A bone-binding radiopharmaceutical for treatment of bone metastases
Development of tin-117m as a radiopharmaceutical was initiated by Suresh Srivastava and colleagues at Brookhaven National Laboratory as a bone-binding radiopharmaceutical. Multiple chelating agents were tested in rodent models which determined that bone binding and biodistribution was optimal for tin (+4)-DTPA. These studies demonstrated that more than half of administered tin-117m-DTPA was rapidly and irreversibly bound to bon, with increased binding in areas of increased bone turnover, and that the remainder was rapidly excreted in the urine. Exposure to organs other than cortical bone was minimal, and marrow sparing was demonstrated.
Three clinical trials involving over 100 patients have been conducted which not only have confirmed the safety and relative marrow sparing effect of tin-117m-DTPA but also have demonstrated excellent pain relief in patients with painful bone metastases, most from prostate or breast cancer. At doses well below the maximum tolerated dose, three quarters of patients experienced major to complete relief of bone pain resulting in a mean onset of pain relief of less than a week and mean duration of relief greater than three months. This compares favorably to published results of other bone-binding radiopharmaceuticals.
Serene has developed a proprietary, high specific activity formulation of tin-117m-DTPA which will allow further dose escalation. In addition, the shelf life of the product is approximately four weeks, far longer than that of other agents in its class. Tin-117m-DTPA also will be less expensive and more easily produced than other products, ensuring adequate supply at a more reasonable cost than other agents. Serene has entered into a cooperative research and development agreement (CRADA) with the US National Cancer Institute through the NCI Experimental Therapeutics (NExT) program, under which Serene will supply tin-117m-DTPA to investigators selected by NCI, which will fund and manage the clinical trials, data analysis, and regulatory development.
Homogeneous tin-117m colloid
Intraarticular treatment of refractory arthritis
Radiosynoviorthesis is a procedure in which an insoluble radiocolloid is injected into the joint space in patients with refractory arthritis. The procedure is routinely performed with several different radiopharmaceuticals, primarily in Europe and Canada.
Serene has developed a homogeneous tin-117m colloid (HTC) for radiosynoviorthesis, and has conducted several veterinary clinical trials of the HTC in the US in dogs with refractory osteoarthritis. Preclinical studies demonstrated that the HTC remained in the joint with no leakage or systemic exposure. Veterinary clinical trials of Synovetin OA®, marketed by Exubrion Therapeutics, a spin-off company from Serene, demonstrated pain relief in 92% of dogs with mild or moderate elbow osteoarthritis, and pain relief lasting up to a year with a single treatment.
Tin-117m colloid for use in humans (SynovacollTM) has been authorized by Health Canada to begin a Phase 1B trial for the treatment of patients with refractory rheumatoid arthritis, osteoarthritis and other arthritides.
Binding to vulnerable plaque in patients with atherosclerosis
Annexin V binds to phosphatidylserine, which is highly expressed and exposed in atherosclerotic plaque cells undergo apoptosis. Binding tin-117m to annexin V allows imaging of apoptotic areas and may, with higher doses of radiation, also target these areas therapeutically.
Five patients with unstable vascular plaque who underwent carotid endarterectomy surgery were treated prior to surgery with tin-117m-DOTA-annexin V in a Phase 1/2 trial. Results indicate that the product is safe, and that vulnerable, unstable plaque in carotid arteries, and abdominal aortic aneurysms can be imaged. Additional trials are planned to examine therapeutic utility.
Tin-117m-DOTA-annexin V may also have oncologic applications. Cancer chemotherapy induces apoptosis, which, as with vulnerable plaque, increases phosphatidylserine on damaged cells. Combining tin-117m-DOTA-annexin V with chemotherapy may enhance the efficacy of chemotherapy.
Tin-117m-plated biliary stent
Treatment of malignant biliary tract obstruction
Tin-117m has been plated onto stents, which may be used for treatment of several conditions, including biliary obstruction caused by cancer. The stents are specially designed to anchor in place, avoiding slippage which may occur with other stents.
Tin-117m has been linked to small molecules and proteins, including monoclonal antibodies, for targeted therapy of malignant and cardiovascular diseases.