SBIR-STTR Award

There is presently no effective therapy for relapsing, metastatic, androgen-independent prostate cancer and the most effective treatment occurs with early and appropriate intervention. Blood PSA screening and digital rectal exams can detect early warning signs of prostate cancer but an effective tissue-specific method for spatial localization of metastatic disease is not available. Human prostate specific membrane antigen (PSMA) is an integral trans-membrane protein, associated with the prostate epithelium, prostatic tumor cells and the neovasculature of other tumor types. PSMA is a 750 amino acid type II glycoprotein which is typically expressed to a small extent in normal human prostate epithelium but is up-regulated in prostate cancer, including metastatic disease. The extracellular portion of PSMA is highly homologous to the enzyme NAALDase (N-acetylated a-linked acidic dipeptidase) which is involved in the deactivation of neuronal signaling peptides. The enzymatic aspect of PSMA is a unique exopeptidase with reactivity toward poly-gamma-glutamated folates, capable of sequentially removing the poly-gamma-glutamyl termini. Since PSMA is expressed by virtually all prostate cancers and especially poorly differentiated, metastatic and hormone-refractory carcinomas, it is a very attractive target for prostate imaging and therapy. A range of PSMA inhibitors have been reported that may serve as platforms for the development of agents targeted to PSMA enzymatic activity. In a successfully completed phase 1 SBIR award (1R43EB004253), Molecular Insight has developed novel radiolabeled inhibitors that interact with PSMA and may provide specific targeting for the detection, treatment and management of prostate cancer. Two of the most active compounds, from in vitro PSMA cell binding assays and normal rat in vivo distribution studies, were tested for acute toxicity in rats and an exploratory IND filed to evaluate them as metastatic prostate cancer imaging agent in humans. Seven patients with confirmed metastatic prostate cancer were compared with two similar I-123 labeled compounds. Exceptional tumor accumulation was observed by both compounds in previously identified prostate metastasis along with localization of previously unknown disease. As required by the FDA, the exploratory IND must be closed and the results presented to the agency before proceeding to more elaborate traditional testing. Subsequently, the sponsor must fulfill all the safety assessments and CMC developments required for a conventional IND to proceed to human efficacy testing. The short physical half life of the Iodine-123 (13 hours) necessitates GMP production for each study and preliminary studies are only performed of small quantities due to radiation protection safeguards, consequently scale up production is required to produce multiple doses. Additionally as an agent progresses down the clinical development pathway more scrutiny is applied further up the chain of components for the drug product. The ultimate goal of this phase 2 SBIR application is to initiate the GMP campaign for the critical component drug precursor, perform CMC optimization and scale up of the final drug product, initiate metabolite studies and complete the preclinical safety testing require to initiate a conventional IND.

Public Health Relevance:
Determination of serum prostate specific antigen (PSA) is an effective early screen for potential prostate cancer with revenues estimated at over $350 million annually. Although the current screening method of PSA levels in the blood is valuable for early detection, the confirmation by fine needle biopsy does not give a representative evaluation of the entire prostate or determine lymph node involvement. A reliable method for non-invasive diagnosis and monitoring of primary and metastatic tumors would be an important addition to the management of prostate cancer victims. New Prostrate Specific Membrane Antigen (PSMA) targeted to the extracellular domain of this protein represents a potential new class of drugs for the diagnosis, management or treatment of prostate cancer and embody a significant commercial opportunity in an area of unmet clinical need. There is presently no effective therapy for relapsing, metastatic, androgen-independent prostate cancer or a tissue specific method to spatially locate disease. In a successfully completed phase 1 SBIR award (1R43EB004253), Molecular Insight has developed novel inhibitors that interact with PSMA and may provide specific targeting for the detection, treatment and management of prostate cancer. Seven patients have been compared with two I-123 labeled compounds in an exploratory IND and both compounds exhibit exceptional tumor accumulation and rapid whole body elimination. The lead compound will be entered into additional safety assessments required for a conventional clinical trial and proceed to dose finding, human safety and efficacy testing. The ultimate goal of this phase 2 SBIR application is to initiate the GMP campaign for the drug precursor, perform CMC optimization and scale up of the final drug product and complete the preclinical safety testing require to initiate a traditional clinical trial.

Public Health Relevance Statement:


Public Health Relevance:
Determination of serum prostate specific antigen (PSA) is an effective early screen for potential prostate cancer with revenues estimated at over $350 million annually. Although the current screening method of PSA levels in the blood is valuable for early detection, the confirmation by fine needle biopsy does not give a representative evaluation of the entire prostate or determine lymph node involvement. A reliable method for non-invasive diagnosis and monitoring of primary and metastatic tumors would be an important addition to the management of prostate cancer victims. New Prostrate Specific Membrane Antigen (PSMA) targeted to the extracellular domain of this protein represents a potential new class of drugs for the diagnosis, management or treatment of prostate cancer and embody a significant commercial opportunity in an area of unmet clinical need. There is presently no effective therapy for relapsing, metastatic, androgen-independent prostate cancer or a tissue specific method to spatially locate disease. In a successfully completed phase 1 SBIR award (1R43EB004253), Molecular Insight has developed novel inhibitors that interact with PSMA and may provide specific targeting for the detection, treatment and management of prostate cancer. Seven patients have been compared with two I-123 labeled compounds in an exploratory IND and both compounds exhibit exceptional tumor accumulation and rapid whole body elimination. The lead compound will be entered into additional safety assessments required for a conventional clinical trial and proceed to dose finding, human safety and efficacy testing. The ultimate goal of this phase 2 SBIR application is to initiate the GMP campaign for the drug precursor, perform CMC optimization and scale up of the final drug product and complete the preclinical safety testing require to initiate a traditional clinical trial.

NIH Spending Category:
Aging; Cancer; Patient Safety; Prostate Cancer; Urologic Diseases

Project Terms:
abstracting; Acute; Acute Toxicity Tests; Amino Acids; androgen independent prostate cancer; Animals; Antigen Targeting; Area; Award; Binding (Molecular Function); Biological Assay; Blood; cancer imaging; Cancer Patient; Canis familiaris; Carcinoma; Cells; Chemicals; Clinical; Clinical trial protocol document; Clinical Trials; Contracts; design; Detection; detector; Development; Diagnosis; Diagnostic; digital; Dipeptidases; Disease; Documentation; Dose; Drug Formulations; Drug Kinetics; Early Diagnosis; effective therapy; efficacy testing; Enzymes; Epithelium; Equilibrium; Evaluation; Excipients; Excretory function; Exhibits; Exopeptidase; extracellular; Extracellular Domain; Fine-needle biopsy; Folate; Free Radical Scavengers; Glutamate Carboxypeptidase II; Glycoproteins; GMP lots; Goals; Half-Life; High Pressure Liquid Chromatography; Hormones; Hour; Human; Human Cell Line; human data; human glutamate carboxypeptidase II; Image; In Vitro; in vivo; inhibitor/antagonist; insight; Intervention; Iodine; Label; Laboratories; Lead; Link; liquid chromatography mass spectrometry; LNCaP; Lymph Node Involvement; Malignant neoplasm of prostate; man; Manufacturer Name; Membrane; Membrane Proteins; Metabolic; Metastatic Prostate Cancer; Methods; Modeling; Molecular; Molecular Target; Monitor; Names; Neoplasm Metastasis; neoplastic cell; neovasculature; Neurons; novel; Pathway interactions; Patients; Peptide Signal Sequences; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; pre-clinical; preclinical safety; preclinical toxicity; Primary Neoplasm; Process; process optimization; Prodrugs; Production; Prostate; Prostate-Specific Antigen; Prostatic Epithelium; Proteins; public health relevance; Radiation Protection; Radioactive; radiochemical; Radioisotopes; Radiolabeled; Radiopharmaceuticals; radiotracer; Rattus; rectal; Reference Standards; Refractory; Regulatory Affairs; Relapse; Reporting; research clinical testing; Resources; Running; Safety; safety study; safety testing; scale up; Screening procedure; Selection Criteria; Series; Serum; Small Business Innovation Research Grant; System; Testing; Tissues; Toxic effect; tumor; uptake; Urine; Validation

There is presently no effective therapy for relapsing, metastatic, androgen-independent prostate cancer and the most effective treatment occurs with early and appropriate intervention. Blood PSA screening and digital rectal exams can detect early warning signs of prostate cancer but an effective tissue-specific method for spatial localization of metastatic disease is not available. Human prostate specific membrane antigen (PSMA) is an integral trans-membrane protein, associated with the prostate epithelium, prostatic tumor cells and the neovasculature of other tumor types. PSMA is a 750 amino acid type II glycoprotein which is typically expressed to a small extent in normal human prostate epithelium but is up-regulated in prostate cancer, including metastatic disease. The extracellular portion of PSMA is highly homologous to the enzyme NAALDase (N-acetylated a-linked acidic dipeptidase) which is involved in the deactivation of neuronal signaling peptides. The enzymatic aspect of PSMA is a unique exopeptidase with reactivity toward poly-gamma-glutamated folates, capable of sequentially removing the poly-gamma-glutamyl termini. Since PSMA is expressed by virtually all prostate cancers and especially poorly differentiated, metastatic and hormone-refractory carcinomas, it is a very attractive target for prostate imaging and therapy. A range of PSMA inhibitors have been reported that may serve as platforms for the development of agents targeted to PSMA enzymatic activity. In a successfully completed phase 1 SBIR award (1R43EB004253), Molecular Insight has developed novel radiolabeled inhibitors that interact with PSMA and may provide specific targeting for the detection, treatment and management of prostate cancer. Two of the most active compounds, from in vitro PSMA cell binding assays and normal rat in vivo distribution studies, were tested for acute toxicity in rats and an exploratory IND filed to evaluate them as metastatic prostate cancer imaging agent in humans. Seven patients with confirmed metastatic prostate cancer were compared with two similar I-123 labeled compounds. Exceptional tumor accumulation was observed by both compounds in previously identified prostate metastasis along with localization of previously unknown disease. As required by the FDA, the exploratory IND must be closed and the results presented to the agency before proceeding to more elaborate traditional testing. Subsequently, the sponsor must fulfill all the safety assessments and CMC developments required for a conventional IND to proceed to human efficacy testing. The short physical half life of the Iodine-123 (13 hours) necessitates GMP production for each study and preliminary studies are only performed of small quantities due to radiation protection safeguards, consequently scale up production is required to produce multiple doses. Additionally as an agent progresses down the clinical development pathway more scrutiny is applied further up the chain of components for the drug product. The ultimate goal of this phase 2 SBIR application is to initiate the GMP campaign for the critical component drug precursor, perform CMC optimization and scale up of the final drug product, initiate metabolite studies and complete the preclinical safety testing require to initiate a conventional IND.

Public Health Relevance:
Determination of serum prostate specific antigen (PSA) is an effective early screen for potential prostate cancer with revenues estimated at over $350 million annually. Although the current screening method of PSA levels in the blood is valuable for early detection, the confirmation by fine needle biopsy does not give a representative evaluation of the entire prostate or determine lymph node involvement. A reliable method for non-invasive diagnosis and monitoring of primary and metastatic tumors would be an important addition to the management of prostate cancer victims. New Prostrate Specific Membrane Antigen (PSMA) targeted to the extracellular domain of this protein represents a potential new class of drugs for the diagnosis, management or treatment of prostate cancer and embody a significant commercial opportunity in an area of unmet clinical need. There is presently no effective therapy for relapsing, metastatic, androgen-independent prostate cancer or a tissue specific method to spatially locate disease. In a successfully completed phase 1 SBIR award (1R43EB004253), Molecular Insight has developed novel inhibitors that interact with PSMA and may provide specific targeting for the detection, treatment and management of prostate cancer. Seven patients have been compared with two I-123 labeled compounds in an exploratory IND and both compounds exhibit exceptional tumor accumulation and rapid whole body elimination. The lead compound will be entered into additional safety assessments required for a conventional clinical trial and proceed to dose finding, human safety and efficacy testing. The ultimate goal of this phase 2 SBIR application is to initiate the GMP campaign for the drug precursor, perform CMC optimization and scale up of the final drug product and complete the preclinical safety testing require to initiate a traditional clinical trial.

Project Terms:
ATGN; Acute; Acute Toxicity Tests; Amino Acids; Animals; Antigen Targeting; Antigens; Area; Assay; Award; Binding; Binding (Molecular Function); Bioassay; Biologic Assays; Biological Assay; Blood; Blood Serum; Body Tissues; Cancer Patient; Cancer of Prostate; Canine Species; Canis familiaris; Carcinoma; Cells; Chemicals; Chemotherapy-Hormones/Steroids; Chromatography, High Performance Liquid; Chromatography, High Pressure Liquid; Chromatography, High Speed Liquid; Clinical; Clinical Evaluation; Clinical Testing; Clinical Trial Protocol; Clinical Trials; Clinical Trials, Phase I; Clinical Trials, Unspecified; Clinical trial protocol document; Common Rat Strains; Contracting Opportunities; Contracts; Detection; Development; Diagnosis; Diagnostic; Dipeptidases; Disease; Disorder; Documentation; Dogs; Dose; Drug Formulations; Drug Kinetics; Drug Precursors; Drugs; EC 3.4.21.34; Early Diagnosis; Early-Stage Clinical Trials; Endocrine Gland Secretion; Enzymes; Epithelial Neoplasms, Malignant; Epithelial Tumors, Malignant; Epithelium; Epithelium of Human Prostate Gland; Equilibrium; Evaluation; Excipients; Excretory function; Exhibits; Exopeptidase; Exoproteases; External Domain; Extracellular Domain; FOLH1 Protein; Fine-needle biopsy; Fletcher Factor; Folate; Folate Hydrolase 1; Folate Hydrolase I; Formulation; Formulations, Drug; Free Radical Scavengers; GMP lots; Genital System, Male, Prostate; Glutamate Carboxypeptidase II; Glycoproteins; Goals; HPLC; Half-Life; Half-Lifes; High Pressure Liquid Chromatography; Hormones; Hour; Human; Human Cell Line; Human Prostate; Human Prostate Gland; Human, General; I- element; Image; In Vitro; Intervention; Intervention Strategies; Iodine; KLK3; Kallikrein 3; LNCaP; Label; Laboratories; Lead; Link; Lymph Node Involvement; Malignant Tumor of the Prostate; Malignant neoplasm of prostate; Malignant prostatic tumor; Mammals, Dogs; Mammals, Rats; Man (Taxonomy); Man, Modern; Manufacturer; Manufacturer Name; Medication; Membrane; Membrane Proteins; Membrane-Associated Proteins; Metabolic; Metastasis; Metastasize; Metastatic Neoplasm; Metastatic Prostate Cancer; Metastatic Tumor; Methods; Modeling; Molecular; Molecular Interaction; Molecular Target; Monitor; N-Acetylaspartylglutamate Peptidase; N-Acetylated-alpha-Linked Acidic Dipeptidase; NAAG Peptidase; NAALADase; NAALADase II; NAALADase L; Names; Neoplasm Metastasis; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; Neurons; P-30 Antigen; PSM antigen; PSMA; Pathway interactions; Patients; Pb element; Peptide Signal Sequences; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmacokinetics; Pharmacologic Substance; Pharmacological Substance; Phase; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Plasma Kallikrein Precursor; Plasma Prekallikrein; Pro-Drugs; Process; Prodrugs; Production; Prostate; Prostate CA; Prostate Cancer; Prostate Carcinoma Metastatic; Prostate Gland; Prostate Specific Antigen Preproprotein; Prostate-Specific Antigen; Prostate-Specific Membrane Antigen; Prostatic Cancer; Prostatic Epithelium; Prostatic Gland; Proteins; Radiation Protection; Radioactive; Radioactive Isotopes; Radioisotopes; Radiolabeled; Radionuclides; Radiopharmaceutical Compound; Radiopharmaceuticals; Rat; Rattus; Reference Standards; Refractory; Regulatory Affairs; Relapse; Reporting; Research Resources; Resources; Reticuloendothelial System, Blood; Running; SBIR; SBIRS (R43/44); Safety; Screening procedure; Secondary Neoplasm; Secondary Tumor; Selection Criteria; Semenogelase; Seminin; Series; Serum; Signal Peptide; Signal Sequences; Signal Sequences, Peptide; Small Business Innovation Research; Small Business Innovation Research Grant; Surface Proteins; System; System, LOINC Axis 4; Testing; Therapeutic Hormone; Tissues; Toxic effect; Toxicities; Tumor Cell; Tumor Cell Migration; Urinary System, Urine; Urine; Validation; abstracting; aminoacid; androgen independent prostate cancer; balance; balance function; cancer imaging; cancer metastasis; canine; clinical investigation; clinical test; design; designing; detector; digital; disease/disorder; domestic dog; drug/agent; early detection; effective therapy; efficacy testing; epithelial carcinoma; excretion; extracellular; folate hydrolase (prostate-specific membrane antigen) 1, human; gamma-Seminoprotein; gene product; glutamate carboxypeptidase II, human; hK3 Kallikrein; heavy metal Pb; heavy metal lead; human data; human glutamate carboxypeptidase II; imaging; immunogen; in vivo; inhibitor; inhibitor/antagonist; insight; interventional strategy; kininogenin; man; man's; membrane structure; neoplastic cell; neovasculature; neuronal; novel; pathway; phase 1 study; phase 1 trial; phase I trial; pre-clinical; preclinical; preclinical safety; preclinical toxicity; process optimization; prostate-specific membrane antigen, human; protein signal sequence; protocol, phase I; public health relevance; radioactive drugs; radiochemical; radiolabel; radiotracer; rectal; research clinical testing; safety study; safety testing; scale up; screening; screenings; tumor; uptake