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Immunologic aspects of targeted therapy of erbB tumors

erbB 肿瘤靶向治疗的免疫学方面

基本信息

批准号：
9895635
负责人：
MARK I GREENE
金额：
$ 36.83万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895635
关键词：
Adjuvant Affect Aftercare Age Alleles Antibodies Antibody Therapy Antibody-Dependent Enhancement Apoptosis Binding Biochemical Breast Cancer Cell CT26 Cell Line Cell surface Cells Characteristics Chimeric Proteins Complex Crystallography Data Disease Dose Down-Regulation Dysplasia ERBB2 gene Early identification Elements Engineering Event FOXP3 gene Fc Immunoglobulins Flow Cytometry Fluorescence GTP-Binding Proteins Genes Genetic Engineering Goals Growth Histologic Human Hyperplasia Immunoglobulin G Immunoglobulins Immunologics In Vitro Inbred BALB C Mice Interferon Gamma Receptor Complex Interferon Type II Internal Ribosome Entry Site Knockout Mice Lead Lesion Lymphocyte Malignant - descriptor Malignant Neoplasms Mammary Neoplasms Mammary gland Mediating Molecular Monitor Monoclonal Antibodies Mouse Mammary Tumor Virus Mus Mutation Myeloid-derived suppressor cells Nude Mice Oncoproteins Patients Pattern Pharmaceutical Preparations Phenotype Phosphotransferases Population Prevention Protein Biochemistry Proteins Recombinant Proteins Regulatory T-Lymphocyte Reporter Genes Resistance Role Signal Transduction Somatic Mutation Structure Survival Rate Tertiary Protein Structure Therapeutic Therapeutic Effect Time Tomatoes Transgenic Mice Transgenic Organisms Trastuzumab Tumor Tissue Tumor-Derived Visual Work Xenograft procedure antibody-dependent cell cytotoxicity cancer cell cell transformation cytotoxic design dimer docetaxel effector T cell genotoxicity human disease humanized monoclonal antibodies in vivo knock-down macrophage malignant breast neoplasm malignant phenotype monomer mouse model neoplastic cell novel novel therapeutic intervention plasma protein Z prevent prototype receptor targeted treatment taxane therapy resistant tumor tumor growth tumor microenvironment tumor progression tumorigenesis

项目摘要

Our overall hypothesis is that ordered therapy with oncoprotein disabling mAb followed by IFN-γ leads to phenotypic changes in tumor cells never achieved with mAb itself. MAb induced phenotypic changes sensitize cells or are permissive for unexpected actions of IFN-γ directly on the tumor. The overall goal of this proposal is to gain a deeper understanding of events of erbB mediated tumorigenesis and to develop more potent therapeutics to treat and prevent the emergence of resistant tumor formation and spread. We will employ MMTV NeuT-tdTomato transgenic mice created to express MMTV-neu proteins in Tomato tagged mammary cells and which develop breast tumors stochastically much like human breast cancer. These unique transgenics will be subjected to the effects of targeted therapy against the p185 oncoprotein followed by or concurrent with IFN-γ therapy. Tumor emergence and spread will be followed and cell lines developed from progressive tumors for further biochemical studies. Other studies will employ paired administration of anti-p185 mAb and IFN-γ, as well as use of a new species of anti-erbB2-scFv with a modified effector domain to which we have genetically attached the IFN-γ molecule. The MMTV NeuT-tdTomato transgenic mice will be hosts to follow the effects of mAb alone, or in combination with IFN-γ, on tumor progression and metastatic spread. Resistant tumors that arise despite treatment with mAb to p185neu will be studied for phenotypic and allelic changes that occur in the tumor itself, through the use of propogated cell lines, in particular genes we have considered to be relevant to the malignant phenotype. Our studies on a newly engineered mAb humanized mAb-IFN-γ recombinant protein fused with a humanized ZZ domain, (which we term the ZED domain) will be extended to Herceptin resistant breast cancers. This highly engineered mAb species simultaneously disables p185erbB2/neu kinases; amplifies immunoglobulin effects through the ZED domain; and, finally, delivers IFN-γ directly to human tumor cells. We will evaluate if effector domain modified targeting anti-erbB2 mAb also affects cells transformed by both the erbB2/neu oncogene and other somatic mutations such as KiRas. This construct may be a prototype of a therapeutic for human disease. Finally, we will also evaluate if cytotoxic/genotoxic signals (such as the taxane, docetaxol) used with this new species of antibody further eliminates Herceptin resistant tumor cells.

我们的总体假设是，先使用癌蛋白失能单克隆抗体进行有序治疗，然后使用 IFN-γ 进行治疗，从而导致单克隆抗体本身从未实现肿瘤细胞表型的改变。 MAb 诱导的表型变化致敏细胞或允许 IFN-γ 直接对肿瘤产生意想不到的作用。本提案的总体目标是为了更深入地了解 erbB 介导的肿瘤发生事件并开发更有效的治疗和预防耐药肿瘤形成和扩散的出现的疗法。我们将聘用 MMTV NeuT-tdTomato 转基因小鼠在番茄标记的乳腺中表达 MMTV-neu 蛋白细胞随机产生乳腺肿瘤，就像人类乳腺癌一样。这些独特的转基因生物将受到针对 p185 癌蛋白的靶向治疗的影响，然后或与 IFN-γ 治疗同时进行。将跟踪肿瘤的出现和扩散，并从中开发细胞系进行性肿瘤以进行进一步的生化研究。其他研究将采用抗 p185 配对给药 mAb 和 IFN-γ，以及使用具有修饰效应结构域的新型抗 erbB2-scFv 我们已经在基因上附着了 IFN-γ 分子。 MMTV NeuT-tdTomato 转基因小鼠将成为跟踪单独使用 mAb 或与 IFN-γ 联合使用对肿瘤进展和转移扩散的影响。尽管使用 p185neu 单克隆抗体治疗后出现的耐药肿瘤将进行表型和等位基因研究通过使用繁殖细胞系，特别是我们拥有的基因，肿瘤本身发生的变化被认为与恶性表型相关。我们对新设计的人源化单克隆抗体的研究与人源化 ZZ 结构域（我们称之为 ZED 结构域）融合的 mAb-IFN-γ 重组蛋白将是扩展到赫赛汀耐药乳腺癌。这种高度工程化的单克隆抗体种类同时禁用 p185erbB2/neu 激酶；通过 ZED 结构域放大免疫球蛋白效应；最后，交付 IFN-γ直接作用于人类肿瘤细胞。我们将评估效应器结构域修饰是否也靶向抗 erbB2 mAb 影响由 erbB2/neu 癌基因和其他体细胞突变（例如 KiRas）转化的细胞。这构建体可能是治疗人类疾病的原型。最后，我们还将评估是否与这种新抗体一起使用的细胞毒性/基因毒性信号（例如紫杉烷、多西紫杉醇）进一步消除赫赛汀耐药肿瘤细胞。