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

Kyeara N Mack; David Bauer; Lukas M Carter; Sebastian E Carrasco; Mohamed I Atmane; Tara D Viray; Cory L Brooks; Michael A Hollingsworth; Prakash Radhakrishnan; Jason S Lewis

doi:10.1016/j.nucmedbio.2024.108976

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

Nucl Med Biol. 2024 Nov 22:140-141:108976. doi: 10.1016/j.nucmedbio.2024.108976. Online ahead of print.

Affiliations

¹ Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pharmacology, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA.
² Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
³ Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, and The Rockefeller University, NY, New York, USA.
⁴ Department of Chemistry and Biochemistry, California State University, Fresno, CA, USA.
⁵ Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, NE, USA.
⁶ Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pharmacology, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: lewisj2@mskcc.org.

PMID: 39615062
DOI: 10.1016/j.nucmedbio.2024.108976

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.