Collage Inc

MOLECULAR MR IMAGING OF THE DESMOPLASTIC RESPONSE IN PANCREATIC CANCER

THERANOSTIC FOR GASTRIC CANCER - PROJECT SUMMARY THE OVERARCHING OBJECTIVE OF THIS APPLICATION IS TO DEVELOP AN IMAGE-GUIDED THERAPY PARADIGM FOR IMPROVING THE MANAGEMENT OF GASTRIC CANCER (GCA) BY TARGETING FIBRIN IN THE TUMOR MICROENVIRONMENT. GCA IS THE FIFTH MOST COMMON CANCER AND THE THIRD LEADING CAUSE OF CANCER-RELATED DEATH WORLDWIDE. DESPITE PROGRESS IN MANAGEMENT OF ADVANCED GCA, THE PROGNOSIS REMAINS POOR WITH A MEDIAN SURVIVAL OF 12-14 MONTHS EVEN WITH COMBINATION CHEMOTHERAPY. THEREFORE, NOVEL THERAPEUTIC APPROACHES ARE OF UTMOST NEED TO IMPROVE CLINICAL OUTCOMES IN PATIENTS WITH ADVANCED DISEASE. THE CENTRAL HYPOTHESIS IS THAT HIGH ENERGY BETA PARTICLE RADIOTHERAPY TARGETED TO THE FIBRIN IN TUMOR MICROENVIRONMENT IMPROVES THE TREATMENT OUTCOME OF GCA. PRIMARY AND METASTATIC GASTRIC TUMORS HAVE LEAKY VASCULATURE WHICH RESULTS IN EXTRAVASATION OF BLOOD PROTEINS AND ABUNDANT DEPOSITION OF FIBRIN IN THE EXTRACELLULAR MATRIX (ECM). GIVEN THAT FIBRIN IS ONLY PRESENT IN THE TUMORS AND THROMBI, BUT NOT IN HEALTHY TISSUES, WE POSIT THAT FIBRIN COULD BE USED AS A THERAPEUTIC TARGET, REPRESENTING A LARGE DEPOT IN THE ECM FOR A HIGH ENERGY BETA PARTICLE TO KILL SURROUNDING TUMOR CELLS. COLLAGEN MEDICAL HAS DEVELOPED AND LICENSED PATENTED FIBRIN-SPECIFIC SHORT CYCLIC PEPTIDES AND DERIVATIZED THEM FOR IMAGING AND THERAPY. WE HAVE SHOWN THAT FIBRIN- TARGETED POSITRON EMISSION TOMOGRAPHY (PET) CAN DETECT THROMBI IN PATIENTS USING A COPPER-64 MODIFIED PEPTIDE, YET PROVIDES MINIMAL BACKGROUND PET SIGNAL IN TISSUES WHERE GCA METASTASIZES. OUR PRELIMINARY DATA SHOWS THAT THE FIBRIN-SPECIFIC PROBE, 64CU-CM500, DETECTS FIBRIN IN A MOUSE MODEL OF GCA. WE HAVE ALSO MODIFIED THE PEPTIDE TO INCORPORATE THE HIGH ENERGY BETA EMITTER YTTRIUM-90 FOR TARGETED THERAPY. BUILDING UPON THIS PRELIMINARY DATA, IN THIS FASTTRACK PROJECT WE PROPOSE TO ESTABLISH A THERANOSTIC APPROACH TO TREATING GCA BY USING 64CU-CM500 PET TO IDENTIFY PATIENTS WITH FIBRIN-RICH GASTRIC TUMORS AND THEN TREATING THEM WITH FIBRIN-TARGETED 90Y-CM600 BETA EMITTING RADIOTHERAPY. IN PHASE 1 WE WILL EVALUATE THE EXTENT OF FIBRIN DEPOSITION IN A WIDE RANGE OF HUMAN GCA TISSUE ARRAYS TO ESTIMATE THE PREVALENCE OF FIBRIN IN GCA. WE WILL ALSO DEMONSTRATE THE SPECIFICITY OF OUR COMPOUNDS FOR BOTH DETECTING TUMOR FIBRIN AND FOR TARGETING FIBRIN FOR RADIOTHERAPY. IN PHASE 2 WE WILL EVALUATE THE KINETICS OF 64CU-CM500 PET IN TUMORS IN GCA PATIENTS AND ESTIMATE HOW LONG THE PROBE REMAINS BOUND TO THE TUMOR. WE WILL ALSO DEMONSTRATE THE EFFICACY OF 90Y-CM600 RADIOTHERAPY IN MULTIPLE MOUSE MODELS OF GCA AND OPTIMIZE THE TREATMENT REGIMEN. LASTLY, TO ENABLE CLINICAL TRANSLATION OF THIS THERAPEUTIC, WE WILL SYNTHESIZE THE CM600 PRECURSOR UNDER CGMP CONDITIONS, VALIDATE THE 90Y RADIOLABELING METHOD, AND PERFORM IND ENABLING GLP TOXICITY, BIODISTRIBUTION AND DOSIMETRY STUDIES IN RODENTS.

PET IMAGING OF RADIATION INDUCED LUNG INJURY

TARGETED IMAGING OF FIBROSIS IN THE LEFT ATRIUM

OPTIMIZATION OF EFFICACY AND SAFETY PHARAMACOLOGY OF FIBROSIS IMAGING AGENT CM-65

CM-65, A TARGETED CONTRAST AGENT FOR CARDIAC MAGNETIC RESONANCE PERFUSION IMAGING

MAGNETIC PARTICLE DETECTION TEST FOR VULNERABLE CAROTID PLAQUE

MOLECULAR IMAGING AGENT TO DETECT THROMBUS - PROJECT SUMMARY THROMBUS AS A CLINICAL ENTITY IS RESPONSIBLE FOR THE LARGEST NUMBER OF DEATHS AND GREATEST MORBIDITY COMPARED TO ANY OTHER PATHOLOGY. MOST MAJOR CARDIOVASCULAR DISEASES, INCLUDING MYOCARDIAL INFARCTION, ATRIAL FIBRILLATION, ACUTE CORONARY SYNDROME, STROKE, PULMONARY EMBOLISM, AND DEEP VEIN THROMBOSIS, ARE EITHER A RESULT OF THROMBOSIS OR CAN CAUSE THROMBOSIS. RECENTLY, THE PANDEMIC COVID-19 HAS BEEN FOUND TO BE ASSOCIATED WITH INCREASED COAGULOPATHY, WHICH LIKELY CONTRIBUTES TO THE DEVELOPMENT OF ACUTE RESPIRATORY DISTRESS AND EVEN MULTI-ORGAN FAILURE IN THESE PATIENTS. DETECTION OF THROMBOEMBOLI AND THEIR SOURCE THROMBUS ARE VITAL TO PROPER PATIENT MANAGEMENT ACROSS ALL OF THESE DISEASES. CURRENTLY THROMBI ARE DETECTED BY DIFFERENT ANATOMICAL IMAGING METHODS DEPENDING ON THE VASCULAR TERRITORY, BUT ALL TECHNIQUES HAVE LIMITATIONS (E.G. REQUIRE SEDATION, REQUIRE NEPHROTOXIC CONTRAST, CANNOT BE USED IN CERTAIN PATIENTS). NO EXISTING METHOD CAN BE USED TO ASSESS DIFFERENT VASCULAR TERRITORIES FOR THROMBUS IN A SINGLE MULTISTATION EXAM, WHILE THIS WOULD BE EXTREMELY VALUABLE IN THROMBOEMBOLIC DISEASES LIKE DEEP VEIN THROMBOSIS (DVT) / PULMONARY EMBOLISM (PE) OR STROKE WHERE IT IS IMPORTANT TO NOT ONLY DETECT THE EMBOLUS BUT THE EMBOLIC SOURCE AS WELL. CURRENT METHODS DO NOT INFORM ON COMPOSITION OF THE THROMBUS AND THE FIBRIN CONTENT, ALTHOUGH THERAPEUTIC STRATEGIES (E.G., THROMBOLYSIS FOR A FIBRIN RICH CLOT IDENTIFIED BY POSITRON EMISSION TOMOGRAPHY (PET) VS. MECHANICAL THROMBECTOMY FOR AN ORGANIZED, FIBRIN- POOR, CHRONIC THROMBUS) WOULD BENEFIT FROM SUCH INFORMATION. COLLAGEN MEDICAL IS DEVELOPING A FIBRIN-SPECIFIC MOLECULAR PET PROBE, 68GA-CM500 THAT CAN IDENTIFY THROMBUS ANYWHERE IN THE BODY FOLLOWING A SINGLE INTRAVENOUS INJECTION FOLLOWED BY PET IMAGING. ULTIMATELY, WE ARE SEEKING REGULATORY APPROVAL FOR THE INDICATION “68GA-CM500 DETECTS THROMBUS” WHICH REQUIRE DEMONSTRATION OF EFFICACY FOR THROMBUS DETECTION IN DIFFERENT VASCULAR TERRITORIES, SUCH AS THE DEEP VEINS, PULMONARY ARTERIES, AND CARDIAC CHAMBERS. USING A CLOSELY RELATED PROBE, WE HAVE EXCELLENT PRELIMINARY HUMAN DATA TO SUGGEST THAT 68GA-CM500 CAN ACCURATELY IDENTIFY THROMBUS IN THE HEART. THE PURPOSE OF THIS CRP GRANT IS TO PROVIDE FUNDING TO 1) FILE AN IND FOR 68GA-CM500, 2) PERFORM SAFETY, PHARMACOKINETIC, AND DOSIMETRY EVALUATIONS IN HEALTHY VOLUNTEERS, AND 3) OBTAIN PROOF OF CONCEPT DATA THAT 68GA-CM500 CAN DETECT THROMBUS IN THE DEEP VEINS AND PULMONARY ARTERIES OF PATIENTS WITH DEEP VEIN THROMBOSIS AND/OR PULMONARY EMBOLISM. THE PROBE 68GA-CM500 DISPLAYS HIGH AFFINITY FOR FIBRIN, FAST BLOOD CLEARANCE, AND HIGH METABOLIC STABILITY. IN RAT AND RABBIT MODELS IT DEMONSTRATED AN EXCELLENT ABILITY TO DETECT THROMBUS WITH A HIGH TARGET-TO-BACKGROUND RATIO. THE GOAL OF THIS COMMERCIALIZATION READINESS PILOT PROGRAM IS TO EVALUATE 68GA-CM500, AS A TOOL TO NONINVASIVELY DIAGNOSE THROMBOSIS IN PATIENTS. WE HAVE ALREADY PREPARED A BATCH OF SOLID DRUG SUBSTANCE PRECURSOR UNDER CGMP CONDITIONS. CLEARANCE, ELIMINATION AND BIODISTRIBUTION HAVE BEEN ASSESSED IN TWO ANIMAL SPECIES (RAT AND RABBIT), AND A SINGLE DOSE TOXICITY STUDY IN RATS WAS CONDUCTED UNDER GLP CONDITIONS. BECAUSE OF THE MICRODOSE GIVEN WITH PET AN ABBREVIATED NONCLINICAL SAFETY PACKAGE IS REQUIRED FOR AN INVESTIGATIONAL NEW DRUG (IND) APPLICATION AND WE HAVE ALREADY MET THESE REQUIREMENTS. THIS CRP PROGRAM WILL ENABLE US TO FILE AN IND AND OBTAIN KEY PRELIMINARY DATA IN VOLUNTEERS AND PATIENTS WITH PE/DVT. HUMAN DATA IS CRUCIAL FOR ATTRACTING INVESTMENT AND ULTIMATE COMMERCIALIZATION. FIRST, WE WILL CONDUCT LATE-STAGE NONCLINICAL ACTIVITIES NECESSARY FOR 68GA-CM500 TO BE ADMINISTERED TO HUMANS BY FINALIZING, ASSEMBLING, AND SUBMITTING AN IND APPLICATION. WE WILL THEN ASSESS THE PHARMACOKINETICS, DISTRIBUTION, AND ELIMINATION OF 68GA-CM500 IN HEALTHY VOLUNTEERS TO ESTABLISH SAFETY, RADIOCHEMICAL DOSE, AND TO ESTIMATE AN OPTIMAL TIME FOR THR

NEW CLASS OF COLLAGEN-TARGETED CONTRAST AGENTS FOR MAGNETIC RESONANCE IMAGING - PROJECT SUMMARY CHRONIC LIVER DISEASE IS ONE OF THE LEADING AND MOST RAPIDLY RISING CAUSES OF MORTALITY WORLDWIDE. CHRONIC LIVER DISEASE IS MULTIFACTORIAL AND CAN BE BROUGHT UPON FROM DAMAGES RANGING FROM VIRAL HEPATITIS INFECTION TO ALCOHOL ABUSE TO POOR DIET. LEADING THESE IS THE EPIDEMIC OF NONALCOHOLIC STEATOHEPATITIS (NASH), BUT ALL CHRONIC LIVER DISEASES PROGRESS TO LIVER FIBROSIS IF UNCHECKED. FIBROSIS MAY RESOLVE FOLLOWING EFFECTIVE TREATMENT, BUT WHEN LEFT UNTREATED LIVER FIBROSIS CAN PROGRESS TO LIVER FAILURE OR LIVER CANCER. ACCURATE DIAGNOSIS, STAGING, AND SURVEILLANCE OF LIVER FIBROSIS IS KEY TO CHRONIC LIVER DISEASE PATIENT MANAGEMENT. THE PRESENT STANDARD OF CARE FOR DIAGNOSIS AND STAGING OF LIVER FIBROSIS IS BIOPSY, WHICH RUNS THE RISK OF INTERNAL BLEEDING, SAMPLES ONLY A SMALL PORTION OF LIVER, AND SUFFERS FROM INTEROBSERVER VARIABILITY. FIBROSIS STAGE, AND NOT STEATOSIS NOR INFLAMMATION, IS THE ONLY FEATURE OF DISEASE ASSOCIATED WITH WORSE OUTCOMES IN NASH. BESIDES BIOPSY WE LACK GOOD TOOLS TO NONINVASIVELY DETECT LIVER FIBROSIS, STAGE FIBROSIS, OR MONITOR RESPONSE TO TREATMENT. ELASTOGRAPHY METHODS ARE NOT SENSITIVE TO EARLY CHANGES IN DISEASE. SERUM BIOMARKERS AND BIOMARKER PANELS TO IDENTIFY NASH AND/OR LIVER FIBROSIS, ARE ALSO LIMITED AND LACK ACCURACY FOR STAGING. NONE OF THESE TECHNIQUES HAS THE ACCURACY TO MONITOR TREATMENT. AN ACCURATE, SAFE METHOD TO DIAGNOSE AND MONITOR NASH AND ASSOCIATED FIBROSIS IS OF UTMOST IMPORTANCE IN BOTH CLINICAL PRACTICE AND CLINICAL RESEARCH. COLLAGEN MEDICAL HAS DEVELOPED TYPE I COLLAGEN-BINDING PEPTIDES (CBP) CONJUGATED TO GADOLINIUM CHELATES FOR NONINVASIVE MRI STAGING OF LIVER FIBROSIS. THESE PROBES (EP-3533 AND CM-101) ARE INJECTED INTRAVENOUSLY, BINDING TO FIBROTIC LIVER IN PROPORTION TO THE DEGREE OF FIBROSIS, WHILE THE UNBOUND PROBE IS RAPIDLY RENALLY ELIMINATED. DESPITE EFFICACY IN MULTIPLE ANIMAL MODELS AT LOW DOSES OF PROBE (5 – 10 ΜMOL/KG), THE ANTICIPATED COST OF GOODS AT THIS DOSE IS EXPECTED TO BE TOO HIGH TO BE COMMERCIALLY VIABLE. THIS PHASE I SBIR PROPOSAL SEEKS TO REDUCE THE COST OF GOODS OF A COLLAGEN-TARGETED MR IMAGING PROBE BY COMBINING COLLAGEN MEDICAL’S CBP TECHNOLOGY WITH EXCEEDINGLY SMALL IRON-OXIDE NANOPARTICLE (ESPION) TECHNOLOGY DEVELOPED AT MIT. ESPIONS PROVIDE STRONG POSITIVE CONTRAST IN T1-WEIGHTED MRI SCANS, ARE SMALL ENOUGH TO EXTRAVASATE FROM BLOOD VESSELS, AND ARE ELIMINATED VIA RENAL FILTRATION. THE RELAXIVITY OF ESPIONS IS 5 – 20 TIMES HIGHER THAN CM-101. A HIGHER RELAXIVITY SHOULD EQUATE TO A LOWER DOSE AND WE HYPOTHESIZE THAT AN ESPION-CBP CONJUGATE WOULD BE AS EFFECTIVE AT A 5 – 20 FOLD LOWER DOSE THAN CM-101, AND THUS A SIGNIFICANTLY LOWER COST OF GOODS. FURTHERMORE, ESPIONS CAN ARE PREPARED FROM CHEAP RAW MATERIALS WHEREAS SYNTHESIS OF THE BIFUNCTIONAL GD-CHELATES THAT HAVE BEEN PREVIOUSLY CONJUGATED TO THE CBP REQUIRE MULTIPLE SYNTHETIC STEPS AND COSTLY CHROMATOGRAPHIC PURIFICATION. OUR APPROACH IS TO SYNTHESIZE A SMALL LIBRARY OF ESPION-CBP CONJUGATES AND SCREEN FOR RELAXIVITY, COLLAGEN-BINDING AFFINITY, COLLAGEN SPECIFICITY, AND METABOLIC STABILITY IN VITRO. WE WILL THEN DEMONSTRATE THAT OUR LEAD ESPION-CBP CONJUGATE IS CAPABLE OF VISUALIZING LIVER FIBROSIS WITH SUPERIOR DETECTION SENSITIVITY TO THE PREVIOUSLY STUDIED GD-BASED COLLAGEN-TARGETING PROBE CM-101 IN A MURINE MODEL OF LIVER FIBROSIS.

FIBRIN TARGETED CANCER THERAPY

HERBAL-DERIVED FACTORS DOWN REGULATE THE PRODUCTION LEVELS OF PRO-INFLAMMATORY CYTOKINES TNF A AND IL-6 IN THE LIVER

PURPOSE: TO SUPPORT THE CREATION AND PRODUCTION OF THE BALLET ROMEO & JULIET, BY ARTISTIC DIRECTOR KEVIN THOMAS.

TO SUPPORT THE CREATION AND PERFORMANCE OF A NEW BALLET BY ARTISTIC DIRECTOR KEVIN THOMAS BASED ON THE NOVEL THEIR EYES WERE WATCHING GOD BY ZORA NEALE HURSTON.

TO SUPPORT RISE, THE CULMINATING EVENT - INCLUDING PERFORMANCES, MASTER CLASSES AND LECTURE DEMONSTRATIONS - OF AN ARTS EDUCATION SERIES HOSTED BY CO