Chimeric anti-fibulin-3 reagents for targeted therapy of glioblastoma

用于胶质母细胞瘤靶向治疗的嵌合抗fibulin-3试剂

基本信息

批准号：
9334499
负责人：
Mariano Sebastian Viapiano
金额：
$ 42.78万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2018-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9334499
关键词：
Address Angiogenesis Inhibitors Antibodies Apoptosis Basal lamina Binding Biodistribution Biological Biological Products Biology Blocking Antibodies Blood Vessels Blood capillaries Brain Brain Neoplasms CD8B1 gene Cells Clinical Connective Tissue Cytotoxic agent Engineering Exotoxins Extracellular Matrix Extracellular Matrix Proteins Family Future Genes Genetic Glioblastoma Glioma Goals Growth Guidelines Health Heterogeneity Immune response Immunoglobulin Variable Region Immunotherapeutic agent Immunotoxins Improve Access Investigational Drugs KDR gene Knowledge Laboratories Lead Ligand Binding Domain Malignant neoplasm of brain Maximum Tolerated Dose Modeling Molecular Monoclonal Antibodies Pathway interactions Peripheral Primary Brain Neoplasms Proteins Pseudomonas Reagent Recombinants Recurrence Resistance Risk S1-5 protein Safety Signal Transduction Specificity T cell response T-Cell Receptor T-Lymphocyte Testing The Cancer Genome Atlas Therapeutic Time Toxic effect Toxin Tumor Cell Invasion Tumor Stem Cells Validation Vascularization antiangiogenesis therapy antitumor effect autocrine bevacizumab brain tissue cancer type capillary chimeric antigen receptor conventional therapy cross reactivity cytotoxic cytotoxicity experience fibulin high reward high risk knock-down meetings member neoplastic cell nervous system disorder notch protein novel novel therapeutics outcome forecast paracrine pre-clinical receptor relating to nervous system response scaffold systemic toxicity targeted agent targeted treatment tumor tumor growth tumor microenvironment tumor progression

项目摘要

Project Description The goal of this project is to develop and validate novel biological reagents against glioblastomas (GBMs), which are one of the most common and the most aggressive kind of brain tumors. GBMs are highly invasive in brain tissue and their dispersion is exacerbated by cytotoxic and antiangiogenic therapies, resulting in a much worse clinical picture when the tumor recurs. Novel therapeutics addressing the biology of GBM should be able to disrupt invasion or vascularization and sensitize tumor cells, thus causing tumor disruption in multiple fronts when combined with conventional therapies. This project will focus on the protein fibulin-3 identified by our group, which is secreted by GBM cells and has unique localization and mechanisms in GBM but is absent from normal brain. Fibulin-3 is a novel activator of the Notch pathway and genetic targeting of this protein disrupts Notch signaling in the tumor and reduces GBM growth and resistance. We have produced a function-blocking antibody against fibulin-3 ("mAb428.2") and in this project we will use it as a starting point to generate and validate a family of anti-fibulin-3 recombinant reagents. In Specific Aim 1, we propose to validate safety and efficacy of mAb428.2 against intracranial GBMs to advance it towards investigational new drug status. We hypothesize that anti-fibulin-3 will reduce tumor growth and vascularization with no significant peripheral toxicity or local off-target effects. We will study mAb428.2 specificity, cross-reactivity, biodistribution, safety and anti-tumor efficacy following FDA guidelines, aiming at completing pre-IND validation. In Specific Aim 2, we propose to develop and validate an anti-fibulin-3 single-chain immunotoxin as cytotoxic agent for GBM. We have already generated a single-chain variable fragment (scFv) derived from mAb428.2 and hypothesize that the smaller size of this fragment will improve access and toxicity against GBM. We will conjugate the scFv with Pseudomonas exotoxin and will validate this novel immunotoxin for specificity, safety and efficacy against intracranial GBM. Successful completion of this project will result in a family of lead biological agents targeting the GBM microenvironment, with different levels of preclinical validation. These results will be used to advance the most promising candidate(s) for submission as investigational new drug(s) for GBM.

项目描述该项目的目的是开发和验证针对胶质母细胞瘤（GBM）的新型生物试剂，该试剂是最常见和最具侵略性的脑肿瘤之一。 GBM在脑组织中具有高度侵入性，其分散因细胞毒性和抗血管生成疗法而加剧，从而在肿瘤复发时会产生更严重的临床情况。针对GBM生物学的新型治疗剂应能够破坏侵袭或血管形成并使肿瘤细胞敏感，从而与常规疗法结合时会导致多个方面的肿瘤破坏。该项目将重点放在我们组识别的蛋白纤维蛋白3上，该蛋白质由GBM细胞分泌，并在GBM中具有独特的定位和机制，但正常脑中没有。 Fibulin-3是Notch途径的新型激活因子，该蛋白质的遗传靶向破坏了肿瘤中的Notch信号，并降低了GBM的生长和耐药性。我们已经产生了针对fibulin-3（“ MAB428.2”）的功能阻滞抗体，在此项目中，我们将使用它作为生成和验证抗纤维蛋白-3重组试剂家族的起点。在特定目标1中，我们建议验证MAB428.2对颅内GBM的安全性和功效，以将其推向研究新药状态。我们假设抗纤维蛋白3将减少肿瘤的生长和血管化，而无明显的外围毒性或局部脱靶作用。我们将研究MAB428.2 FDA指南之后的特异性，交叉反应性，生物分布，安全性和抗肿瘤功效，旨在完成预指名。在特定目标2中，我们建议开发和验证抗纤维蛋白3单链免疫毒素作为GBM的细胞毒性剂。我们已经生成了源自MAB428.2的单链变量片段（SCFV），并假设该片段的尺寸较小将改善对GBM的访问和毒性。我们将将SCFV与假单胞菌异毒素结合在一起，并将验证这种新型免疫毒素针对颅内GBM的特异性，安全性和有效性。该项目的成功完成将导致针对GBM微环境的铅生物学剂家族，并具有不同水平的临床前验证。这些结果将用于推进最有希望的候选人，以作为GBM的研究新药提交。