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
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.
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nucl Med Biol. 2025 Jan-Feb;140-141:108976. doi: 10.1016/j.nucmedbio.2024.108976. Epub 2024 Nov 22.
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.
We utilized the humanized antibody, AR9.6, labeled with actinium-225 (Ac). 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 [Ac]Ac-mcp-PEG-Tz, e.g. using a 1,2,4,5-tetrazine conjugated to the macropa chelator via a polyethylene glycol (PEG) linker.
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 [Ac]Ac-mcp-PEG-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.
We confirmed that pretargeting with AR9.6-TCO and [Ac]Ac-mcp-PEG-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.
Biological Sciences; Applied Biological Sciences.
伴有微转移细胞簇的腹膜转移是晚期卵巢癌的常见特征。靶向α治疗（TAT）是治疗微转移疾病的一种有吸引力的方法，因为α粒子在短距离内释放大量能量。一种预靶向方法——利用四嗪（Tz）与反式环辛烯（TCO）之间的逆电子需求狄尔斯-阿尔德反应——可以将与TAT相关的脱靶毒性降至最低，这种毒性通常与全长抗体有关。我们假设预靶向策略可以有效治疗高级别浆液性（HGS）卵巢肿瘤，同时将毒性降至最低。
我们使用了标记有锕-225（Ac）的人源化抗体AR9.6。AR9.6靶向MUC16的完全糖基化和低糖基化异构体。为了进行生物分布和放射免疫治疗研究，在给予[Ac]Ac-mcp-PEG-Tz前72小时，将AR9.6-TCO注射到荷OVCAR3小鼠体内，例如使用通过聚乙二醇（PEG）接头与大分子螯合剂偶联的1,2,4,5-四嗪。
生物分布数据显示，预靶向方法实现了大量肿瘤摄取。切伦科夫发光成像证实了TAT研究期间体内预靶向的成功。与对照组相比，用AR9.6-TCO和[Ac]Ac-mcp-PEG-Tz进行的TAT显著抑制了荷OVCAR3肿瘤小鼠的肿瘤生长并改善了总体生存期。除了短暂的血液学毒性外，在小鼠中还观察到了与毒性相符的肾脏和卵巢病理学变化。
我们证实，用AR9.6-TCO和[Ac]Ac-mcp-PEG-Tz进行预靶向在高表达MUC16的肿瘤中具有持久的抗肿瘤作用。这些发现表明，预靶向与TAT联合用于治疗卵巢癌具有巨大潜力。
生物科学；应用生物科学。
