A highly sensitive and specific clinical imaging agent to detect, stage and monitor response to therapeutic intervention is urgently needed for prostate cancer patients. To address this unmet need we initially generated a radiolabeled minibody (Mb) fragment (89Zr-Df-IAB2M) directed to Prostate Specific Membrane Antigen (PSMA). PSMA is significantly upregulated in the majority of human prostate cancers and its expression increases with increasing grade, with the spread of metastatic disease and emergence of castration resistant phenotype, making it one of the best validated markers and targets in prostate cancer. In Phase IIa of the contract, GMP grade 89Zr-Df-IAB2M was manufactured enabling early Phase 1/2a clinical trials that are now complete. The trials assessed safety, dose ranges, PK, dosimetry, biodistribution, immunogenicity and initial signs of imaging efficacy. Excellent data obtained in these early trials allowed us to advance 89Zr-Df-IAB2M compound into Phase 2 clinical trials in March 2015. During the transfer of the minibody manufacturing to another CMO to enable upcoming Phase 3 clinical studies and commercialization, ImaginAb introduced minor changes in the primary structure of the original IAB2M to generate a more optimal Mb that is now called IAB2M-A. These changes did not affect binding to PSMA but greatly improved stability, manufacturability and homogeneity of the product candidate which will decrease manufacturing costs and potentially reduce immunogenicity. 89Zr-Df-IAB2M-A has also demonstrated greater circulation stability in vivo in preclinical models, with reduced renal clearance while maintaining excellent targeting to PSMA expressing tumors. These results suggest that 89Zr-Df-IAB2M-A will retain similar targeting properties in patients while reducing the radioactive dose delivered to human kidneys, a radiosensitive organ. This improved Mb variant is currently in GMP manufacturing. The overall goal of this SBIR Phase IIb contract proposal is to advance the clinical development of the 89Zr-Df-IAB2M-A compound towards BLA submission and commercialization. In Phase IIb of the contract ImaginAb proposes to: (1) Complete the development and optimization of protein formulation(s), Df- isothiocyanate conjugation process transfer to CMO and all product related characterization/release assays for manufacturing of IAB2M-A, Df-IAB2M-A and 89Zr-IAB2M-A; (2) Conduct preclinical characterization studies to compare the early Phase 1/2a clinical material and the new 89Zr-Df-IAB2M-A; (3) Perform bridging Phase 1/2 studies with 89Zr-IAB2M-A in 50 patients to evaluate safety/PK/biodistribution and to compare to the original product candidate. Achievement of these specific aims will enable proper design of future Phase 3 study that will support potential of a subsequent BLA filing.
Public Health Relevance Statement: Public Health Relevance: Prostate cancer remains a formidable disease with over 233,000 men expected to be diagnosed and greater than 29,480 expected to die in the U.S. in 2014 alone. Importantly, diagnostic imaging to detect, stage and guide prostate cancer treatment remains a clear unmet clinical need. The work proposed in this project will cover multiple activities required for the clinical development of 89Zr-Df-IAB2M-A as a commercially viable prostate cancer imaging agent. The successful development of 89Zr-Df-IAB2M-A as an imaging reagent will provide a transformative asset in guiding therapy against this disease
NIH Spending Category: Aging; Bioengineering; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Diagnostic Radiology; Prostate Cancer; Urologic Diseases
Project Terms: Achievement; Address; Affect; Binding; Biodistribution; Biological Assay; Blood Circulation; cancer imaging; Cancer Patient; cancer therapy; Castration; Clinical; clinical material; Clinical Research; Clinical Trials; commercialization; Contracts; cost; Data; design; Development; Diagnosis; Diagnostic Imaging; Disease; Dose; dosimetry; FDA approved; FOLH1 gene; Formulation; Future; Goals; Human; Image; imaging agent; immunogenicity; improved; In Vitro; in vivo; Isothiocyanates; Kidney; Low Dose Radiation; Malignant neoplasm of prostate; Medical; meetings; men; Minor; Monitor; novel; Organ; Patients; Phase; phase 1 study; phase 3 study; Phase II Clinical Trials; Phenotype; Positron-Emission Tomography; pre-clinical; Pre-Clinical Model; Preparation; Process; Property; Proteins; Protocols documentation; public health relevance; Radioactive; Radiolabeled; radiosensitive; radiotracer; Reagent; Renal clearance function; Reporting; Resistance; response; Rodent; Safety; scale up; Small Business Innovation Research Grant; Staging; Structure; Target Populations; Therapeutic Intervention; Time; Toxicology; Translating; tumor; uptake; Variant; Work
