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

使用 89ZR-曲妥珠单抗对乳腺癌 HER2 受体进行可行性宠物研究

• 批准号: 8788511
• 负责人: FARROKH DEHDASHTI
• 金额: $ 31.54万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8788511
• 关键词: Address; Adverse effects; Animals; Antigen Targeting; Behavior; Binding; Biodistribution; Biological; Biopsy; Breast Cancer Patient; Cancer Etiology; Clinical Data; Country; Detection; Development; Diagnostic; Disease; Dose; ERBB2 gene; Evaluation; Extracellular Domain; Feasibility Studies; Fluorescent in Situ Hybridization; Goals; Growth; Half-Life; Health; Heterogeneity; Human; Image; Image Analysis; Imaging Device; Immunohistochemistry; Immunotherapy; In Vitro; Individual; Label; Lesion; Malignant Neoplasms; Measurable; Metastatic Lesion; Metastatic breast cancer; Methods; Molecular and Cellular Biology; Monoclonal Antibodies; Morbidity - disease rate; Mutation; Neoplasm Metastasis; Patients; Pilot Projects; Positron; Positron-Emission Tomography; Primary Lesion; Property; Radioimmunoconjugate; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Recurrence; Resistance; Resolution; Risk; Safety; Sampling Errors; Site; Staining method; Stains; Therapeutic Monoclonal Antibodies; Time; Tracer; Trastuzumab; Treatment Effectiveness; Tumor Burden; Visual; Woman; Xenograft procedure; Zirconium; base; burden of illness; chemotherapy; cost; dosimetry; improved; in vitro Assay; in vivo; malignant breast neoplasm; mortality; novel; outcome forecast; pre-clinical; radiotracer; receptor; receptor expression; response; targeted treatment; tumor; tumor xenograft; uptake; zirconium oxide

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.

描述（由申请人提供）：单克隆抗体（mab）用于治疗肿瘤患者的用途正在迅速扩大，而用于评估这些疗法靶向的特异性肿瘤抗原的成像工具落后。乳腺癌仍然是西方国家妇女癌症死亡的主要原因。her2扩增型乳腺癌占乳腺癌的20-30%，与her2阴性乳腺癌相比，其生长速度更快，转移风险更高，总体生存期更差。HER2扩增作为这些癌症的驱动突变的鉴定以及随后开发的曲妥珠单抗（一种针对HER2受体细胞外结构域的单抗）显著改善了这些患者的预后。然而，只有一半的her2阳性患者接受一线曲妥珠单抗和转移性疾病化疗有客观反应。这表明，目前体外试验中HER2阳性的存在并不能准确预测对治疗的反应，可能与患者体内肿瘤异质性有关。使用放射性标记抗体（免疫PET）的PET是一种新的选择，可以无创地识别全身特定靶点的存在，追踪和量化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使用单克隆抗体治疗的体内行为和有效性。在本申请中，我们提出了一项使用锆-89 （89Zr）标记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单抗的生物半衰期相匹配（即曲珠单抗的平均半衰期为5.8天），89Zr比68Ga- (t1/2 = 1.13 h)和64Cu- (t1/2 = 12.7 h)更适合用于单抗的放射性标记。在肿瘤异种移植研究中，HER2阳性肿瘤部位的89zr -曲妥珠单抗摄取明显高于HER2阴性肿瘤部位。在一项针对her2阳性乳腺癌患者的小型研究中，89Zr-曲妥珠单抗- pet已被证明具有最佳生物分布和良好肿瘤摄取的高图像质量。我们提议进行一项试点研究，目的是证明用89Zr-曲妥珠单抗- pet对乳腺癌患者进行成像的可行性，评估肿瘤89Zr-曲妥珠单抗摄取与HER2体外状态的关系，评估89Zr-曲妥珠单抗的安全性，并确定该放射性药物的人体剂量学。