Periodic Reporting for period 1 - Hypo-Imag (A 64Cu(II)-based radiotracer for diagnosing hypoxic conditions in cancer cells)
Reporting period: 2022-04-01 to 2023-09-30
Imaging of hypoxia (low oxygen level in tissues) is important in many disease states in oncology, cardiology, and neurology. Hypoxia is a common condition encountered within the tumor microenvironment that drives proliferation, angiogenesis, and resistance to therapy . Despite on-going efforts to identify hypoxia, until now there is no clinically approved imaging biomarker that is being used routinely, due to both low tumor uptake, and a low tumor to muscle (T/M) ratio. Our lab has shown that a 64Cu(II) radio isotope, coordinated by a small ligand and a small (6 amino acids) peptide (both ligand and peptide are non-toxic), named CuCysPhe, will provide both high sensitivity and improved selectivity to hypoxic conditions of tumors. Each part of the complex scaffold (chelating ligand and peptide) has a distinct role, such as tuning the appropriate reduction potential for Cu(II) intracellular reduction (ligand), and the selective intracellular delivery (peptide) via the main human copper transporter, termed hCtr1.
Three aims and activities were planned and completed:
Activity 1: in vivo validation of the designed radiotracer in mice, including toxicological tests, and evaluation of the efficacy. The outcome is a report on safety and imaging efficacy, which will be the core for the preclinical studies for advancing towards clinical studies and regulatory approval which will be pursued within the EIC transition project if funded.
Activity 2: consolidate the IP strategy and eliminate any IP-related barriers towards commercialization. The outcome is a report on IP strategy and advancing patent applications.
Activity 3: Market analysis as well as investigating the regulatory requirements. The outcome is market analysis report and regulatory assessment that will be the basis of EIC -transition application.
Three aims and activities were planned and completed:
Activity 1: in vivo validation of the designed radiotracer in mice, including toxicological tests, and evaluation of the efficacy. The outcome is a report on safety and imaging efficacy, which will be the core for the preclinical studies for advancing towards clinical studies and regulatory approval which will be pursued within the EIC transition project if funded.
Activity 2: consolidate the IP strategy and eliminate any IP-related barriers towards commercialization. The outcome is a report on IP strategy and advancing patent applications.
Activity 3: Market analysis as well as investigating the regulatory requirements. The outcome is market analysis report and regulatory assessment that will be the basis of EIC -transition application.
Within ERC-PoC (Hypo-Imag), we have finalized the lead compound synthesis (64CuCysPhe), we characterized its chemical and physical properties, and resolved its mechanism of action. We gained from our institutional ethical committee approval numbers 14-02-2018 and 80-11-2021 to conduct these in-vivo experiments. Under this approval we conducted various pre-clinical tests including the following: stability tests in mice serum; toxicological tests on the non-radioactive compound in mice were performed up to 800 times the clinical dose. We then performed in-vivo imaging experiments on mice with breast cancer tumors (ethical approval no. MD-20-16223-4, MD-21-16761-4). We identified the required dose amount needed for mice experiments, the preferred imaging time window, and characterized the biodistribution of 64CuCysPhe and its metabolic fate using a range of imaging experiments. We also compared the efficacy of 64CuCysPhe to 18F-FDG and 64Cu-ATSM radiotracers, showing a higher uptake ratio of our radiotracer as well as the potency to provide a good overview of the tumor’s state. Immunohistochemical experiments and ultrasound experiments were also conducted to correlate between the gamma radiation intensity from the imaging with the degree of hypoxia within the tumor. We are currently in TRL4 and are ready to conduct GLP studies in mice via a sub-contractor to evaluate the biodistribution, pharmacokinetics, toxicology and safety pharmacology of the candidate compound (in preparation for a clinical trial phase I). We have a patent pending in US and Europe. We prepared a regulatory package, which describe all the required pre-clinical experiments that are needed tp apply for FIH trials. We have been in touch with various biotech and phrama companies for future coopertaion. We also applied for an EIC-transition grant.
Our designed radiotracer is able to detect tumors at early stage, and provide good overview on the state of the tumor, in regrad to hypoxic and apopotosis regions. Moreover, it can detect cancer types that cen not be easily detect by other technologies such as prostate and liver. It can also help to follow thepay repsonse, since the tumor/muscle ratio is high and it porivdes good image of the tumor boundaries and necrotic cneters of the tumor.