Open Communication and Organized Learning Solved a Customer’s Problem
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: IsoTherapeutics and the customer worked seamlessly as one team and with a sense of urgency to address critical isotope processing and protein labeling issues. IsoTherapeutics leased an appropriate facility to process the cyclotron target to recover and purify the isotope. IsoTherapeutics also brought to bear its full capabilities and experts in analytical, chelation, separation and purification technologies to produce the radioisotope. IsoTherapeutics was able to purify the isotope then complex it with a bifunctional chelant and ultimately to radiolabel the protein. IsoTherapeutics 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. IsoTherapeutics 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.
Meeting the Challenge of Radiopharma Development – Project Coordination Saves Time and Money
Problem: A company developing a novel radioimmunotherapy for leukemia approached IsoTherapeutics for help with improving the product yield and overall process chemistry that would produce consistent product. The company’s existing process involved attaching a monoclonal antibody to a unique isotope. However, the amount of isotope they could attach to their monoclonal antibody was at best 10% of the isotope they started with. In addition, the process produced product that was “hit and miss” in meeting the release criteria. The product was already in Phase 1 clinical stage; hence the company had a strong sense of urgency in finding solutions to the problems.
Solution: IsoTherapeutics 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. IsoTherapeutics worked with a cGMP manufacturing site and deployed its own laboratory resources to determine the release criteria. IsoTherapeutics brought to bear its capabilities in analytical science, radiochemistry, and instrumentation for determining the quality of the final product. IsoTherapeutics used Germanium detectors for measuring isotope equilibrium and size exclusion chromatography for separating monoclonal antibody and conjugates.
Throughout the development process IsoTherapeutics stayed actively engaged with the customer and its collaborators (including one in Europe) to develop an alternative process that improved the yield.
It’s a Dog’s Life! Dedication of a Pet Owner Leads to Treatment for Osteosarcoma
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 IsoTherapeutics 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 IsoTherapeutics 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.
Collaborative Relationships Help to Address FDA Questions on an IND
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 IsoTherapeutics for help with the validation of the concept and the chemistry.
Solution: IsoTherapeutics evaluated the chemistry and advised the physician that changing the isotope would require a new chelating agent. The customer asked that IsoTherapeutics to demonstrate that in the laboratory. In a short period of time IsoTherapeutics designed and conducted the experiments and obtained the data showing that changing the isotope was not appropriate. In addition, IsoTherapeutics 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 IsoTherapeutics for additional help in obtaining an IND for the new construct. IsoTherapeutics facilitated meetings with the customer, the isotope production facility, and the manufacturer of the radiopharmaceutical. Based on these meetings, IsoTherapeutics quickly determined the critical issues and performed analytical work to answer questions raised by the FDA.