放射性标记的双重靶向重组抗体在HER2阳性乳腺癌的诊疗研究

HER2-positive breast cancer is often high in malignancy. Its prognosis is poor. Therefore, the effective diagnosis and treatment is the focus of clinical attention. The detection of HER2 protein is crucial for the clinical treatment and prognosis of breast cancer. However, pathological examination is invasive, and all suspicious lesions cannot be detected. Molecular imaging method provides a noninvasive diagnostic method. Although trastuzumab has been used for many years, the efficacy of a single drug is less than 36%. Moreover, HER2-positive resistance tends to occur. Pertuzumab reacts on different sites of HER2. The combination of these antibodies can effectively prolong the survival of patients, but at the same time increase the drug side effects. Therefore, our study aims at the field of targeted diagnosis and treatment of HER2-positive breast cancer. HER2 double-targeting recombinant antibody will be constructed by antibody recombination and click chemistry, and then labeled with radionuclide Cu-64 or Lu-177. Therefore, the advantages of the technology of monoclonal antibody and radionuclide are combined. A tumor targeting diagnostic probe that can be highly specific, sensitive and effective in vivo in this study is developed. The cellular level and molecular mechanism are evaluated in xenografts, metastasis of breast cancer and PDX models in vivo. PET imaging and targeted therapy is performed to aim at non-invasive diagnosis and accurate treatment of HER2-positive tumors.

HER2阳性乳腺癌往往恶性度高，预后较差，有效诊疗是临床关注的重点。HER2蛋白检测对乳腺癌的临床治疗和预后判断至关重要，但是病理检查具有创伤性，且无法全部检测所有可疑病灶，分子影像则可提供无创性诊断方法。虽然曲妥珠单抗应用多年，但单药有效率不足36%且容易出现HER2阳性耐药。帕妥珠单抗作用于HER2的不同位点，二者联用能有效延长患者生存期，但是同时增大药物毒副作用。因此，本课题瞄准HER2阳性乳腺癌靶向诊疗领域，拟通过抗体重组及点击化学技术构建HER2双重靶向重组抗体，进行放射性核素铜-64或镥-177标记，将单克隆抗体、放射性核素示踪及内照射治疗技术优势相结合，研发一种在活体水平能够高特异、高灵敏、有效的肿瘤靶向诊疗探针，进行细胞水平及分子机制研究，并在乳腺癌原位、转移和PDX模型进行活体PET显像和靶向治疗，旨在为HER2阳性肿瘤的无创诊断和精准治疗提供一种新手段。

HER2阳性乳腺癌往往恶性度高，进展快，预后较差。HER2蛋白表达对乳腺癌的临床治疗和预后判断至关重要，但是常规病理检查需要活检取得离体组织，具有创伤性，而且无法对所有可疑病灶全部检测，如何通过活体无创的方式特异准确的评估或显示病灶的HER2表达情况是亟待解决的问题。虽然曲妥珠单抗治疗HER2阳性乳腺癌近20余年，但单药有效率仅为11%~36%，而且易出现疾病进展的HER2阳性复发。帕妥珠单抗作用于HER2的不同位点，二者联用能有效延长患者生存期，但是同时增大药物毒副作用。通过本课题研究组瞄准HER2阳性乳腺癌靶向诊疗领域，通过抗体重组及点击化学技术构建HER2双重靶向重组抗体片段，通过偶联双功能偶联剂，实现放射性核素铜-64或镥-177标记，结合核医学无创性显像和内照射杀伤的独特优势，将单克隆抗体、放射性核素示踪及内照射治疗技术优势相结合，研发一种在活体水平能够高特异灵敏性的肿瘤靶向诊疗探针，进行活体PET显像和靶向治疗，为HER2阳性肿瘤的无创诊断和精准治疗提供新手段。希望对乳腺癌肿瘤患者的治疗决策、疗效监测和预后评价等产生重要的临床应用价值，并有望大大提高乳腺癌靶向药物疗效评估及促进靶向药物的使用准确性。在课题的依托下，项目负责人以第一作者或通讯作者在国内外专业杂志上发表论文17篇，其中SCI收录论文12篇，总影响因子120.329，影响因子大于10以上的论文6篇。于2021年获北京自然科学基金杰出青年，2019年晋升副主任医师并破格晋升副教授。申请并授权多项专利，多次在国际、国内学术大会进行交流并获奖。

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