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

David S. Geller, Jonathan Morris, Ekaterina Revskaya, Mani D. Kahn, Wendong Zhang, Sajida Piperdi, Amy Park, Pratistha Koirala, Hillary Guzik, Charles B. Hall, Bang H. Hoang, Rui Yang, Michael Roth, Jonathan Gill, Richard Gorlick, Ekaterina Dadachova

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)812-817
Number of pages6
JournalNuclear Medicine and Biology
Volume43
Issue number12
DOIs
StatePublished - Dec 1 2016

Fingerprint

Somatomedin Receptors
Osteosarcoma
Monoclonal Antibodies
Radioimmunotherapy
Therapeutics
Neoplasms
Immunoconjugates
Rhenium
Normal Distribution
Growth
Heterografts
Patient Care

Keywords

  • Insulin-like growth factor-2 receptor (IGF2R)
  • OS
  • Radioimmunotherapy
  • Rhenium-188

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

Targeted therapy of osteosarcoma with radiolabeled monoclonal antibody to an insulin-like growth factor-2 receptor (IGF2R). / Geller, David S.; Morris, Jonathan; Revskaya, Ekaterina; Kahn, Mani D.; Zhang, Wendong; Piperdi, Sajida; Park, Amy; Koirala, Pratistha; Guzik, Hillary; Hall, Charles B.; Hoang, Bang H.; Yang, Rui; Roth, Michael; Gill, Jonathan; Gorlick, Richard; Dadachova, Ekaterina.

In: Nuclear Medicine and Biology, Vol. 43, No. 12, 01.12.2016, p. 812-817.

Research output: Contribution to journalArticle

Geller, DS, Morris, J, Revskaya, E, Kahn, MD, Zhang, W, Piperdi, S, Park, A, Koirala, P, Guzik, H, Hall, CB, Hoang, BH, Yang, R, Roth, M, Gill, J, Gorlick, R & Dadachova, E 2016, 'Targeted therapy of osteosarcoma with radiolabeled monoclonal antibody to an insulin-like growth factor-2 receptor (IGF2R)', Nuclear Medicine and Biology, vol. 43, no. 12, pp. 812-817. https://doi.org/10.1016/j.nucmedbio.2016.07.008
Geller, David S. ; Morris, Jonathan ; Revskaya, Ekaterina ; Kahn, Mani D. ; Zhang, Wendong ; Piperdi, Sajida ; Park, Amy ; Koirala, Pratistha ; Guzik, Hillary ; Hall, Charles B. ; Hoang, Bang H. ; Yang, Rui ; Roth, Michael ; Gill, Jonathan ; Gorlick, Richard ; Dadachova, Ekaterina. / Targeted therapy of osteosarcoma with radiolabeled monoclonal antibody to an insulin-like growth factor-2 receptor (IGF2R). In: Nuclear Medicine and Biology. 2016 ; Vol. 43, No. 12. pp. 812-817.
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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.",
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AU - Geller, David S.

AU - Morris, Jonathan

AU - Revskaya, Ekaterina

AU - Kahn, Mani D.

AU - Zhang, Wendong

AU - Piperdi, Sajida

AU - Park, Amy

AU - Koirala, Pratistha

AU - Guzik, Hillary

AU - Hall, Charles B.

AU - Hoang, Bang H.

AU - Yang, Rui

AU - Roth, Michael

AU - Gill, Jonathan

AU - Gorlick, Richard

AU - Dadachova, Ekaterina

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N2 - 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.

AB - 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.

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