Karlsson Jenny, Hagemann Urs B, Cruciani Véronique, Schatz Christoph A, Grant Derek, Ellingsen Christine, Kristian Alexander, Katoozi Shirin, Mihaylova Dessislava, Uran Steinar R, Suominen Mari, Bjerke Roger M, Ryan Olav B, Cuthbertson Alan
Targeted Radiopharmaceuticals, Bayer AS, 0283 Oslo, Norway.
Bayer AG, 13342 Berlin, Germany.
Cancers (Basel). 2023 Jun 29;15(13):3419. doi: 10.3390/cancers15133419.
Human epidermal growth factor receptor 2 (HER2) is overexpressed in 15-30% of breast cancers but has low expression in normal tissue, making it attractive for targeted alpha therapy (TAT). HER2-positive breast cancer typically metastasizes to bone, resulting in incurable disease and significant morbidity and mortality. Therefore, new strategies for HER2-targeting therapy are needed. Here, we present the preclinical in vitro and in vivo characterization of the HER2-targeted thorium-227 conjugate (HER2-TTC) TAT in various HER2-positive cancer models. In vitro, HER2-TTC showed potent cytotoxicity in various HER2-expressing cancer cell lines and increased DNA double strand break formation and the induction of cell cycle arrest in BT-474 cells. In vivo, HER2-TTC demonstrated dose-dependent antitumor efficacy in subcutaneous xenograft models. Notably, HER2-TTC also inhibited intratibial tumor growth and tumor-induced abnormal bone formation in an intratibial BT-474 mouse model that mimics breast cancer metastasized to bone. Furthermore, a match in HER2 expression levels between primary breast tumor and matched bone metastases samples from breast cancer patients was observed. These results demonstrate proof-of-concept for TAT in the treatment of patients with HER2-positive breast cancer, including cases where the tumor has metastasized to bone.
人表皮生长因子受体2（HER2）在15%至30%的乳腺癌中过表达，但在正常组织中表达较低，这使其成为靶向α治疗（TAT）的理想靶点。HER2阳性乳腺癌通常会转移至骨骼，导致疾病无法治愈，并带来严重的发病率和死亡率。因此，需要新的HER2靶向治疗策略。在此，我们展示了HER2靶向钍-227偶联物（HER2-TTC）在多种HER2阳性癌症模型中的临床前体外和体内特性。在体外，HER2-TTC在多种表达HER2的癌细胞系中显示出强大的细胞毒性，并增加了DNA双链断裂的形成以及诱导BT-474细胞的细胞周期停滞。在体内，HER2-TTC在皮下异种移植模型中表现出剂量依赖性的抗肿瘤疗效。值得注意的是，在模拟乳腺癌转移至骨骼的胫骨内BT-474小鼠模型中，HER2-TTC还抑制了胫骨内肿瘤生长和肿瘤诱导的异常骨形成。此外，观察到乳腺癌患者的原发性乳腺肿瘤与匹配的骨转移样本之间HER2表达水平相匹配。这些结果证明了TAT在治疗HER2阳性乳腺癌患者（包括肿瘤已转移至骨骼的病例）中的概念验证。
