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Case Study #2: Disialoganglioside GD2 as a Target for Radiopharmaceutical Therapy

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Radiopharmaceutical Therapy

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Abstract

Disialoganglioside GD2 is found in stem cells, some neurons and nerve fibers, and the basal layer of the skin and is overexpressed in solid tumors, including neuroblastoma, osteosarcoma, soft tissue sarcomas, and others. Dinutuximab (chimeric 14.18) and naxitamab (humanized 3F8 or hu3F8) are Food and Drug Administration (FDA)-approved monoclonal antibodies (mAb) that are specific for the penta-oligosaccharide epitope in GD2. Immuno-oncology, radioimmunodiagnosis (RID), and radioimmunotherapy (RIT) investigations with 3F8, a murine Immunoglobulin G3 (IgG3), formed the basis for the clinical development of hu3F8. The exceptional tumor selectivity of murine 3F8 in preclinical models quickly translated into clinical studies with 131I- and 124I-labeled 3F8 in the early 1990s, building a strong clinical rationale for RIT with the same platform. Yet patient survival did not improve at myeloablative doses of intravenous 131I-3F8 that required stem cell rescue. To achieve a curative therapeutic index (TI, area under the curvetumor (AUCtumor) vs. AUCnormal organs), compartmental intraommaya 131I-3F8 was developed with modest success in patients with leptomeningeal indications. Most recently, pretargeted radioimmunotherapy (PRIT) using a radiolabeled, DOTA (1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid)-based hapten has shown promise by combining the tumor targeting properties of an immunoglobulin with the rapid pharmacokinetic profile of a small molecule. This approach is non-immunogenic, does not produce neuropathic side effects, is modular, and can achieve high therapeutic indices for critical organs such as marrow, kidney, liver, and gut. This novel technology should help RIT scale the hurdle for successful clinical translation.

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Acknowledgement

We want to thank Dr. Floro D. Miraldi, Dr. Dennis Nelson, Ms., Bonnie Landmeier, and Dr. Ulla Saarinen of Case Western Reserve University; Dr. Samuel D.J. Yeh, Ms. Hongfen Guo, Dr. John L. Humm, Dr. Keith S. Pentlow, Dr. Pat Zanzonico, Dr. Lawrence T. Dauer, Dr. Jason Lewis, Dr. Serge K. Lyaschenko of Memorial Sloan Kettering Cancer Center; and the dedicated nurses, physicians, and technicians at both institutions. We also want to thank Dr. Irene Cheung and Joe Olechnowicz for their expert editorial assistance.

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Authors and Affiliations

  1. Vitruviae, Nutley, NJ, USA

    Mahiuddin Ahmed

  2. Y-mAbs Therapeutics, New York, NY, USA

    Brian Santich

  3. Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, USA

    Sarah Cheal

  4. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Nai-Kong V. Cheung, Kim Kramer, Shakeel Modak, Brian H. Kushner & Steven Larson

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  1. Nai-Kong V. Cheung
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  2. Kim Kramer
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  3. Shakeel Modak
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  4. Brian H. Kushner
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  5. Mahiuddin Ahmed
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  6. Brian Santich
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  7. Sarah Cheal
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  8. Steven Larson
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Correspondence to Nai-Kong V. Cheung .

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Editors and Affiliations

  1. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Lisa Bodei

  2. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Jason S. Lewis

  3. Hunter College - CUNY, New York, NY, USA

    Brian M. Zeglis

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Cheung, NK.V. et al. (2023). Case Study #2: Disialoganglioside GD2 as a Target for Radiopharmaceutical Therapy. In: Bodei, L., Lewis, J.S., Zeglis, B.M. (eds) Radiopharmaceutical Therapy. Springer, Cham. https://doi.org/10.1007/978-3-031-39005-0_11

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  • DOI: https://doi.org/10.1007/978-3-031-39005-0_11

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