Developing radioimmunotherapy for osteosarcoma using comparative oncology

Abstract

Osteosarcoma (OS) is one of the most common primary malignant bone cancer in children wherein the mortality rate within 5 years is 30% and patients suffer from bone pain, limited or loss of limb function, or fatigue. In addition, OS is one of the most widespread cancers in companion dogs, particularly larger breeds, and closely resembles human OS. Unfortunately, in over 30 years, there has been no significant advancement in treatment options in humans; and canine treatment options are also limited. The cation independent mannose-6- phosphate/insulin-like growth factor-2 receptor (IGF2R) was found to be consistently overexpressed on multiple standard OS cell lines, including patient-derived xenografts, as well as on tumors from dogs with OS, making it a promising therapeutic target for radioimmunotherapy (RIT). RIT involves the use of an antibody labeled with an alpha- or beta- emitting radioisotope which delivers cytotoxic radiation to targeted cells. Our objective is to develop a novel, effective and safe treatment for OS using RIT using a comparative oncology approach. Antibodies against IGF2R were developed using phage-display, a combinatorial protein engineering technique wherein bacteriophages are used to select for high affinity reagents. The IGF2R-specific antibodies were tested in vitro by performing ELISA and flow cytometry and were also tested in vivo by performing microSPECT/CT imaging which confirmed that the antibody bound to the OS tumors in mice. This was followed by therapy studies which involved the testing of the IGF2R-specific antibody radiolabeled with Lutetium-177, a β-emitting theranostic radioisotope, for therapeutic efficacy studies in mouse models of human and canine OS. Future studies will involve a clinical trial in canine OS patients. The development of IGF2R-specific RIT will lead to a better therapeutic strategy for not only human OS but also for canine OS and will pave the way to increase survival for OS patients.