Nuclear medicine and biology · 2024
Pretargeted alpha therapy in MUC16-positive high-grade serous ovarian cancer.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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Mack Kyeara N, Bauer David, Carter Lukas M, Carrasco Sebastian E, Atmane Mohamed I, Viray Tara D, Brooks Cory L, Hollingsworth Michael A, Radhakrishnan Prakash, Lewis Jason S
Аннотация
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.
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.