Problem: While working in close concert with a customer to develop a radiolabeled protein for diagnosing vulnerable plaque, a major problem arose in the midst of the project when the customer lost the ability to process their isotope. Without an alternate supplier of isotope there was a strong probability that product development and subsequent path to clinical trial may have to be delayed.

Solution: ITG and the customer worked seamlessly as one team and with a sense of urgency to address critical isotope processing and protein labeling issues. ITG leased an appropriate facility to process the cyclotron target to recover and purify the isotope. ITG also brought to bear its full capabilities and experts in analytical, chelation, separation and purification technologies to produce the radioisotope. ITG was able to purify the isotope then complex it with a bifunctional chelant and ultimately to radiolabel the protein. ITG also performed the final purification. Stability studies to determine the shelf life of the product were also designed and executed. Gamma spectroscopy was used to assist in the isotope recovery. Inductively-coupled plasma atomic emission spectroscopy was used to identify types and levels of metal impurities that needed to be addressed. An HPLC equipped with both UV and radiometric detectors was used to separate product from impurities and excess reagents. ITG also performed many biodistribution studies on normal mice to determine the uptake of radioisotope in various organs and tissues. Radiation dosimetry was performed to assess the safety of the product. The product is now ready for human clinical trial.

Results: Our customer was pleased with ITG's capabilities and expert resources it brought to bear to solve and manage the complex chemistry. They were very complementary on the high level of communication and innovation exhibited. The information gained in this process is now an integral part of the company's manufacturing process.

Solution: ITG scientists engaged with the company and its isotope vendors, consultants, and the clinical researchers to fully understand the scope of the problems and map out possible solutions. ITG worked with a cGMP manufacturing site and deployed its own laboratory resources to determine the release criteria. ITG brought to bear its capabilities in analytical science, radiochemistry, and instrumentation for determining the quality of the final product. ITG used Germanium detectors for measuring isotope equilibrium and size exclusion chromatography for separating monoclonal antibody and conjugates.

Throughout the development process ITG stayed actively engaged with the customer and its collaborators (including one in Europe) to develop an alternative process that improved the yield.

Results: Improvements in the final purification process allowed the cGMP manufacturing facility to consistently produce material that passed all the release criteria. The FDA has thus given approval to continue human clinical trials. In addition, the improved process has increased the yield from 4-10% to >90% without compromising the quality of the product. We expect that dramatic improvement in yield will substantially reduce materials and manufacturing costs providing the company with a significant competitive advantage with its new radioimmunotherapy for leukemia and other cancers. ITG is helping to qualify the product and the customer plans to use this new process for producing product for clinical trials as soon as possible.

Problem: Osteosarcoma (OS) is the most common bone cancer in dogs which affects approximately 10,000, mostly large-breed, dogs every year. Current treatments include radiation, chemotherapy, and surgical removal of the primary tumors; almost all cases result in amputation of the affected limb. Despite these aggressive treatments nearly all dogs die of this disease within 1 to 2 years of diagnosis.

When the St. Bernard "Gabriel" was affected by osteosarcoma, its owner Stan Stearns left no stone unturned to save and improve the quality of life of his companion. Stan, founder and owner of Valco Instruments Company, Inc (VICI) aggressively researched and worked with experts in the field of veterinary oncology, nuclear medicine, and pharmaceuticals to find the best treatment for Gabe. Stan's research led him to the radiopharmaceutical Quadramet® (Sm-153-EDTMP) used for bone palliation and Jim Simón, the principle scientist who had invented it at the Dow Chemical Company prior to founding ITG with his partner Keith Frank.  Stan found in them the expertise and problem solving approach that he was looking for to come up with a solution for treating companion animals affected by osteosarcoma. Although Gabe did not survive osteosarcoma, Stan did not give up on finding the solution for osteosarcoma in companion animals. He founded the non-profit Gabriel Institute to fund research for developing a treatment for OS.

Solution: The collaboration between ITG and VICI has led to bringing forth each company's expertise in radiopharmaceuticals and drug delivery systems, respectively. A series of experiments led to the ability to create a formulation that can deliver and retain certain beta-emitting isotopes in practically any type of tissue. A new treatment for solid cancers was thus developed. The treatment entails injecting a measured dose of the proprietary "Liquid Brachytherapy" material into the tumor to deliver a radiation dose prescribed by the practitioner. The Liquid Brachytherapy formulation comprises a beta-emitting radiometal, such as ¹⁶⁶Ho, ¹⁵³Sm, ¹⁷⁷Lu, or ⁹⁰Y, and a proprietary carrier agent. These radiometals have a short physical half-life and a tightly constrained range of irradiation. The drug delivery tools, developed by VICI, allow for the accurate delivery of the agent to tumors leaving surrounding normal tissues unaffected.

Results: This novel "system" approach has been used to treat eight canines with various states of primary bone cancer. The results have been outstanding especially for early diagnosed tumors with no metastatic disease. In several cases the tumors have been completely resolved. The partners are moving forward to work with universities and veterinary hospitals to develop programs that can be used to increase acceptance of the treatment and gather data for the clinical trial. In addition to bone cancer, the team is initiating work in solid soft tissue cancers. The Gabriel Institute is continuing to support and fund the treatment of companion animals.

Problem: Dr. Ebrahim Delpassand, founder and director of Excel Diagnostic Imaging Clinics wanted to change the isotope without altering the chelation chemistry in an existing radiopharmaceutical. The change in isotope was expected to combine diagnostic and therapeutic treatment of certain cancers. He approached ITG for help with the validation of the concept and the chemistry.

Solution: ITG evaluated the chemistry and advised the physician that changing the isotope would require a new chelating agent. The customer asked that ITG to demonstrate that in the laboratory. In a short period of time ITG designed and conducted the experiments and obtained the data showing that changing the isotope was not appropriate. In addition, ITG introduced the customer to its network of R&D and manufacturing operations; one in the U.S. and one in Italy to further assist him with obtaining the correct formulated product. This introduction yielded in collaborative relationships among the parties and the customer now has acquired the necessary compounds for his research.

More recently the same customer asked ITG for additional help in obtaining an IND for the new construct. ITG facilitated meetings with the customer, the isotope production facility, and the manufacturer of the radiopharmaceutical. Based on these meetings, ITG quickly determined the critical issues and performed analytical work to answer questions raised by the FDA.

Results: The data and suggestions from ITG will be used to continue the dialogue with the FDA and obtain an IND in a short time. The ITG's professional network (built over the years) accelerated problem solving and made a solid return on customer's time and money.