A FEASIBILITY PET STUDY OF HER2 RECEPTORS IN BREAST CANCER USING 89ZR-TRASTUZUMAB

描述（由申请方提供）：单克隆抗体（MAb）用于治疗肿瘤患者的使用正在迅速扩大，而用于评价这些治疗靶向的特异性肿瘤抗原的成像工具却落后。乳腺癌仍然是西方国家妇女癌症死亡的主要原因。HER 2扩增乳腺癌占乳腺癌的20-30%，与HER 2阴性乳腺癌相比，其生长速度更快，转移风险增加，总生存期更差。HER 2扩增作为这些癌症中的驱动突变的鉴定以及曲妥珠单抗（一种针对HER 2受体胞外结构域的MAb）的后续开发显著改善了这些患者的预后。然而，接受一线曲妥珠单抗和化疗治疗转移性疾病的HER 2阳性患者中只有一半有客观缓解。这表明，通过目前的体外试验，HER 2阳性的存在并不是对治疗反应的准确预测，可能与患者内肿瘤异质性有关。使用放射性标记抗体的PET（Immuno-PET）是一种新的选择，可用于非侵入性鉴定全身特定靶点的存在，跟踪和定量与靶点结合的单克隆抗体，并最终帮助更好地了解个体患者体内行为和单克隆抗体治疗的有效性。在本申请中，我们提出了一项使用锆-89（89 Zr）标记的曲妥珠单抗治疗乳腺癌的可行性研究。由于其较长的物理半衰期与MAb的生物半衰期相匹配（即，曲妥珠单抗的平均半衰期为5.8天），89 Zr优于68 Ga-（t1/2 = 1.13 h）和64 Cu-（t1/2 = 12.7 h）用于单克隆抗体的放射性标记。在肿瘤异种移植物研究中，在HER 2阳性肿瘤部位检测到的89 Zr-曲妥珠单抗摄取显著高于HER 2阴性肿瘤部位。在一项HER 2阳性乳腺癌患者的小型研究中，89 Zr-曲妥珠单抗-PET显示了高图像质量、最佳生物分布和出色的肿瘤摄取。我们建议进行一项初步研究，目的是证明使用89 Zr-曲妥珠单抗-PET对乳腺癌患者进行成像的可行性，评价肿瘤89 Zr-曲妥珠单抗摄取与HER 2体外状态之间的关系，评估89 Zr-曲妥珠单抗的安全性并确定该放射性药物的人体剂量学。

DESCRIPTION (provided by applicant): The use of monoclonal antibodies (MAbs) for treatment of oncologic patients is rapidly expanding while the imaging tools for evaluation of the specific tumor antigens targeted by these therapies lagged behind. Breast cancer remains the leading cause of cancer mortality among women in Western countries. HER2-amplified breast cancers, which consist of 20-30% of breast cancers, are associated with a more aggressive growth rate, increased risk of metastasis and worse overall survival compared with HER2-negative breast cancers. The identification of HER2 amplification as the driver mutation in these cancers and the subsequent development of trastuzumab, a MAb directed against the extracellular domain of the HER2 receptor, have dramatically improved the prognosis in these patients. However, only half of HER2-positive patients receiving first-line trastuzumab and chemotherapy for metastatic disease have objective responses. This suggests that the presence of HER2 positivity by current in vitro assays is not an accurate predictor of response to therapy, possibly related to within-patient tumor heterogeneity. PET using radiolabeled antibodies (Immuno-PET) is a novel option for non-invasive identification of the presence of specific targets throughout the body, tracing and quantification of monoclonal antibodies binding to the target and ultimately helping in better understanding of in vivo behavior and effectiveness of treatment with MAbs in individual patients. In this application, we are proposing a feasibility study using Zirconium-89 (89Zr) labeled trastuzumab in breast cancer. Because of its longer physical half-life that matches the biological half-life of a MAb (i.e., the mean half-life of trastuzumab is 5.8 days), 89Zr is preferred to 68Ga- (t1/2 = 1.13 h) and 64Cu- (t1/2 = 12.7 h) for radiolabeling of MAbs. In studies with tumor xenografts, significantly greater 89Zr-trastuzumab uptake has been detected in HER2- positive than in HER2-negative tumor sites. In a small study of patients with HER2-positive breast cancer, high image quality with optimal biodistribution and excellent tumor uptake has been demonstrated with 89Zr- trastuzumab-PET. We are proposing to perform a pilot study with goals of demonstrating the feasibility of imaging breast cancer patients with 89Zr-trastuzumab-PET, evaluating the relationship between tumor 89Zr- trastuzumab uptake and in vitro status of HER2, assessing the safety of 89Zr-trastuzumab and determining the human dosimetry of this radiopharmaceutical.