Abstract 1798: Targeted therapy of osteosarcoma with radiolabeled monoclonal antibody to an insulin-like growth factor-2 receptor
Authors: Geller David S. , Revskaya Ekaterina , Khan Mani , Morris Jonathan , Gorlick Richard , Dadachova Ekaterina 
Published: August 2015

Abstract
Introduction: Overall survival for patients with osteosarcoma has not meaningfully improved in over 30 years and there is a tremendous need for novel treatment strategies. Consistent overexpression of the insulin-like growth factor-2 receptor (IGF2R) has been previously demonstrated in osteosarcoma. Radioimmunotherapy (RIT) is a means of delivering cytotoxic radiation in a targeted manner, independent of specific pathway, using an antigen-specific antibody bound to a radioisotope. RIT has been successfully used in numerous oncologic scenarios. The purpose of this project was to perform a biodistribution experiment to determine if 188Re-labeled IGF2R-specific mAB preferentially localizes to tumor and to evaluate if it will effectively target and treat osteosarcoma cells without toxicity to normal tissue.
Materials and Methods: Twenty SCID mice underwent heterotopic implantation of OS17. Tumor was allowed to grow to 5mm in diameter. Ten mice were randomized to receive 50μCi via intraperitoneal injection of 188Re-MEM-238 (IGF2R specific murine Ab) and 10 were randomized to receive 188Re-MOPC-21 (isotype control). Radioactivity was measured from harvested organs at 24 and 48 hours and percentage of injected radiolabeled Ab was calculated for each animal. A Scatchard plot analysis was used to calculate binding site number per OS17 cell. Twenty female SCID mice underwent heterotopic tumor implantation and thereafter were randomized into 4 groups; 300μCi 188Re-MEM-238, 300μCi188 Re-MOPC-21, unlabeled MEM-238, and untreated. Tumor size was measured over a 14-day period and repeated thereafter over a 24-day period. Immunohistochemistry was performed to assess IGF2R staining.
Results: 188Re-MEM-238 preferentially localizes within the tumor at both 24 and 48 hours, reaching statistical significance at 48 hours (p = 0.001). Preferential uptake of 188Re-MEM-238 in the bone was not demonstrated. A moderate number of binding sites are available per OS17 cell however the binding constant is very high (Ka = 5.8 × 1010 M-1), which is directly proportional to the efficacy of RIT. There was nearly complete abrogation of the tumor growth by 188Re-MEM-238. There was minimal IGF2R staining in tumor treated with 188Re-MEM-238, moderate staining for tumor treated with 188Re-MOPC-21 and robust staining in the control groups.
Conclusions: These findings indicate that the IGF2R expression differential between tumor and healthy tissue is substantial enough to permit for RIT targeting. Further characterization and development of this novel approach appears to be warranted. Future goals will include dosimetry calculation to establish the maximally tolerated dose, to characterize single and repeated dosing schemas across a panel of osteosarcoma tumors in both immunodeficient and immunocompetent murine models and to assess the safety of such treatments.
Citation Format: David S. Geller, Ekaterina Revskaya, Mani Khan, Jonathan Morris, Richard Gorlick, Ekaterina Dadachova. Targeted therapy of osteosarcoma with radiolabeled monoclonal antibody to an insulin-like growth factor-2 receptor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1798. doi:10.1158/1538-7445.AM2015-1798