TCR-like antibodies for HPV-induced cancer basic research and theranostics

用于 HPV 诱导的癌症基础研究和治疗诊断的 TCR 样抗体

基本信息

批准号：
9319153
负责人：
Roland K Strong
金额：
$ 43.5万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-20 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9319153
关键词：
Alleles Antibodies Antibody Affinity Antigen Presentation Antigen Targeting Antigens Basic Cancer Research Basic Science Binding Biochemical Biological Models Cancer Burden Cancer Etiology Cancer Patient Cancerous Cause of Death Cell Line Cell surface Cells China Chinese People Clinical Complex Crystallization Cytotoxic agent Developing Countries Development Diagnosis Diagnostic Disease Engineering Epitopes Future Goals HIV vaccine HLA-A gene HLA-A2 Antigen Human Human Herpesvirus 4 Human Papilloma Virus Vaccine Human Papillomavirus Human papilloma virus infection Immune system Incidence Infection Infection prevention Knowledge Lesion Ligands Literature MS4A1 gene Maintenance Major Histocompatibility Complex Malignant Neoplasms Malignant Vaginal Neoplasm Malignant neoplasm of anus Malignant neoplasm of cervix uteri Malignant neoplasm of penis Malignant neoplasm of vulva Mediating Methodology Monoclonal Antibodies Nature Normal Cell Oncoproteins Operative Surgical Procedures Patients Pattern Peptide/MHC Complex Peptides Preventive screening Process Protein Engineering Proteins Radiation therapy Reagent Recurrence Refractory Disease Sampling Series Specificity Structure Surface T-Cell Receptor T-Lymphocyte Technology Therapeutic Therapeutic Effect Therapeutic antibodies Tumor Antigens Tumor Specific Peptide Tumor-Derived Vaccination Vaccines Viral Woman Work base cancer cell cancer therapy clinical application clinical development cohort design experience feeding high throughput screening improved in vivo interest killings malignant oropharynx neoplasm melanoma mortality neoplastic cell new technology novel patient population prevent protein E protein complex receptor response theranostics therapeutic development tumor virtual

项目摘要

Project Summary/Abstract The era of targeted anti-cancer therapies was ushered in by the development of therapeutic antibodies specific for antigens expressed primarily on tumors, improving the lives of countless cancer patients. Current antibodies, however, are limited to intact cell surface ligands, such as CD20, which are often also expressed on normal cells. However, methodological improvements have made it possible to produce antibodies specific for peptides from tumor antigens or viral oncoproteins presented in the context of major histocompatibility complex (MHC) class I proteins (in humans: HLA-A, -B, -C), which are often better restricted to tumor cells. These antibodies mimic how T cell receptors (TCR) recognize peptide/MHC complexes (pMHCs). These “TCR mimic” or mTCR antibodies combine the specificity of a TCR with the affinity of an antibody, allowing the targeting of antigens expressed by cancerous cells, while sparing normal cells. However, mTCR Abs are difficult to elicit, because of the precise nature of the target surface on a pMHC. The best current approaches require specialized high-throughput screening to isolate true mTCR antibodies. We will improve this developing technology by increasing the efficiency that mTCR antibodies can be generated in conventional monoclonal antibody facilities. We will accomplish this by engineering immunogens to focus responses to the desired target epitope surface, drawing on our previous experience with HIV vaccines. In order to fully develop and demonstrate our platform, we will focus on cancers caused by human papillomavirus (HPV) as a model system. The mTCR antibodies against HPV we will generate will be useful immediately for basic studies of HPV pMHC expression, and eventually as ex vivo and in vivo diagnostics, and for treatment of refractory disease. While the proximate goal of this project is to develop our mTCR Ab platform using HPV as a model system, our mTCR technology is completely generalizable to any application. HPV infection causes about 5% of all human cancers, and virtually all cervical cancers, but also provides well- defined antigens that can be targeted by mTCR antibodies. We plan to target the HPV E6/E7 oncoproteins responsible for the induction and maintenance of malignancy. We will validate these mTCR antibodies in a large cohort of patients with HPV-induced cervical cancers of known HPV strain and HLA allele usage through the FHCRC China initiative. The need for improved treatments for advanced cervical cancer in China is particularly great, because of limited access to preventative screening and HPV vaccines. This project will deliver (1) a novel technology for generating mTCR Abs against any desired pMHC target; (2) basic science on the presentation and expression patterns of HLA-restricted HPV E6/E7 epitopes; (3) crystal structures of novel MHC/HPV peptide complexes; and (4) a panel of biochemically-validated HPV mTCR Abs for immediate basic science applications and future development as clinical theranostics.

项目摘要/摘要特定于治疗抗体的开发使靶向抗癌疗法的时代引入了对于主要在肿瘤上表达的抗原，改善了无数癌症患者的生活。当前的然而，抗体仅限于完整的细胞表面配体，例如CD20，通常也表达在正常细胞上。但是，方法学改进使得产生特定的抗体在主要组织相容性的背景下提出的肿瘤抗原或病毒癌蛋白的辣椒复合物（MHC）I类蛋白质（在人类：HLA -A，-b，-c），通常更好地限于肿瘤细胞。这些抗体模仿T细胞接收器（TCR）如何识别肽/MHC复合物（PMHC）。这些“ TCR 模仿”或MTCR抗体将TCR的特异性与抗体的亲和力结合在一起，从而允许靶向取消细胞表达的抗原，同时占据正常细胞。但是，由于PMHC上靶表面的精确性，MTCR ABS很难引起。这最佳当前方法需要专门的高通量筛选，以隔离真正的MTCR抗体。我们将通过提高MTCR抗体可以生成的效率来改善这项发展的技术常规的单克隆抗体设施。我们将通过工程免疫剂来集中精力来实现这一目标对所需的靶位表面表面的反应，借鉴了我们先前使用HIV疫苗的经验。为了充分开发和演示我们的平台，我们将重点关注由人类引起的癌症乳头瘤病毒（HPV）作为模型系统。我们将生成的针对HPV的MTCR抗体将是有用的立即用于HPV PMHC表达的基础研究，最终作为体内和体内诊断，以及治疗难治性疾病。虽然该项目的最接近目标是开发我们的MTCR AB平台使用HPV作为模型系统，我们的MTCR技术完全可以推广到任何应用程序。 HPV感染会导致所有人类癌症的5％，几乎所有宫颈癌，但也提供很好的癌症可以用MTCR抗体靶向的定义抗原。我们计划靶向HPV E6/E7癌蛋白负责诱导和维持恶性肿瘤。我们将在A中验证这些MTCR抗体大量患有HPV诱导的已知HPV菌株宫颈癌和HLA等位基因使用的患者通过 FHCRC中国倡议。需要改善中国晚期宫颈癌的治疗方法是特别好，由于预防性筛查和HPV疫苗的访问有限。该项目将提供（1）针对任何所需的PMHC目标生成MTCR ABS的新技术；（2）基础科学关于HLA限制的HPV E6/E7表位的表达和表达模式；（3）晶体新型MHC/HPV胡椒复合物的结构；（4）一组生化验证的HPV MTCR ABS 作为临床治疗学的直接基础科学应用和未来发展。