Montreal Road W Tucker

ALLOGENEIC CELL AND GENE THERAPY FOR NEUROENDOCRINE TUMORS - PROJECT SUMMARY/ABSRACT NEUROENDOCRINE TUMORS (NETS) ARE A TYPE OF RARE NEOPLASM THAT ORIGINATES FROM CELLS OF THE DIFFUSE NEUROENDOCRINE SYSTEM. IT IS ESTIMATED THAT MORE THAN 12,000 PEOPLE IN THE U.S. ARE DIAGNOSED WITH A NET EACH YEAR AND, IN TOTAL, APPROXIMATELY 171,000 PEOPLE IN THE U.S. ARE LIVING WITH NETS IN 2023. THE NUMBER OF INDIVIDUALS DIAGNOSED WITH THIS TYPE OF TUMOR HAS BEEN INCREASING CONSISTENTLY OVER THE PAST 30 YEARS, FROM 1.09 PER 100,000 PERSONS IN 1973 TO 6.98 PER 100,000 PERSONS BY 2012. THIS OBSERVED INCREASE IN NET INCIDENCE IS THOUGHT TO BE THE RESULT OF IMPROVEMENTS IN AWARENESS AND DIAGNOSTICS, INCLUDING BETTER IMAGING TESTS AND ENDOSCOPY. THE MAJORITY OF NETS, AND SPECIFICALLY WELL-DIFFERENTIATED AND FUNCTIONAL GEPNETS, EXPRESS THE SURFACE PROTEIN, SOMATOSTATIN RECEPTOR TYPE 2 (SSTR2), WHICH IS THE BASIS FOR BOTH DIAGNOSIS, IMAGING (INCLUDING MONITORING FOR PROGRESSION), AND SYMPTOMATIC THERAPY. TREATMENT OPTIONS FOR NEUROENDOCRINE TUMORS DEPEND ON FACTORS SUCH AS TUMORS SIZE, LOCATION, GRADE, AND MALIGNANT SPREAD. APPROACHES INCLUDE SURGICAL REMOVAL (IF POSSIBLE), TARGETED DRUG THERAPY, CHEMOTHERAPY, AND PEPTIDE RECEPTOR RADIONUCLIDE THERAPY (PRRT). OTHER THAN RARE CASES LOCALIZED, SURGICALLY ACCESSIBLE DISEASE, THERE ARE NO CURATIVE THERAPIES FOR NETS. THE PRIMARY APPROVED DRUGS ARE SOMATOSTATIN ANALOGS (SSAS), SSA-BASED PRRT, AND A TRYPTOPHAN HYDROXYLASE INHIBITOR (BLOCKS SEROTONIN BIOSYNTHESIS; TELOTRISTAT ETHYL). WHILE THESE DRUGS CAN HELP ALLEVIATE SOME OF THE SYMPTOMS ASSOCIATED WITH THE SECRETION OF BIOACTIVE SUBSTANCES FROM FUNCTIONAL NETS, THEY DEMONSTRATE LITTLE TO NO EFFECT ON REDUCING TUMOR BURDEN OR GENERATING COMPLETE REMISSION. FURTHERMORE, PRRT AFFECTS ORGAN FUNCTION AND CAN LEAD TO SECONDARY MALIGNANCIES. THEREFORE, OTHER THAN THE LIMITED CASES WHERE COMPLETE SURGICAL RESECTION IS POSSIBLE, NO CURATIVE TREATMENT OPTIONS CURRENTLY EXIST. CELL AND GENE THERAPY (CGT)-BASED IMMUNO-ONCOLOGY (1-0) DRUGS ARE TRANSFORMING CANCER OUTCOME EXPECTATIONS. EXPRESSION THERAPEUTICS, INC. (ET) IS A FULLY INTEGRATED CGT COMPANY WITH AN ESTABLISHED EXECUTIVE TEAM THAT HAS DEMONSTRATED PROVEN SUCCESS IN PRECLINICAL EXECUTION, CLINICAL DEVELOPMENT, AND GMP MANUFACTURING OF TRANSFORMATIVE THERAPIES IN THE HEMOPHILIA AND ONCOLOGY SPACES. ET POSSESSES DIFFERENTIATED, PROPRIETARY PLATFORM TECHNOLOGIES INCLUDING THE LENTET GENE TRANSFER SYSTEM, EXPRESSION CASSETTE OPTIMIZATION (ECO), SECRETED T CELL ACTUATORS (STARS), AND ALLOGENEIC DONOR EXPANDED AND PROGRAMMED T (ADEPT) CELLS. EXPRESSION THERAPEUTICS HAS DEVELOPED CANDIDATE STAR EXPRESSED BY ADEPT CELLS THAT DISPLAYS POTENT CYTOTOXICITY AGAINST CANCER CELL LINES. THE OVERALL GOAL OF THE PROPOSED STUDIES IS TO ADVANCE A PROMISING LEAD ADEPT-STAR-NET CANDIDATE TOWARDS CLINICAL TESTING.

NATURAL GLYCANS FOR FUNCTIONAL GLYCOMICS - NATURAL GLYCANS FOR FUNCTIONAL GLYCOMICS PROJECT SUMMARY/ ABSTRACT DURING THE FIRST DECADE OF THE 21ST CENTURY, NIH MADE SIGNIFICANT INVESTMENTS IN GLYCOMICS. THE CONSORTIUM FOR FUNCTIONAL GLYCOMICS (SUPPORTED BY NIGMS 2001-2012) LED A MAJOR INTERNATIONAL EFFORT USING A MICROARRAY OF 611 DEFINED GLYCANS TO IDENTIFY THE PROTEIN-GLYCAN INTERACTIONS ASSOCIATED WITH NORMAL PHYSIOLOGY AND DISEASE (HTTP://WWW.FUNCTIONALGLYCOMICS.ORG/CFGPARADIGMS/INDEX.PHP/WELCOME_TO_THE_CFG_PARADIGM_PAGES). THIS 611 GLYCAN LIBRARY TRANSFORMED STUDIES ON PROTEIN-GLYCAN INTERACTIONS AND REVEALED THE IMPORTANCE OF DEFINING THE HUMAN GLYCOME, ESTIMATED TO BE IN THE RANGE OF 10,000 DETERMINANTS. A MICROARRAY COMPRISED OF ALL POSSIBLE GLYCANS WOULD ALLOW US TO DETECT AND DEFINE ALL PHYSIOLOGICALLY RELEVANT GLYCAN BINDING PROTEINS (GBP), BUT THE CFG LIBRARY IS NOW ONLY 575 GLYCANS MAKING THE PRODUCTION OF LARGE QUANTITIES OF PURE, DEFINED GLYCANS FOR FUNCTIONAL STUDIES CRITICAL FOR ADVANCING GLYCOMICS; E.G, MGS OF PURE HUMAN MILK OLIGOSACCHARIDES (HMO), AVAILABLE SINCE THE 1950’S SUPPORTED RESEARCH THAT LED TO OUR UNDERSTANDING OF THE BENEFITS OF HMO IN BREASFED INFANTS, RESULTING IN INFANT FORMULA MANUFACTURERS INTRODUCING HMO INTO THEIR PRODUCTS IN 2014, BASED ON CLINICAL TRIALS SUPPORTING THEIR EFFICACY. MAMMALIAN GLYCANS,ON THE OTHER HAND, EXPRESSED ON THE SURFACES OF ALL CELLS, ARE GENERALLY AVAILABLE ONLY IN MINUTE QUANTITIES; MAKING THEM AS AVAILABLE AS HMO TO THE RESEARCH COMMUNITY WOULD RAPIDLY ADVANCE UNDERSTANDING OF THEIR FUNCTIONS IN ANIMAL CELLS. THIS IS NOW POSSIBLE USING OUR PROPRIETARY TECHNOLOGY, OXIDATIVE RELEASE OF NATURAL GLYCANS (ORNG), WHICH CHEMICALLY RELEASES GLYCANS FROM GLYCOCONJUGATES OF ANY NATURAL MATERIAL USING HOUSEHOLD BLEACH. NATGLYCAN, LLC (NGC) WAS ESTABLISHED TO PROVIDE BIOLOGICALLY RELEVANT NATURAL GLYCANS RELIABLY, ECONOMICALLY, AND IN LARGE QUANTITIES. IN PHASE I WE DEMONSTRATED THE FEASIBILITY OF PRODUCING HIGH MANNOSE N-GLYCANS IN MG QUANTITIES FOR SALE TO THE GLYCOSCIENCE COMMUNITY FOR THE FIRST TIME. WE BELIEVE THE ECONOMY OF SCALE WILL SUPPORT REASONABLE PRICES. SIGMA-ALDRICH SELLS 20ΜG OF MAN9GLCNAC2 FOR $688, WHILE NGC IS SELLING 5 MG OF MAN9GLCNAC2-AEAB FOR $750. IN PHASE II OF THIS PROJECT WE WILL COMPLETE A MANUFACTURING FACILITY TO PRODUCE 100’S OF MG (PURITY >95%) OF ALL HIGH MANNOSE N- GLYCANS AND DERIVATIVES THAT WILL BE USEFUL TO THE GLYCOBIOLOGY COMMUNITY. IN ADDITION, WE PLAN TO LAUNCH HIGHLY PURIFIED N-GLYCANS REPRESENTING ALL OF THE STRUCTURES EXPRESSED ON HUMAN AND RECOMBINANT IGG FOR USE AS QC STANDARDS IN MAB MANUFACTURING; CURRENTLY AN UNMET NEED IN THE PHARMACEUTICAL INDUSTRY. SINCE ORNG RELEASES ALL CLASSES OF GLYCANS SIMULTANEOUSLY FROM NATURAL PRODUCTS, WE WILL RAPIDLY EXPAND OUR PRODUCT OFFERINGS. WE WILL PURIFY THE MAJOR O-GLYCANS THAT ARE IN GREAT DEMAND, BUT NOT CURRENTLY AVAILABLE AT REASONABLE COST. WE ANTICIPATE THAT BY THE END OF PHASE II, WE WILL BE OFFERING HUNDREDS OF N-GLYCANS AND O-GLYCANS (PURITY >95%) AND USEFUL DERIVATIVES IN MULTI-MILIGRAM AMOUNTS. BASED ON SIGNIFICANT SALES AND ORDERS AFTER OUR INITIAL PRODUCT CATALOG LAUNCH, WE ANTICIPATE BEING ABLE TO SUPPORT OUR GLYCAN MANUFACTURING COSTS AND INCREASE PROFIT MARGINS AS WE INCREASE MANUFACTURING SCALE IN THE FUTURE.

A HUMAN SALIVARY GLYCOME DISCOVERY PLATFORM FOR INTERROGATING GLYCAN FUNCTION IN ORAL INNATE IMMUNITY - PROJECT SUMMARY THE ORAL CAVITY IS THE FIRST CRITICAL INTERFACE BETWEEN POTENTIALLY HARMFUL SUBSTANCES OR PATHOGENS IN THE HOST ENVIRONMENT, AND EVOLUTION OF THE ADAPTIVE AND INNATE IMMUNE DEFENSE MECHANISMS TO INACTIVATE OR ELIMINATE PATHOGENIC MICROBES HAS TO A GREAT EXTENT USED PROTEIN-GLYCAN INTERACTION. THE GLYCAN COMPONENTS OF SALIVA HAVE BEEN SHOWN TO PLAY IMPORTANT ROLES IN BIOLOGICAL AND IMMUNOLOGICAL ASPECTS OF ORAL HOST-MICROBE, MICROBE- HOST, AND MICROBE-MICROBE INTERACTIONS, AND WE HAVE SHOWN THAT GLYCANS ATTACHED SALIVARY GLYCOPROTEINS CAN ACT AS A FIRST LINE OF HOST DEFENSE IN THE HUMAN MOUTH AND THAT GLYCAN RECOGNITION CONTRIBUTES TO BOTH COLONIZATION AND CLEARANCE OF ORAL MICROBES. A REVOLUTIONARY INNOVATION IN STUDIES OF PROTEIN-GLYCAN INTERACTIONS WAS THE GLYCAN MICROARRAY, WHICH PERMITTED THE IDENTIFICATION GLYCAN LIGANDS FOR BIOLOGICALLY RELEVANT GLYCAN BINDING PROTEINS (GBP) BY THEIR SIMULTANEOUS INTERROGATION WITH HUNDREDS OF GLYCAN STRUCTURES PRINTED ON A MICROSCOPE SLIDE. COMPARISONS OF THE STRUCTURES OF BOUND AND NON-BOUND GLYCANS REVEAL THE GLYCAN SPECIFICITY OF GBP, AND THIS INFORMATION IS USED IN FURTHER BIOLOGICAL STUDIES TO UNDERSTAND THE BIOLOGICAL FUNCTION OF GBP. IN THIS PROJECT WE WILL GENERATE A GLYCAN MICROARRAY COMPOSED OF GLYCANS THAT REPRESENT THE SALIVARY GLYCOME, I.E. THE ENTIRETY OF GLYCANS IN SALIVA. THIS WILL BE ACCOMPLISHED BY FIRST PRODUCING A LIBRARY OF PURIFIED, NATURALLY OCCURRING N- AND O-LINKED GLYCANS RELEASED FROM 10 LITERS OF POOLED HUMAN SALIVA BY AN INNOVATIVE PROCESS FOR THE OXIDATIVE RELEASE OF NATURAL GLYCANS (ORNG) USING SIMPLE HOUSEHOLD BLEACH. THE LIBRARY OF GLYCANS WILL BE PRINTED AS A GLYCAN MICROARRAY AND INTERROGATED WITH ORAL STREPTOCOCCAL GLYCAN-BINDING ADHESINS TO IDENTIFY THEIR CORRESPONDING NATURAL HIGH-AFFINITY GLYCAN LIGANDS. WE WILL USE OUR RECENTLY ESTABLISHED TOOLBOX OF STREPTOCOCCAL SERINE-RICH-REPEAT PROTEIN ADHESINS THAT EACH CONTAIN SIALIC-ACID-BINDING SIGLEC-LIKE DOMAINS OF DIFFERING SPECIFICITY FOR SUBTYPES OF SIALIC ACIDS IN THE WIDER CONTEXT OF THEIR UNDERLYING SUBTERMINAL GLYCANS. FOR SOME OF THESE LECTINS, THE NATURAL GLYCAN LIGANDS WERE NOT IDENTIFIED USING CURRENTLY AVAILABLE ARRAYS, PRESUMABLY DUE TO THE ABSENCE OF THEIR CORRESPONDING NATURAL GLYCAN LIGANDS PRESENTED IN THE ASSAYS TO DATE. SINCE THESE ARE LECTINS EXPRESSED BY ORAL MICROBES, WE ANTICIPATE THAT THERE IS A HIGH PROBABILITY THAT THEIR NATURAL GLYCAN LIGANDS WILL BE PRESENT IN THE GLYCOME OF HUMAN SALIVA, THE NATURAL BIOLOGICAL FLUID IN WHICH THESE MICROORGANISMS THRIVE. THIS PHASE I PROJECT SHOULD PROVIDE AN EXAMPLE OF HOW A COMPLETE GLYCOME CAN BE USED AS A DISCOVERY PLATFORM FOR IDENTIFYING A NOVEL PROTEIN-GLYCAN INTERACTION. ONCE THE DETAILS OF THE STRUCTURE OF THE GLYCAN LIGAND ARE DEFINED, THE INFORMATION WILL BECOME INTELLECTUAL PROPERTY THAT WILL LEAD TO STRATEGIES TO THERAPEUTICALLY INTERFERE WITH MICROBIAL COLONIZATION OR PATHOGEN INFECTION IN THE MOUTH AND BEYOND. THIS PLATFORM FOR UNDERSTANDING THE INTERACTIONS OF ORAL MICROORGANISMS AND EXTRAORAL SYSTEMIC PATHOGENS WITH THE HUMAN MAY ULTIMATELY LEAD TO THE DEVELOPMENT OF AN IMPROVED ARTIFICIAL SALIVA, MORE CLOSELY MIMICKING THE GLYCAN LANDSCAPE OF NATURAL HUMAN SALIVA, AS ADDITION OF HUMAN MILK OLIGOSACCHARIDES HAS LAID THE GROUNDWORK FOR IMPROVEMENT OF INFANT FORMULA.

NATURAL GLYCANS FOR FUNCTIONAL GLYCOMICS - NATURAL GLYCANS FOR FUNCTIONAL GLYCOMICS PROJECT SUMMARY/ ABSTRACT DURING THE FIRST DECADE OF THE 21ST CENTURY, NIH MADE SIGNIFICANT INVESTMENTS IN GLYCOMICS. THE CONSORTIUM FOR FUNCTIONAL GLYCOMICS (SUPPORTED BY NIGMS 2001-2012) LED A MAJOR INTERNATIONAL EFFORT USING A MICROARRAY OF 611 DEFINED GLYCANS TO IDENTIFY THE PROTEIN-GLYCAN INTERACTIONS ASSOCIATED WITH NORMAL PHYSIOLOGY AND DISEASE (HTTP://WWW.FUNCTIONALGLYCOMICS.ORG/CFGPARADIGMS/INDEX.PHP/WELCOME_TO_THE_CFG_PARADIGM_PAGES). THIS 611 GLYCAN LIBRARY TRANSFORMED STUDIES ON PROTEIN-GLYCAN INTERACTIONS AND REVEALED THE IMPORTANCE OF DEFINING THE HUMAN GLYCOME, ESTIMATED TO BE IN THE RANGE OF 10,000 DETERMINANTS. A MICROARRAY COMPRISED OF ALL POSSIBLE GLYCANS WOULD ALLOW US TO DETECT AND DEFINE ALL PHYSIOLOGICALLY RELEVANT GLYCAN BINDING PROTEINS (GBP), BUT THE CFG LIBRARY IS NOW ONLY 575 GLYCANS MAKING THE PRODUCTION OF LARGE QUANTITIES OF PURE, DEFINED GLYCANS FOR FUNCTIONAL STUDIES CRITICAL FOR ADVANCING GLYCOMICS; E.G, MGS OF PURE HUMAN MILK OLIGOSACCHARIDES (HMO), AVAILABLE SINCE THE 1950’S SUPPORTED RESEARCH THAT LED TO OUR UNDERSTANDING OF THE BENEFITS OF HMO IN BREASFED INFANTS, RESULTING IN INFANT FORMULA MANUFACTURERS INTRODUCING HMO INTO THEIR PRODUCTS IN 2014, BASED ON CLINICAL TRIALS SUPPORTING THEIR EFFICACY. MAMMALIAN GLYCANS,ON THE OTHER HAND, EXPRESSED ON THE SURFACES OF ALL CELLS, ARE GENERALLY AVAILABLE ONLY IN MINUTE QUANTITIES; MAKING THEM AS AVAILABLE AS HMO TO THE RESEARCH COMMUNITY WOULD RAPIDLY ADVANCE UNDERSTANDING OF THEIR FUNCTIONS IN ANIMAL CELLS. THIS IS NOW POSSIBLE USING OUR PROPRIETARY TECHNOLOGY, OXIDATIVE RELEASE OF NATURAL GLYCANS (ORNG), WHICH CHEMICALLY RELEASES GLYCANS FROM GLYCOCONJUGATES OF ANY NATURAL MATERIAL USING HOUSEHOLD BLEACH. NATGLYCAN, LLC (NGC) WAS ESTABLISHED TO PROVIDE BIOLOGICALLY RELEVANT NATURAL GLYCANS RELIABLY, ECONOMICALLY, AND IN LARGE QUANTITIES. IN PHASE I WE DEMONSTRATED THE FEASIBILITY OF PRODUCING HIGH MANNOSE N-GLYCANS IN MG QUANTITIES FOR SALE TO THE GLYCOSCIENCE COMMUNITY FOR THE FIRST TIME. WE BELIEVE THE ECONOMY OF SCALE WILL SUPPORT REASONABLE PRICES. SIGMA-ALDRICH SELLS 20ΜG OF MAN9GLCNAC2 FOR $688, WHILE NGC IS SELLING 5 MG OF MAN9GLCNAC2-AEAB FOR $750. IN PHASE II OF THIS PROJECT WE WILL COMPLETE A MANUFACTURING FACILITY TO PRODUCE 100’S OF MG (PURITY >95%) OF ALL HIGH MANNOSE N- GLYCANS AND DERIVATIVES THAT WILL BE USEFUL TO THE GLYCOBIOLOGY COMMUNITY. IN ADDITION, WE PLAN TO LAUNCH HIGHLY PURIFIED N-GLYCANS REPRESENTING ALL OF THE STRUCTURES EXPRESSED ON HUMAN AND RECOMBINANT IGG FOR USE AS QC STANDARDS IN MAB MANUFACTURING; CURRENTLY AN UNMET NEED IN THE PHARMACEUTICAL INDUSTRY. SINCE ORNG RELEASES ALL CLASSES OF GLYCANS SIMULTANEOUSLY FROM NATURAL PRODUCTS, WE WILL RAPIDLY EXPAND OUR PRODUCT OFFERINGS. WE WILL PURIFY THE MAJOR O-GLYCANS THAT ARE IN GREAT DEMAND, BUT NOT CURRENTLY AVAILABLE AT REASONABLE COST. WE ANTICIPATE THAT BY THE END OF PHASE II, WE WILL BE OFFERING HUNDREDS OF N-GLYCANS AND O-GLYCANS (PURITY >95%) AND USEFUL DERIVATIVES IN MULTI-MILIGRAM AMOUNTS. BASED ON SIGNIFICANT SALES AND ORDERS AFTER OUR INITIAL PRODUCT CATALOG LAUNCH, WE ANTICIPATE BEING ABLE TO SUPPORT OUR GLYCAN MANUFACTURING COSTS AND INCREASE PROFIT MARGINS AS WE INCREASE MANUFACTURING SCALE IN THE FUTURE.

NOVEL TARGETED CAR-T MULTIPLE MYELOMA THERAPY - PROJECT SUMMARY MULTIPLE MYELOMA (MM), A MALIGNANCY OF PLASMA CELLS (PCS), IS RESPONSIBLE FOR OVER 12,500 DEATHS IN THE US AND OVER 117,000 DEATHS WORLDWIDE ANNUALLY. OVER 91,000 INDIVIDUALS IN THE US AND OVER 300,000 WORLDWIDE CURRENTLY LIVE WITH MM. IN SPITE OF MAJOR THERAPEUTIC ADVANCES IN THE PAST TWO DECADES, MM REMAINS INCURABLE AND MOST MM PATIENTS SUCCUMB TO THE UNDERLYING MALIGNANCY. RECENT THERAPIES REDIRECTING T CELLS VIA CHIMERIC ANTIGEN RECEPTOR-T CELLS (CAR-TS) OR BISPECIFIC ANTIBODIES THAT TARGET B CELL MATURATION ANTIGEN (BCMA) HAVE SIGNIFICANTLY IMPROVED SURVIVAL OF PATIENTS WITH DISEASE REFRACTORY TO PRIOR THERAPIES. HOWEVER, NEARLY ALL MM PATIENTS EXPERIENCE DISEASE PROGRESSION AND BECOME REFRACTORY TO THESE BCMA-TARGETED T CELL THERAPIES. THERE IS THEREFORE AN URGENT UNMET NEED TO DEVELOP NEW TARGETS FOR THESE POTENT T CELL-DIRECTED MM THERAPIES. THIS PHASE 1 SBIR APPLICATION ADDRESSES THAT NEED WITH A NOVEL MONOCLONAL ANTIBODY (MAB) DESIGNATED MM3. MM3 BELONGS TO A NEW CLASS OF ANTIBODIES, VARIABLE LYMPHOCYTE RECEPTOR B (VLRB) ANTIBODIES PRODUCED BY THE B CELLS OF JAWLESS VERTEBRATES, LAMPREY AND HAGFISH, AND SPECIFICALLY BINDS TO A DISTINCTIVE FORM OF A WELL-VALIDATED MM THERAPEUTIC TARGET, MULTIMERIC FORMS OF THE CD38 CELL SURFACE PROTEIN, WITH NO DETECTABLE BINDING TO CD38 MONOMERS. CD38 MULTIMERS ARE UNIQUELY EXPRESSED BY PCS AND MM TUMORS, WHEREAS CD38 MONOMERS ARE EXPRESSED BY NUMEROUS OTHER NORMAL CELL TYPES, INCLUDING NK AND T CELL IMMUNE EFFECTORS. CAR-T CELLS THAT UTILIZE MM3 AS TARGET RECOGNITION DOMAIN THEREFORE AVOID POTENTIAL “ON-TARGET/OFF-TUMOR” TOXICITY ASSOCIATED WITH BINDING TO MONOMERIC CD38, “FRATRICIDE” AMONG CAR-T CELLS THAT EXPRESS BOTH MONOMERIC CD38 AND CAR ANTIGEN BINDING DOMAINS THAT BIND MONOMERIC CD38, AND DEPLETION OF NK AND T CELL IMMUNE EFFECTORS. MULTIMERIC CD38 IS HIGHLY EXPRESSED BY THE TUMOR CELLS OF RELAPSED-REFRACTORY MM (RRMM) PATIENTS REFRACTORY TO PROTEASOME AND/OR IMMUNOMODULATOR DRUGS. ALTHOUGH DOWNREGULATION OF CD38 EXPRESSION IS ONE OF SEVERAL MECHANISMS OF RESISTANCE TO ANTI-CD38 MAB THERAPY, E.G., DARATUMUMAB, HIGH LEVELS OF CD38 AND MULTIMERIC CD38 EXPRESSION RETURN WITHIN 3 TO 6 MONTHS OF ANTI-CD38 MAB THERAPY DISCONTINUATION, AND MM TUMOR CELLS OF OVER 87% OF RRMM PATIENTS EXPRESS HIGH LEVELS OF CD38 MULTIMERS DETECTED WITH MM3. MM3 HUMAN CAR-T CELLS HAVE BEEN PRODUCED AND SHOWN WITH IN VITRO ASSAYS TO DIRECT CAR-T KILLING ONLY TO CELLS THAT EXPRESS MULTIMERIC CD38. THIS APPLICATION WILL EXTEND THOSE RESULTS BY: (1) PRODUCING MM3 CAR-T CELLS WITH T CELL PREPARATIONS DERIVED FROM HEALTHY HUMAN VOLUNTEERS AND FROM PATIENTS RELAPSED FOLLOWING ANTI-BCMA CAR-T THERAPY AND EVALUATING IN VITRO TARGET-SPECIFIC ACTIVATION AND CYTOTOXICITY AGAINST A MM CELL LINE AND AUTOLOGOUS MM TUMOR CELLS FROM ANTI-BCMA CAR-T RELAPSED MM PATIENTS, AND (2) EVALUATING THE IN VIVO ANTI-TUMOR EFFICACY OF MM3 CAR-T CELLS WITH MISTRG6 “HUMANIZED” MICE ENGRAFTED WITH A HUMAN MM TUMOR CELL LINE. THESE PHASE 1 STUDIES WILL BE FOLLOWED BY PHASE 2 IN VIVO EVALUATIONS OF MM3 CAR-TS PRODUCED WITH RRMM PATIENT T CELLS AGAINST TUMORS FROM THOSE SAME PATIENTS IN THE MISTRG6 MODEL AND BY GMP PRODUCTION OF MM3 CAR LENTIVIRUS AND MM3 CAR-T CELLS, AND IND-ENABLING PHARMACOLOGY/TOXICOLOGY STUDIES TO SUPPORT FIRST IN HUMAN CLINICAL TRIALS OF THIS NEW CAR-T THERAPY FOR MM PATIENTS THAT HAVE FAILED ALL OTHER THERAPIES.

A HUMAN SALIVARY GLYCOME DISCOVERY PLATFORM FOR INTERROGATING GLYCAN FUNCTION IN ORAL INNATE IMMUNITY - PROJECT SUMMARY THE ORAL CAVITY IS THE FIRST CRITICAL INTERFACE BETWEEN POTENTIALLY HARMFUL SUBSTANCES OR PATHOGENS IN THE HOST ENVIRONMENT, AND EVOLUTION OF THE ADAPTIVE AND INNATE IMMUNE DEFENSE MECHANISMS TO INACTIVATE OR ELIMINATE PATHOGENIC MICROBES HAS TO A GREAT EXTENT USED PROTEIN-GLYCAN INTERACTION. THE GLYCAN COMPONENTS OF SALIVA HAVE BEEN SHOWN TO PLAY IMPORTANT ROLES IN BIOLOGICAL AND IMMUNOLOGICAL ASPECTS OF ORAL HOST-MICROBE, MICROBE- HOST, AND MICROBE-MICROBE INTERACTIONS, AND WE HAVE SHOWN THAT GLYCANS ATTACHED SALIVARY GLYCOPROTEINS CAN ACT AS A FIRST LINE OF HOST DEFENSE IN THE HUMAN MOUTH AND THAT GLYCAN RECOGNITION CONTRIBUTES TO BOTH COLONIZATION AND CLEARANCE OF ORAL MICROBES. A REVOLUTIONARY INNOVATION IN STUDIES OF PROTEIN-GLYCAN INTERACTIONS WAS THE GLYCAN MICROARRAY, WHICH PERMITTED THE IDENTIFICATION GLYCAN LIGANDS FOR BIOLOGICALLY RELEVANT GLYCAN BINDING PROTEINS (GBP) BY THEIR SIMULTANEOUS INTERROGATION WITH HUNDREDS OF GLYCAN STRUCTURES PRINTED ON A MICROSCOPE SLIDE. COMPARISONS OF THE STRUCTURES OF BOUND AND NON-BOUND GLYCANS REVEAL THE GLYCAN SPECIFICITY OF GBP, AND THIS INFORMATION IS USED IN FURTHER BIOLOGICAL STUDIES TO UNDERSTAND THE BIOLOGICAL FUNCTION OF GBP. IN THIS PROJECT WE WILL GENERATE A GLYCAN MICROARRAY COMPOSED OF GLYCANS THAT REPRESENT THE SALIVARY GLYCOME, I.E. THE ENTIRETY OF GLYCANS IN SALIVA. THIS WILL BE ACCOMPLISHED BY FIRST PRODUCING A LIBRARY OF PURIFIED, NATURALLY OCCURRING N- AND O-LINKED GLYCANS RELEASED FROM 10 LITERS OF POOLED HUMAN SALIVA BY AN INNOVATIVE PROCESS FOR THE OXIDATIVE RELEASE OF NATURAL GLYCANS (ORNG) USING SIMPLE HOUSEHOLD BLEACH. THE LIBRARY OF GLYCANS WILL BE PRINTED AS A GLYCAN MICROARRAY AND INTERROGATED WITH ORAL STREPTOCOCCAL GLYCAN-BINDING ADHESINS TO IDENTIFY THEIR CORRESPONDING NATURAL HIGH-AFFINITY GLYCAN LIGANDS. WE WILL USE OUR RECENTLY ESTABLISHED TOOLBOX OF STREPTOCOCCAL SERINE-RICH-REPEAT PROTEIN ADHESINS THAT EACH CONTAIN SIALIC-ACID-BINDING SIGLEC-LIKE DOMAINS OF DIFFERING SPECIFICITY FOR SUBTYPES OF SIALIC ACIDS IN THE WIDER CONTEXT OF THEIR UNDERLYING SUBTERMINAL GLYCANS. FOR SOME OF THESE LECTINS, THE NATURAL GLYCAN LIGANDS WERE NOT IDENTIFIED USING CURRENTLY AVAILABLE ARRAYS, PRESUMABLY DUE TO THE ABSENCE OF THEIR CORRESPONDING NATURAL GLYCAN LIGANDS PRESENTED IN THE ASSAYS TO DATE. SINCE THESE ARE LECTINS EXPRESSED BY ORAL MICROBES, WE ANTICIPATE THAT THERE IS A HIGH PROBABILITY THAT THEIR NATURAL GLYCAN LIGANDS WILL BE PRESENT IN THE GLYCOME OF HUMAN SALIVA, THE NATURAL BIOLOGICAL FLUID IN WHICH THESE MICROORGANISMS THRIVE. THIS PHASE I PROJECT SHOULD PROVIDE AN EXAMPLE OF HOW A COMPLETE GLYCOME CAN BE USED AS A DISCOVERY PLATFORM FOR IDENTIFYING A NOVEL PROTEIN-GLYCAN INTERACTION. ONCE THE DETAILS OF THE STRUCTURE OF THE GLYCAN LIGAND ARE DEFINED, THE INFORMATION WILL BECOME INTELLECTUAL PROPERTY THAT WILL LEAD TO STRATEGIES TO THERAPEUTICALLY INTERFERE WITH MICROBIAL COLONIZATION OR PATHOGEN INFECTION IN THE MOUTH AND BEYOND. THIS PLATFORM FOR UNDERSTANDING THE INTERACTIONS OF ORAL MICROORGANISMS AND EXTRAORAL SYSTEMIC PATHOGENS WITH THE HUMAN MAY ULTIMATELY LEAD TO THE DEVELOPMENT OF AN IMPROVED ARTIFICIAL SALIVA, MORE CLOSELY MIMICKING THE GLYCAN LANDSCAPE OF NATURAL HUMAN SALIVA, AS ADDITION OF HUMAN MILK OLIGOSACCHARIDES HAS LAID THE GROUNDWORK FOR IMPROVEMENT OF INFANT FORMULA.

ADEPT-STAR THERAPY FOR HIGH RISK NEUROBLASTOMA - PROJECT SUMMARY CANCER REMAINS A PRIMARY HEALTH CONCERN DESPITE SIGNIFICANT ADVANCEMENTS IN TREATMENT. IN THE PAST DECADE, CELL AND GENE (C&G) THERAPIES ALONG WITH IMMUNO-ONCOLOGY (I-O) THERAPIES HAVE TRANSFORMED TREATMENT EXPECTATIONS BY EXTENDING CANCER FREE SURVIVAL AND COMPLETE REMISSIONS. DESPITE THESE REMARKABLE SUCCESSES, THEY ARE LIMITED TO A SUBSET OF CANCERS AND MANY SIGNIFICANT CHALLENGES REMAIN FOR BROADER APPLICATION AND TO UNLOCK THE PERCEIVED MEDICAL AND COMMERCIAL POTENTIAL. EXPRESSION THERAPEUTICS, INC. (ET) IS A FULLY INTEGRATED C&G THERAPY COMPANY ADDRESSING THESE UNMET CLINICAL NEEDS BY USING PROPRIETARY AND COMPLEMENTARY PLATFORM TECHNOLOGIES THAT OPTIMIZE THERAPEUTIC TRANSGENE EXPRESSION AND GENE DELIVERY FOR THE DEVELOPMENT OF OFF-THE-SHELF ALLOGENEIC- BASED GENE THERAPIES. THESE TECHNOLOGIES ADDRESS MAJOR CHALLENGES BEING ENCOUNTERED IN C&G I-O: IDENTIFICATION OF SAFE AND EFFECTIVE TUMOR TARGETS, MAXIMIZING TREATMENT DURABILITY AND EFFICACY AND REDUCING THE COST OF GOODS. RESULTS OF PRELIMINARY IN VITRO AND IN VIVO STUDIES SUPPORT FEASIBILITY OF THE PROPOSED APPLICATION AND THE SUCCESSFUL DEVELOPMENT OF THIS ROBUST PLATFORM FOR THE TREATMENT OF PEDIATRIC NEUROBLASTOMAS AND OTHER FORMS OF NEUROENDOCRINE TUMORS (NETS) PROPOSED IN THIS APPLICATION.