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，用癌蛋白禁用MAB的有序治疗，然后是IFN-γ导致肿瘤细胞的表型变化从未用mAb本身实现。 mAb诱导的表型变化灵敏度细胞或允许直接在肿瘤上进行IFN-γ的意外作用。该提议的总体目标是为了深入了解ERBB介导的肿瘤发生的事件并发展更有效治疗和防止抗性肿瘤形成和扩散的治疗方法。我们将雇用 MMTV Neut-TDTOMATO转基因小鼠在番茄标记的乳腺标记中产生的MMTV-NEU蛋白细胞和形成乳腺肿瘤的人随随机乳腺癌与人类乳腺癌一样。这些独特转基因学将受到针对P185癌蛋白的靶向疗法的影响，然后是OR 与IFN-γ疗法并发。肿瘤出现和扩散将被遵循，并从进行进一步生化研究的进行性肿瘤。其他研究将采用抗P185配对的给药 mAb和ifn-γ，以及使用具有修饰效应子域的新型抗erbb2-SCFV 我们通常附着IFN-γ分子。 MMTV Neut-TDTOMATO转基因小鼠将成为宿主遵循单独使用MAB或与IFN-γ联合使用肿瘤进展和转移扩散的影响。用MAB到P185NEU出现目的地治疗的抗性肿瘤将研究表型和等位基因通过使用所提出的细胞系，肿瘤本身发生的变化，特别是我们的基因被认为与恶性表型有关。我们对新设计的mab人源化的研究 MAB-IFN-γ重组蛋白与人源化ZZ结构域融合（我们称为ZED域）将是扩展到抗赫斯蒂蛋白的乳腺癌。这种高度工程的mAb物种只是禁用 p185erbb2/neu激酶；通过ZED结构域的放大器免疫球蛋白作用；最后，提供了 IFN-γ直接对人类肿瘤细胞。我们将评估效应域是否修改了靶向抗erbb2 mAb 影响细胞，由ERBB2/NEU癌基因和其他体细胞突变（例如Kiras）转化。这构造可能是人类疾病疗法的原型。最后，我们还将评估是否这种新型抗体与细胞毒性/遗传毒性信号（例如紫杉烷，多西昔二醇）进一步使用消除了抗赫斯蒂蛋白的抗肿瘤细胞。