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

• 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
• 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

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（申请人提供）：由于迫切需要开发用于胰腺癌（PDAC）的新的有效疗法，该提议将测试新的假设，即靶向在PDAC细胞上选择性表达的B7-H3表位的212Pb标记的基于mAb的放射免疫疗法（RIT）将增强吉西他滨和Sonic hedgehog（SHH）抑制剂LDE 225根除PDAC的能力，通过不仅消除分化的PDAC细胞，而且消除胰腺癌起始细胞（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识别共抑制分子B7-H3的细胞外表位，其在人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。该提议将测试PDAC可以通过不仅靶向分化/分化胰腺癌细胞（其形成肿瘤的大部分）而且靶向胰腺CIC（疾病的根源）来根除的假设，其中212Pb缀合至新型mAb 376.96。这一假说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。我们的组合策略的有效性得到了我们的初步结果的支持：如图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。吉西他滨目前是PDAC的标准化疗药物。然而，单独使用吉西他滨的效果有限，大多数患者对治疗产生耐药性。这种耐药性可能反映了CIC的化学耐药性。具有212 Pb的靶向RIT（其衰变为212 Bi）将与吉西他滨和LDE 225（SHH途径的抑制剂）组合，因为该抑制剂已被证明可有效减少胰腺CIC。 这项建议的具体目标将检验：用212 Pb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LDE 225组合抑制人胰腺CIC肿瘤球的体外增殖。 二.用212 Pb标记的B7-H3特异性mAb 376.96与吉西他滨和LDE 225组合根除了移植有人PDAC细胞的免疫缺陷小鼠中的原位疾病，因为这种组合不仅消除了分化的PDAC细胞，而且消除了胰腺CIC。 三.用212 Pb标记的B7-H3特异性mAb 376.96与吉西他滨和LDE 225组合根除了移植有人PDAC细胞的免疫缺陷小鼠中的微转移性疾病。从概述的研究中获得的信息将为拟议的212Pb-376.96抗体和CIC治疗胰腺癌的临床转化提供坚实的基础。