Antibody Therapy of Cancer

抗体治疗组的目标是为肝癌和其他癌症开发新的抗体疗法。项目1：靶向glypcan-3治疗肝细胞癌肝癌是世界上第五大常见癌症，也是导致癌症死亡的第三大原因。肝细胞癌约占肝癌病例的75%。胆管细胞癌(CCA)是第二常见的原发性肝肿瘤。迫切需要新的治疗方法，能够成功地应用于大量的肝癌患者。GPC3主要用于研究GPC3，鉴于其在肝细胞癌中的高蛋白表达，该靶点具有治疗肝癌的潜力。在FY11-12年，我们用杂交瘤技术获得了与GPC3高亲和力的YP7单抗。在2012财年，我们进行了动物实验，发现YP7对小鼠肝细胞癌移植瘤生长有显著的抑制作用。这项研究发表在《单抗》杂志上，并出现在封面上。正在进行的研究集中在探索GPC3在肝癌发病机制中的作用机制，以及针对GPC3的人抗体的开发用于肝癌治疗。NCI已经提交了基于我们的GPC3单抗的专利申请。我们希望找到业界合作伙伴，与我们合作开发新型GPC3靶向抗体疗法来治疗肝癌。2012财年，GPC3项目在《mAbs》、《BioDrugs》和《癌症报告》杂志上发表了三篇论文。我们在国际研讨会上介绍了我们的工作，如第二届年度PEGS癌症治疗抗体研讨会，蛋白质发现和治疗，以及第21届抗体。项目2：针对肝癌、间皮瘤和卵巢癌的中间蛋白在间皮瘤、胆管细胞癌、卵巢癌以及胰腺癌和肺癌中高水平表达。在2010财年，我们分析了间充质蛋白在肝癌组织中的蛋白表达，并假设间充质蛋白是胆管细胞癌(CCA)的潜在治疗靶点。在NCI的Ira Pastan的合作下，我们应用我们在噬菌体展示技术方面的专业知识来鉴定HN1，一种针对间皮蛋白的人类单抗。HN1单抗能高亲和力结合细胞表面相关的间充质蛋白，具有良好的抗体依赖细胞介导的细胞毒作用(ADCC)，可杀伤肿瘤细胞，有望用于间充质蛋白表达肿瘤的治疗。在2011财年，我们在《国际癌症杂志》上发表了HN1的研究成果。我们的间皮蛋白项目部分得到了间皮瘤应用研究基金会的研究拨款和卵巢癌研究基金授予Mitchell Ho的个人研究人员奖的支持。在2012财年，我们与Ira Pastan和Dimiter Dimitrov(NCI的Frederick National Lab)合作，通过噬菌体展示技术分离出了新的单域人源抗体。这些人类抗体可能对间皮蛋白阳性的肿瘤细胞具有新的抗肿瘤活性。NCI已经提交了我们用于癌症治疗的间硫蛋白抗体的专利申请。NCI还提供了我们实验室开发的LMB-H226-GL间皮瘤模型，作为科学界的研究工具。项目3：建立体外肿瘤球体，研究抗体治疗。大多数抗癌药物的研究只考虑单细胞水平上的遗传和/或细胞机制。然而，药物渗透是一个非常重要的额外机制，需要更复杂的细胞环境来研究。在2011-2012财年，我们与V.Courtney Broaddus(加州大学旧金山分校)和Shuichi Takayama(密歇根大学)合作，建立了体外肿瘤球体来研究单抗治疗。这些肿瘤球体除了为筛选更有效的抗肿瘤抗体提供了一个创新的平台外，还可能被证明是识别潜在治疗靶点的宝贵价值。在2012财年，我们使用微阵列分析比较了3D球体和传统2D单层的基因表达谱，发现了100多个与间皮瘤3D生物学结构相关的基因。其中一些基因可能具有作为治疗靶点和诊断生物标志物的潜力。在2011-2012财年，这项工作在《公共科学图书馆·综合》上发表了两篇研究文章，并在国际研讨会上发表，如蛋白质治疗论坛和用于癌症治疗的PEGS抗体研讨会。椭球体的工作部分得到了NCI主任颁发给Mitchell Ho的壁内创新奖(首席调查员奖)的支持。

The Antibody Therapy Section aims to develop novel antibody therapies for liver cancer as well as other cancers. Project 1: Targeting glypican-3 in hepatocellular carcinoma Liver cancer is the fifth most common cancer and the third leading cause of cancer mortality in the world. Hepatocellular carcinoma (HCC) accounts for approximately 75% of liver cancer cases. Cholangiocarcinoma (CCA) is the second most common primary liver tumor. There is an urgent need for new treatments that can be successfully applied to a large population of liver cancer patients. With a primary interest in investigating glypican-3 (GPC3), this target holds potential for liver cancer therapy, given its high protein expression in HCC. In FY11-12, we generated the YP7 monoclonal antibody (mAb) with high affinity to GPC3 by hybridoma technology. In FY12, we conducted animal testing and showed that YP7 exhibited significant HCC xenograft tumor growth inhibition in mice. This work was published in the journal mAbs and featured on its cover. Ongoing studies are focused on exploring the mechanisms underlying the role of GPC3 in HCC pathogenesis and on the development of human antibodies targeting GPC3 for liver cancer therapy. The NCI has filed patent applications based on our GPC3 monoclonal antibodies. We hope to find industrial partners to collaborate with us in the development of novel GPC3-targeted antibody therapy to treat liver cancer. In FY12, the GPC3 project yielded three publications in the journals mAbs, BioDrugs and Cancer Reports. We presented our work at international symposia such as 2nd Annual PEGS Antibodies for Cancer Therapy Symposium, Protein Discovery & Therapeutics, and Antibodies for the 21st. Project 2: Targeting mesothelin in liver cancer, mesothelioma and ovarian cancer Mesothelin is expressed at high levels in mesothelioma, cholangiocarcinoma, ovarian as well as pancreatic and lung cancers. In FY10, we analyzed protein expression of mesothelin in liver cancer tissues and hypothesized that mesothelin is a potential therapeutic target in cholangiocarcinoma (CCA). In collaboration with Ira Pastan at the NCI, we applied our expertise in phage display technology to identify HN1, a human mAb specific for mesothelin. The HN1 mAb binds cell surface-associated mesothelin with high affinity and kills cancer cells with excellent antibody-dependent cell mediated cytotoxicity (ADCC) and is promising for the treatment of mesothelin-expressing cancers. In FY11, we published the HN1 work in the International Journal of Cancer. Our mesothelin project was supported in part by a Mesothelioma Applied Research Foundation research grant and the Ovarian Cancer Research Fund Individual Investigator Award to Mitchell Ho. In FY12, in collaboration with Ira Pastan and Dimiter Dimitrov (NCI's Frederick National Lab), we isolated novel single-domain human antibodies against mesothelin by phage display technology. These human antibodies may have novel anti-tumor activities against mesothelin-positive tumor cells. The NCI has filed patent applications on our mesothelin antibodies for cancer therapy. NCI also provides the LMB-H226-GL mesothelioma model developed in our lab as a Research Tool to the scientific community. Project 3: Establish in vitro tumor spheroids to investigate antibody therapy. Most studies of anticancer drugs consider only genetic and/or cellular mechanisms at the level of the single cell. However, drug penetration is a highly important additional mechanism and requires a more complex cellular environment for study. In FY11-12, in collaboration with V. Courtney Broaddus (University of California San Francisco) and Shuichi Takayama (University of Michigan), we established in vitro tumor spheroids to study monoclonal antibody therapy. These tumor spheroids may prove invaluable for identifying potential therapeutic targets in addition to providing an innovative platform for screening more effective anti-tumor antibodies. In FY12, we compared the gene expression profiles of 3D spheroids and conventional 2D monolayers using microarray analysis and identified over 100 genes specific to the 3D biological structure of mesothelioma. Some of these genes may have potential as therapeutic targets and diagnostic biomarkers. In FY11-12, this work yielded two research articles in PloS ONE and presented at international symposia such as the Protein Therapeutics Forum and PEGS Antibodies for Cancer Therapy Symposium. The spheroid work was supported in part by the NCI Director's Intramural Innovation Award (Principal Investigator Award) to Mitchell Ho.