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 30 years. 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 48 h ¹⁸⁸Re-MEM-238 exhibited a 1.8 fold selective uptake within tumor compared to the isotype control (p = 0.057). Over 24 days, 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.

Introduction

Osteosarcoma (OS) is the most common non-hematologic primary bone malignancy [2], [3]. Additionally it is the most common primary malignant bone tumor and the fifth most common primary malignancy among adolescents and young adults [4]. Unfortunately, overall 5 year survival has plateaued at approximately 70%, with no meaningful improvement realized in over 30 years [3], [4], [5], [6]. Patients with metastatic disease have poor outcomes, with pulmonary and osseous metastases portending an overall survival of less than 40% and 20%, respectively. Recent studies have demonstrated an inability to improve outcomes using conventional chemotherapy strategies, underscoring the need for novel treatment approaches [7].

Overexpression of the cation-independent mannose-6-phosphate/insulin-like growth factor-2 receptor (IGF2R) has been demonstrated across a panel of OS cell lines [1]. Additionally, a single nucleotide polymorphism (SNP) within a haplotype block in IGF2R has been associated with an increased risk of developing OS [8], however, the role of IGF2R in the pathogenesis of OS is still being investigated. Although IGF2R is expressed normally across a wide array of tissue types, the consistent overexpression of IGF2R in OS suggests that it may serve as a valuable therapeutic target.

Radioimmunotherapy (RIT) is a method of delivering cytotoxic radiation therapy in a targeted fashion whereby an antigen-specific antibody is bound to either an α- or β-emitting radioisotope [9], [10]. The technique has been successfully employed in a number of challenging oncologic settings [11], [12]. RIT delivers cytocidal radiation to the targeted cell, is less affected by the multidrug resistance ensuing mechanisms than chemotherapy, and does not depend on the immune status of a patient or microenvironmental fluctuations the way immunotherapy with naked antibodies or T cells does. It permits for systemic administration, antibody-mediated specificity, and physical cytocidal damage in a manner which is well-tolerated by the patient.

The purpose of this study was to investigate a novel therapeutic approach to OS, using IGF2R-targeted RIT. We have selected 188-Rhenium (¹⁸⁸Re), a powerful β-emitter (E_max = 2.01 meV) with relatively short physical half-life of 16.9 h for radiolabeling the IGF2R-specific antibody. ¹⁸⁸Re has been successfully used in both pre-clinical and clinical RIT with insignificant side effects [12 and references therein]. We hypothesized that ¹⁸⁸Re-labeled IGF2R-specific mAb will serve to effectively target OS tumor cells and that ¹⁸⁸Re will be able to deliver high tumoricidal doses to the tumors without toxicity to healthy tissues.