Therapy of pancreatic cancer with 212Pb-labeled B7-H3 specific Ab and LDE225

使用 212Pb 标记的 B7-H3 特异性抗体和 LDE225 治疗胰腺癌

基本信息

批准号：
8637541
负责人：
DONALD J. BUCHSBAUM
金额：
$ 18.6万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8637541
关键词：
Adenocarcinoma Cell Antibodies Base Sequence Binding Blood Cells Cancer cell line Cell Line Cell Therapy Cells Clinical Combined Modality Therapy Complementary DNA Data Daughter Disease Epitopes Erinaceidae Figs - dietary Foundations Frequencies Funding Human Immunodeficient Mouse Immunotherapy In Vitro Investigation Label Length Lesion Linear Energy Transfer Literature Liver Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Monoclonal Antibodies Neoplasm Metastasis Normal Cell Normal tissue morphology Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Patients Plant Roots Radiation Radiation-Sensitizing Agents Radioimmunoconjugate Radioimmunotherapy Radioisotopes Recurrence Relative Biological Effectiveness Reporting Resistance Resistance development Solid Sonic Hedgehog Pathway Source Specificity Stem cells Testing Translations Tumor Antigens base cancer cell cancer stem cell cell growth chemotherapeutic agent combinatorial effective therapy extracellular gemcitabine glycosylation inhibitor/antagonist killings novel novel therapeutics outcome forecast pancreatic cancer cells patient population public health relevance selective expression stem theories therapy resistant tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Because of the urgent need to develop novel effective therapies for pancreatic adenocarcinoma (PDAC), this proposal will test the novel hypothesis that a 212Pb-labeled mAb-based radioimmunotherapy (RIT) targeting a B7-H3 epitope selectively expressed on PDAC cells will enhance the ability of gemcitabine and the Sonic hedgehog (SHH) inhibitor LDE225 to eradicate PDAC, by eliminating not only differentiated PDAC cells, but also pancreatic cancer initiating cells (CICs). The combination strategy we plan to optimize takes advantage of the unique specificity of mAb 376.96. This mAb recognizes an extracellular epitope of the coinhibitory molecule B7-H3 which is expressed on human PDAC cell lines and in surgically removed PDAC lesions, including pancreatic CICs, but has a restricted distribution in normal tissues. This proposal will test the hypothesis that PDAC can be eradicated by targeting not only differentiated/differentiating pancreatic cancer cells, which form the bulk of the tumor, but also pancreatic CICs, the root of the disease, with 212Pb conjugated to the novel mAb 376.96. This hypothesis stems from the cancer stem cell theory which postulates that CICs have to be eliminated to "cure" a malignant disease, since CICs are responsible for disease recurrence and metastatic spread. The validity of our combination strategy is supported by our preliminary results: as shown in Figs. 4, 5, and 6 mAb 376.96 enhances the anti-proliferative activity of gemcitabine and its ability to eliminate CICs. Gemcitabine is currently the standard chemotherapeutic agent for PDAC. However, the effect of gemcitabine alone is limited and most patients develop resistance to the therapy. This resistance may reflect the chemo-resistance of CICs. Targeted RIT with 212Pb, which decays to 212Bi, will be combined with gemcitabine and LDE225, an inhibitor of the SHH pathway, since this inhibitor has been shown to be effective in reducing pancreatic CICs. The specific aims of this proposal will test whether: i. B7-H3-specific mAb 376.96 labeled with 212Pb binds to human PDAC cell lines and inhibits in vitro proliferation of human pancreatic CIC tumorspheres alone or in combination with gemcitabine and LDE225. ii. B7-H3-specific mAb 376.96 labeled with 212Pb, in combination with gemcitabine and LDE225 eradicates orthotopic disease in immunodeficient mice grafted with human PDAC cells, since this combination eliminates not only differentiated PDAC cells, but also pancreatic CICs. iii. B7-H3-specific mAb 376.96 labeled with 212Pb, in combination with gemcitabine and LDE225, eradicates micrometastatic disease in immunodeficient mice grafted with human PDAC cells. The information derived from the outlined studies will provide a solid foundation for clinical translation of the proposed 212Pb-376.96 antibody and CIC therapy to treat pancreatic cancer.

描述（由申请人提供）：由于迫切需要开发针对胰腺腺癌（PDAC）的新型有效疗法，本提案将测试新的假设，即基于 212Pb 标记的单克隆抗体的放射免疫疗法（RIT）选择性靶向 B7-H3 表位PDAC 细胞上表达的 PDAC 不仅通过消除分化的 PDAC，还将增强吉西他滨和 Sonic Hedgehog (SHH) 抑制剂 LDE225 根除 PDAC 的能力细胞，还包括胰腺癌起始细胞（CIC）。我们计划优化的组合策略利用了 mAb 376.96 的独特特异性。该 mAb 可识别共抑制分子 B7-H3 的细胞外表位，该分子在人 PDAC 细胞系和手术切除的 PDAC 病变（包括胰腺 CIC）中表达，但在正常组织中分布有限。该提案将检验以下假设：通过将 212Pb 与新型 mAb 376.96 结合，不仅可以靶向构成肿瘤主体的已分化/正在分化的胰腺癌细胞，还可以靶向疾病的根源胰腺 CIC，从而根除 PDAC。这一假设源于癌症干细胞理论，该理论假设必须消除 CIC 才能“治愈”恶性疾病，因为 CIC 是疾病复发和转移扩散的原因。我们的初步结果支持了我们组合策略的有效性：如图 1 和 2 所示。 4、5 和 6 mAb 376.96 增强吉西他滨的抗增殖活性及其消除 CIC 的能力。吉西他滨是目前 PDAC 的标准化疗药物。然而，单独使用吉西他滨的效果有限，大多数患者会对治疗产生耐药性。这种耐药性可能反映了 CIC 的化疗耐药性。具有 212Pb（衰变为 212Bi）的靶向 RIT 将与吉西他滨和 SHH 途径抑制剂 LDE225 联合使用，因为该抑制剂已被证明可有效减少胰腺 CIC。该提案的具体目标将测试： i．用 212Pb 标记的 B7-H3 特异性 mAb 376.96 与人 PDAC 细胞系结合，并单独或与吉西他滨和 LDE225 联合抑制人胰腺 CIC 肿瘤球的体外增殖。二.标记有 212Pb 的 B7-H3 特异性 mAb 376.96 与吉西他滨和 LDE225 联合使用，可以根除移植人 PDAC 细胞的免疫缺陷小鼠的原位疾病，因为这种组合不仅消除了分化的 PDAC 细胞，还消除了胰腺 CIC。三.用 212Pb 标记的 B7-H3 特异性 mAb 376.96 与吉西他滨和 LDE225 联合使用，可以根除移植人 PDAC 细胞的免疫缺陷小鼠的微转移性疾病。从概述的研究中获得的信息将为拟议的 212Pb-376.96 抗体的临床转化和治疗胰腺癌的 CIC 疗法提供坚实的基础。