Pretargeted alpha therapy in MUC16-positive high-grade serous ovarian cancer Journal Article
| Authors: | Mack, K. N.; Bauer, D.; Carter, L. M.; Carrasco, S. E.; Atmane, M. I.; Viray, T. D.; Brooks, C. L.; Hollingsworth, M. A.; Radhakrishnan, P.; Lewis, J. S. |
| Article Title: | Pretargeted alpha therapy in MUC16-positive high-grade serous ovarian cancer |
| Abstract: | Background: Peritoneal metastasis with micrometastatic cell clusters is a common feature of advanced ovarian cancer. Targeted alpha therapy (TAT) is an attractive approach for treating micrometastatic diseases as alpha particles release enormous amounts of energy within a short distance. A pretargeting approach — leveraging the inverse-electron-demand Diels-Alder reaction between tetrazines (Tz) and trans-cyclooctene (TCO) — can minimize off-target toxicity related to TAT, often associated with full-length antibodies. We hypothesized that a pretargeting strategy could effectively treat high-grade serous (HGS) ovarian tumors while minimizing toxicity. Methods: We utilized the humanized antibody, AR9.6, labeled with actinium-225 (225Ac). AR9.6 targets fully glycosylated and hypoglycosylated isoforms of MUC16. For biodistribution and radioimmunotherapy studies, AR9.6-TCO was injected into OVCAR3-bearing mice 72 h before administering [225Ac]Ac-mcp-PEG8-Tz, e.g. using a 1,2,4,5-tetrazine conjugated to the macropa chelator via a polyethylene glycol (PEG) linker. Results: Biodistribution data revealed that the pretargeting approach achieved substantial tumor uptake. Cerenkov luminescence imaging confirmed successful in vivo pretargeting during TAT studies. Compared to the control groups, TAT with AR9.6-TCO and [225Ac]Ac-mcp-PEG8-Tz significantly suppressed tumor growth and improved overall survival in OVCAR3 tumor-bearing mice. Renal and ovarian pathology compatible with toxicity was observed in mice in addition to transient hematologic toxicity. Conclusion: We confirmed that pretargeting with AR9.6-TCO and [225Ac]Ac-mcp-PEG8-Tz has durable antitumor effects in high MUC16-expressing tumors. These findings demonstrate great potential for using pretargeting in combination with TAT for the treatment of ovarian cancer. Classification: Biological Sciences; Applied Biological Sciences. © 2024 Elsevier Inc. |
| Keywords: | cancer survival; controlled study; human cell; overall survival; nonhuman; cancer grading; ovarian cancer; cell proliferation; mouse; animal experiment; animal model; in vivo study; cancer therapy; luminescence; dosimetry; radioimmunotherapy; diels alder reaction; macrogol; muc16; actinium 225; pretargeting; human; female; article; ovarian cancer cell line; targeted alpha therapy; ar9.6 |
| Journal Title: | Nuclear Medicine and Biology |
| Volume: | 140-141 |
| ISSN: | 0969-8051 |
| Publisher: | Elsevier Science Inc. |
| Date Published: | 2025-01-01 |
| Start Page: | 108976 |
| Language: | English |
| DOI: | 10.1016/j.nucmedbio.2024.108976 |
| PROVIDER: | scopus |
| PUBMED: | 39615062 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Jason S. Lewis -- Source: Scopus |
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