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. 2025 Jan-Feb:140-141:108976.
doi: 10.1016/j.nucmedbio.2024.108976. Epub 2024 Nov 22.

Pretargeted alpha therapy in MUC16-positive high-grade serous ovarian cancer

Kyeara N Mack  1 , David Bauer  2 , Lukas M Carter  2 , Sebastian E Carrasco  3 , Mohamed I Atmane  3 , Tara D Viray  2 , Cory L Brooks  4 , Michael A Hollingsworth  5 , Prakash Radhakrishnan  5 , Jason S Lewis  6
Affiliations

Pretargeted alpha therapy in MUC16-positive high-grade serous ovarian cancer

Kyeara N Mack et al. Nucl Med Biol. 2025 Jan-Feb.

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.

Keywords: AR9.6; MUC16; Ovarian cancer; Pretargeting; Targeted alpha therapy.

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Conflict of interest statement

Declaration of competing interest The author (Lewis) is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for Nuclear Medicine and Biology and was not involved in the editorial review or the decision to publish this article. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C.L. Brooks received grants from Quest PharmaTech Inc. (AR9.6 patent assignee, US-11773183‐44 B2) during the conduct of the study and grants from Quest PharmaTech Inc.

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