Targeted therapy of osteosarcoma with radiolabeled monoclonal antibody to an insulin-like growth factor-2 receptor (IGF2R)

Abstract

Introduction: Osteosarcoma overall survival has plateaued around 70%, without meaningful improvements in over 30years. Outcomes for patients with overt metastatic disease at presentation or who relapse are dismal. In this study we investigated a novel osteosarcoma therapy utilizing radioimmunotherapy (RIT) targeted to IGF2R, which is widely expressed in OS.

Methods: Binding efficiency of the Rhenium-188(¹⁸⁸Re)-labeled IGF2R-specific monoclonal antibody (mAb) to IGF2R on OS17 OS cells was assessed with Scatchard plot analysis. Biodistribution studies were performed in heterotopic murine osteosarcoma xenografts. Tumor growth was compared over a 24-day period post-treatment between mice randomized to receive ¹⁸⁸Re-labeled IGF2R-specific murine mAb MEM-238 (¹⁸⁸Re-MEM-238) or one of three controls: ¹⁸⁸Re-labeled isotype control mAb, unlabeled MEM-238, or no treatment.

Results: Results demonstrate that the radioimmunoconjugate had a high binding constant to IGF2R. Both ¹⁸⁸Re-MEM-238 and the isotype control had similar initial distribution in normal tissue. After 48h ¹⁸⁸Re-MEM-238 exhibited a 1.8 fold selective uptake within tumor compared to the isotype control (p=0.057). Over 24days, the tumor growth ratio was suppressed in animals treated with RIT compared to unlabeled and untreated controls (p=0.005) as demonstrated by a 38% reduction of IGF2R expressing osteosarcoma cells in the RIT group (p=0.002).

Conclusions: In conclusion, given the lack of new effective therapies in osteosarcoma, additional investigation into this target is warranted.

Advances in knowledge: High expression of IGF2R on osteosarcoma tumors, paired with the specificity and in vivo anti-cancer activity of ¹⁸⁸Re-labeled IGF2R-specific mAb suggests that IGF2R may represent a novel therapeutic target in the treatment of osteosarcoma.

Implications for patient care: This targeted approach offers the benefits of being independent of a specific pathway, a resistance mechanism, and/or an inherent biologic tumor trait and therefore is relevant to all OS tumors that express IGF2R.

Keywords: Insulin-like growth factor-2 receptor (IGF2R); OS; Radioimmunotherapy; Rhenium-188.