Division of Developmental Therapeutics, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
Department of Strategic Programs, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
Cancer Sci. 2021 May;112(5):1975-1986. doi: 10.1111/cas.14857. Epub 2021 Mar 30.
Tissue factor (TF), the trigger protein of the extrinsic blood coagulation cascade, is abundantly expressed in various cancers including gastric cancer. Anti-TF monoclonal antibodies (mAbs) capable of targeting cancers have been successfully applied to armed antibodies such as antibody-drug conjugates (ADCs) and molecular imaging probes. We prepared an anti-TF mAb, clone 1084, labeled with astatine-211 ( At), as a promising alpha emitter for cancer treatment. Alpha particles are characterized by high linear energy transfer and a range of 50-100 µm in tissue. Therefore, selective and efficient tumor accumulation of alpha emitters results in potent antitumor activities against cancer cells with minor effects on normal cells adjacent to the tumor. Although the At-conjugated clone 1084 ( At-anti-TF mAb) was disrupted by an At-induced radiochemical reaction, we demonstrated that astatinated anti-TF mAbs eluted in 0.6% or 1.2% sodium ascorbate (SA) solution were protected from antibody denaturation, which contributed to the maintenance of cellular binding activities and cytocidal effects of this immunoconjugate. Although body weight loss was observed in mice administered a 1.2% SA solution, the loss was transient and the radioprotectant seemed to be tolerable in vivo. In a high TF-expressing gastric cancer xenograft model, At-anti-TF mAb in 1.2% SA exerted a significantly greater antitumor effect than nonprotected At-anti-TF mAb. Moreover, the antitumor activities of the protected immunoconjugate in gastric cancer xenograft models were dependent on the level of TF in cancer cells. These findings suggest the clinical availability of the radioprotectant and applicability of clone 1084 to At-radioimmunotherapy.
组织因子（TF），外源性血液凝固级联的触发蛋白，在包括胃癌在内的各种癌症中大量表达。能够靶向癌症的抗 TF 单克隆抗体（mAb）已成功应用于武装抗体，如抗体药物偶联物（ADC）和分子成像探针。我们制备了一种抗 TF mAb，克隆 1084，用放射性碘-211（At）标记，作为癌症治疗有前途的α发射体。α粒子的特点是线性能量转移高，在组织中的射程为 50-100µm。因此，α发射体对肿瘤的选择性和高效积累导致对肿瘤细胞具有强大的抗肿瘤活性，而对肿瘤附近的正常细胞影响较小。尽管 At 标记的克隆 1084（At-anti-TF mAb）被 At 诱导的放射化学反应破坏，但我们证明，在 0.6%或 1.2%的抗坏血酸钠（SA）溶液中洗脱的放射性碘标记的抗 TF mAb 可以防止抗体变性，这有助于维持该免疫偶联物的细胞结合活性和细胞杀伤作用。尽管给予 1.2%SA 溶液的小鼠体重减轻，但这种减轻是短暂的，放射保护剂在体内似乎是可以耐受的。在高 TF 表达的胃癌异种移植模型中，1.2%SA 中的 At-anti-TF mAb 比未保护的 At-anti-TF mAb 具有更显著的抗肿瘤作用。此外，在胃癌异种移植模型中，保护免疫偶联物的抗肿瘤活性依赖于癌细胞中 TF 的水平。这些发现表明了放射保护剂的临床可用性和克隆 1084 应用于 At-放射免疫治疗的适用性。
