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Case Study #6: [177Lu]Lu-DOTA-JR11: A Somatostatin Receptor Subtype 2 Antagonist for Radiopharmaceutical Therapy

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Radiopharmaceutical Therapy

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Abstract

Peptide receptor radionuclide therapy (PRRT) is a special type of radiopharmaceutical therapy (RPT) that employs peptide-based radiopharmaceuticals such as 177Lu-labeled agonists of somatostatin receptor subtype 2 (SST2) (e.g., [177Lu]Lu-DOTA-TOC and [177Lu]Lu-DOTA-TATE (Lutathera®)). SST2 are highly overexpressed in neuroendocrine tumors (NETs), which are most commonly found in the stomach, intestines, pancreas, and lungs. Until recently, it was thought that the internalization of the radiopharmaceutical was needed for effective SST-targeted RPT. However, radiolabeled SST antagonists have been shown to recognize more binding sites on SST-expressing tumor cells, produce higher tumor doses, and cause a greater number of DNA double strand breaks than agonists despite their poor internalization rates. As a result, several SST2 antagonists were synthesized and evaluated in a preclinical setting. Of these, [177Lu]Lu-DOTA-JR11 and [177Lu]Lu-DOTA-LM3 have produced the most promising results and were thus selected for clinical evaluation. Indeed, [177Lu]Lu-DOTA-JR11 produced tumor radiation doses in NET patients that were several times higher than either [177Lu]Lu-DOTA-TATE or [177Lu]Lu-DOTA-TOC, yielding an objective response rate between 30% and 45% as well as 1 year disease control rate of up to 90%. At the same time, however, [177Lu]Lu-DOTA-JR11 produced higher bone marrow toxicity than either [177Lu]Lu-DOTA-TATE or [177Lu]Lu-DOTA-TOC. Future developments in this area will include the use of SST2 antagonists together with α-emitting and combined β−/Auger electron-emitting radionuclides as well as the expansion of the radiolabeled antagonist approach to other receptor systems and other indications, such as small cell lung cancer, breast cancer, renal cell carcinoma, non-Hodgkin lymphoma, paraganglioma, pheochromocytoma, medullary thyroid cancer, meningioma, prostate cancer, and ovarian cancers.

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Author information

Authors and Affiliations

  1. Division of Nuclear Medicine, University Hospital Basel, Basel, Switzerland

    Damian Wild

  2. Center for Neuroendocrine and Endocrine Tumors, University Hospital Basel, Basel, Switzerland

    Damian Wild

  3. Division of Radiopharmaceutical Chemistry, University Hospital Basel, Basel, Switzerland

    Melpomeni Fani

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  1. Damian Wild
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  2. Melpomeni Fani
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Correspondence to Damian Wild .

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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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Wild, D., Fani, M. (2023). Case Study #6: [177Lu]Lu-DOTA-JR11: A Somatostatin Receptor Subtype 2 Antagonist 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_16

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  • DOI: https://doi.org/10.1007/978-3-031-39005-0_16

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  • Online ISBN: 978-3-031-39005-0

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