The overall goal of this SBIR is to develop an innovative theranostic agent for imaging andtreatment of cancer, by combining PET imaging and targeted radionuclide therapy (TRT) agentsvia a single chelator-minibody conjugate precursor.The novel theranostic agent described here employs a chelator, Lumi804, that can quickly andstably chelate the most widely used positron emitter for antibodies (Zr-89) and the most widelyused therapeutic beta-emitting radionuclide (Lu-177), and an alpha emitting isotope (Th-227)currently undergoing clinical evaluation in multiple phase I efficacy trials. To our knowledge,there are no chelator-antibody or chelator-minibody conjugates that are in human trials or usedclinically that can be labeled with both Zr-89 (PET imaging) and Lu-177 (TRT) quickly at roomtemperature.Small molecule peptide analogues based on a dipeptide urea motif such as F-18-PSMA-1007 orGa-68-PSMA-11 have recently improved imaging of prostate cancer, and analogues such asLu-177-PSMA-617 and Ac-225-PSMA-617 are showing significant efficacy in patients. However,patients treated with Lu-177-PSMA-617 often recur, and salvage therapy with Ac-225-PSMA-617, while effective, is limited due to salivary gland toxicity. Use of radiolabeled antibodies hasbeen shown to avoid salivary gland localization, but can lead to bone marrow suppression dueto the longer biological half-life of antibodies. The Zr-89-DFO-IAB2M minibody has beenevaluated in Phase I clinical study and found to display low salivary gland localization whileexhibiting a biological half-life that is much shorter than the corresponding Zr-89-DFO-J591antibody conjugate. The proposed research in this SBIR Phase I project will develop thesynthesis and evaluate the performance of a novel Zr-89, Lu-177, and Th-227 labeled anti-prostate specific membrane antigen (PSMA) intact minibody construct, leveraging a singlechelator suitable for all three radiometals, for lesion detection, treatment, and monitoring patientresponse to radionuclide therapy. These studies will enable the development in Phase II of thefirst theranostic agent to target positron, beta particle, and alpha particle radiation to PSMAexpressing tumors.
Public Health Relevance Statement: Narrative
Small molecule peptide analogue radiopharmaceuticals have recently improved imaging of
prostate cancer, and are showing significant efficacy in patients. However, patients often recur,
and salvage therapy is limited due to salivary gland toxicity. The proposed research in this SBIR
Phase I project will develop the synthesis and evaluate the performance of a novel Zr-89, Lu-
177, and Th-227 labeled anti-prostate specific membrane antigen (PSMA) intact minibody
theranostic agent that will minimize bone marrow suppression and salivary gland toxicity.
Project Terms: Alpha Particles ; Alpha Particle Radiation ; Alpha Radiation ; α Particles ; inhibitor/antagonist ; inhibitor ; Antibodies ; Beta Particle ; Beta Radiation ; Beta Rays ; Charged Particles-Electrons Radiation ; β-Particle ; β-Rays ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Buffers ; Cations ; Chelating Agents ; Chelators ; Complexons ; Chemistry ; High Pressure Liquid Chromatography ; HPLC ; High Performance Liquid Chromatography ; High Speed Liquid Chromatography ; Clinical Research ; Clinical Study ; Clinical Trials ; Dipeptides ; Pentetic Acid ; DTPA ; Detarex ; Diethylenetriamine Pentaacetic Acid ; Pentaind ; Penthanil ; Exhibits ; Goals ; Half-Life ; Human ; Modern Man ; In Vitro ; Isotopes ; Kinetics ; Lacrimal gland structure ; Lacrimal Glands ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Mus ; Mice ; Mice Mammals ; Murine ; Patient Monitoring ; Patients ; Positron-Emission Tomography ; PET ; PET Scan ; PET imaging ; PETSCAN ; PETT ; Positron Emission Tomography Medical Imaging ; Positron Emission Tomography Scan ; Rad.-PET ; positron emission tomographic (PET) imaging ; positron emission tomographic imaging ; positron emitting tomography ; Positron ; Prostatic Neoplasms ; Prostate Neoplasms ; Prostate Tumor ; Prostatic Neoplasia ; Radioisotopes ; Radioactive Isotopes ; Radionuclides ; Radiation therapy ; Radiotherapeutics ; Radiotherapy ; radiation treatment ; radio-therapy ; treatment with radiation ; Research ; Salivary Glands ; Salivary Glands Head and Neck ; Temperature ; Time ; single photon emission computed tomography ; SPECT ; SPECT imaging ; Single-Photon Emission-Computed Radionuclide Tomography ; Urea ; Carbamide ; Elaqua XX ; Urea Carbamide ; Ureaphil ; Measures ; Salvage Therapy ; Salvage-Tx ; animal-assisted therapy ; pet therapy ; base ; Label ; Radiopharmaceuticals ; Radiopharmaceutical Compound ; radioactive drugs ; radiotherapeutic drugs ; improved ; Radionuclide therapy ; therapeutic radionuclide ; Left ; Clinical ; Phase ; Biological ; Chemicals ; Lesion ; Structure of base of prostate ; Base of Human Prostate ; Base of the Prostate ; Serum ; Blood Serum ; Cell Surface Proteins ; Patient Selection ; Radioimmunoconjugate ; Radiolabeled Antibodies ; analog ; Funding ; uptake ; Bone Marrow Suppression ; Phase II Clinical Trials ; Phase 2 Clinical Trials ; phase II protocol ; Malignant Tumor of the Prostate ; Malignant prostatic tumor ; Prostate CA ; Prostate Cancer ; Prostatic Cancer ; Malignant neoplasm of prostate ; Complex ; subdermal ; subcutaneous ; peptide analog ; Performance ; success ; antibody conjugate ; dosimetry ; Toxicities ; Toxic effect ; Biologic Development ; novel ; Exclusion ; Modeling ; Property ; Myeloid Cells ; Cancer Treatment ; Malignant Neoplasm Therapy ; Malignant Neoplasm Treatment ; anti-cancer therapy ; anticancer therapy ; cancer-directed therapy ; cancer therapy ; Prostate Carcinoma Metastatic ; Metastatic Prostate Cancer ; Molecular Interaction ; Binding ; Therapeutic Uses ; J591 ; MAb J591 ; J591 Monoclonal Antibody ; small molecule ; FOLH ; FOLH1 ; Folate Hydrolase 1 ; GCP2 ; Glutamate Carboxypeptidase II ; N-Acetylated Alpha-Linked Acidic Dipeptidase 1 ; NAALAD1 ; NAALADase I ; PSM ; PSMA ; Prostate-Specific Membrane Antigen ; FOLH1 gene ; CD11b ; CR3A ; ITGAM ; MAC1A ; MO1A ; ITGAM gene ; Macrocycle Compounds ; Macrocyclic Compounds ; Affinity ; Detection ; Radioactive ; research clinical testing ; Clinical Evaluation ; Clinical Testing ; clinical test ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Xenograft Model ; xenograft transplant model ; xenotransplant model ; Radiolabeled ; Development ; developmental ; Image ; imaging ; PC3 cell line ; PC-3 ; PC-3 cell line ; PC3 ; Biodistribution ; efficacy trial ; innovation ; innovate ; innovative ; CWR22Rv1 ; 22RV1 ; tumor ; overexpression ; overexpress ; Biological Markers ; bio-markers ; biologic marker ; biomarker ; theranostics ; prostate cancer cell ; prostate tumor cell ; imaging agent ; efficacy study ; clinical development ; patient response ; patient specific response ; responsive patient ;
