROUPS. THE OVERALL PURPOSE OF THE PLANB CONSORTIUM IS TO ACCELERATE THE PRE-CLINICAL DEVELOPMENT OF SAFE AND EFFECTIVE IGH- REPROGRAMMED B CELL-BASED THERAPIES THAT WOULD PROVIDE LIFE-LONG BNAB TITERS CAPABLE OF MAINTAINING SUPPRESSION OF THE VIRAL RESERVOIR, ALLOWING PATIENTS TO DISCONTINUE ART THERAPY. OUR AIM IS TO DEVELOP AND COMPARE TWO DISTINCT OPTIONS FROM WHICH ONE COULD BE SELECTED FOR CLINICAL DEVELOPMENT UPON COMPLETION OF THE PROGRAM. THE FIRST IS AN EX VIVO REPROGRAMMED B CELL PRODUCT THAT CAN BE AUTOLOGOUSLY TRANSFERRED AND VACCINATED IN PATIENTS. THE SECOND IS AN IN VIVO B CELL TARGETING AND IGH-REPROGRAMMING SYSTEM THAT WILL BE USED IN CONJUNCTION WITH VACCINATION. IN BOTH CASES, DURABLE HIV BROADLY NEUTRALIZING ANTIBODY MEMORY RESPONSES MUST BE ELICITED FROM THE ENGINEERED CELLS.

Scripps Research Institute

THE DIVISION OF BLOOD DISEASES AND RESOURCES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE PATHOPHYSIOLOGY, DIAGNOSIS, TREATMENT, AND PREVENTION OF NON-MALIGNANT BLOOD DISEASES, INCLUDING ANEMIAS, SICKLE CELL DISEASE, THALASSEMIA, LEUKOCYTE BIOLOGY, PRE-MALIGNANT PROCESSES SUCH AS MYELODYSPLASIA AND MYELOPROLIFERATIVE DISORDERS, HEMOPHILIA AND OTHER ABNORMALITIES OF HEMOSTASIS AND THROMBOSIS, AND IMMUNE DYSFUNCTION. FUNDING ENCOMPASSES A BROAD SPECTRUM OF HEMATOLOGIC INQUIRY, RANGING FROM STEM CELL BIOLOGY TO MEDICAL MANAGEMENT OF BLOOD DISEASES AND TO ASSURING THE ADEQUACY AND SAFETY OF THE NATION'S BLOOD SUPPLY. PROGRAMS ALSO SUPPORT THE DEVELOPMENT OF NOVEL CELL-BASED THERAPIES TO BRING THE EXPERTISE OF TRANSFUSION MEDICINE AND STEM CELL TECHNOLOGY TO THE REPAIR AND REGENERATION OF HUMAN TISSUES AND ORGANS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

La Jolla, California 920371000 United States

Single Zip Code

Cell and Gene Therapies for HIV Cure: Developing a Pipeline (P01 Clinical Trial Not Allowed) (RFA-AI-24-013)