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Pretargeted alpha therapy in MUC16-positive high-grade serous ovarian cancer
Kyeara N Mack1, David Bauer2, Lukas M Carter2
1Department 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.
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.
Insights
Targeted alpha therapy (TAT) combined with pretargeting effectively treats ovarian cancer by targeting MUC16, showing durable antitumor effects and improved survival with manageable toxicity.
Area of Science:
- Oncology
- Radiochemistry
- Immunotherapy
Background:
- Peritoneal metastasis is common in advanced ovarian cancer, often involving micrometastatic cell clusters.
- Targeted alpha therapy (TAT) offers potent localized cancer cell killing but faces challenges with off-target toxicity.
- A pretargeting strategy using inverse-electron-demand Diels-Alder chemistry can enhance TAT safety and efficacy.
Purpose of the Study:
- To evaluate a pretargeting strategy for treating high-grade serous (HGS) ovarian tumors using targeted alpha therapy.
- To assess the efficacy and toxicity of a pretargeting approach involving a MUC16-targeting antibody and actinium-225 labeled tetrazine.
Main Methods:
- Humanized antibody AR9.6, targeting MUC16, was conjugated with trans-cyclooctene (TCO).
- AR9.6-TCO was administered to OVCAR3 tumor-bearing mice 72 hours prior to injecting 225Ac-labeled tetrazine (Tz).
- Biodistribution, Cerenkov luminescence imaging, and radioimmunotherapy studies were performed.
Main Results:
- The pretargeting approach demonstrated substantial tumor uptake and successful in vivo targeting.
- Targeted alpha therapy with AR9.6-TCO and 225Ac-Tz significantly suppressed tumor growth and improved overall survival.
- Observed toxicities included renal and ovarian pathology, along with transient hematologic effects.
Conclusions:
- Pretargeting with AR9.6-TCO and 225Ac-Tz provides durable antitumor effects against MUC16-expressing ovarian tumors.
- This pretargeting strategy shows significant potential for improving ovarian cancer treatment outcomes when combined with TAT.
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