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：
9178025
负责人：
Roland K Strong
金额：
$ 44.23万
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/9178025
关键词：
Alleles Antibodies Antibody Affinity Antigen Presentation Antigen Targeting Antigens Anus Basic Cancer Research Basic Science Binding Biological Models Cancer Burden Cancer Etiology Cancer Patient Cancerous Cause of Death Cell Line Cell surface Cells China Chinese People Clinical Complex Cytotoxic agent Developing Countries Development Diagnosis Diagnostic Diagnostic Neoplasm Staging 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 neoplasm of cervix uteri Mediating Metastatic/Recurrent Monoclonal Antibodies Nature Normal Cell Oncogenes Operative Surgical Procedures Oropharyngeal Patients Pattern Peptide/MHC Complex Peptides Preventive screening Process Protein Engineering Proteins Radiation therapy Reagent Recurrent Malignant Neoplasm Refractory Disease Sampling Series Specificity Staging Structure Surface T-Cell Receptor T-Lymphocyte Technology Therapeutic Therapeutic Effect Therapeutic antibodies Tumor Antigens Tumor-Derived Vaccination Vaccines Vagina Viral Vulva Woman Work abstracting base cancer cell cancer therapy clinical application cohort design experience feeding high throughput screening improved in vivo interest killings melanoma mortality neoplastic cell new technology novel patient population penis prevent receptor response theranostics tumor

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.

项目概要/摘要随着特异性治疗抗体的开发，迎来了靶向抗癌治疗的时代主要在肿瘤上表达的抗原，改善了无数癌症患者的生活。然而，抗体仅限于完整的细胞表面配体，例如 CD20，它们通常也表达然而，方法的改进使得产生特异性抗体成为可能。用于在主要组织相容性背景下呈现的来自肿瘤抗原或病毒癌蛋白的肽复合体 (MHC) I 类蛋白（人类：HLA-A、-B、-C），通常更好地限制于肿瘤细胞。这些抗体模仿 T 细胞受体 (TCR) 识别肽/MHC 复合物 (pMHC) 的方式。模拟”或 mTCR 抗体结合了 TCR 的特异性和抗体的亲和力，允许靶向癌细胞表达的抗原，同时不伤害正常细胞。然而，由于 pMHC 靶标表面的精确性质，mTCR Ab 很难引出。目前最好的方法需要专门的高通量筛选来分离真正的 mTCR 抗体。将通过提高 mTCR 抗体的生成效率来改进这项技术我们将通过设计免疫原来聚焦传统的单克隆抗体设施。借鉴我们之前在艾滋病毒疫苗方面的经验，对所需目标表位表面的反应。为了充分开发和展示我们的平台，我们将重点关注人类引起的癌症我们将生成的针对 HPV 的 mTCR 抗体作为模型系统将很有用。立即用于 HPV pMHC 表达的基础研究，并最终用于离体和体内诊断，以及该项目的近期目标是开发我们的 mTCR Ab 平台。使用 HPV 作为模型系统，我们的 mTCR 技术完全可推广到任何应用。 HPV 感染导致约 5% 的人类癌症，以及几乎所有宫颈癌，但也提供了良好的我们计划针对 HPV E6/E7 癌蛋白。我们将在一个实验中验证这些 mTCR 抗体。已知 HPV 毒株和 HLA 等位基因使用的 HPV 诱发宫颈癌的一大群患者 FHCRC 中国倡议指出，中国需要改进晚期宫颈癌的治疗方法。特别重要的是，因为预防性筛查和 HPV 疫苗的获取机会有限。该项目将提供 (1) 一种针对任何所需 pMHC 靶标生成 mTCR 抗体的新技术； HLA 限制性 HPV E6/E7 表位的呈现和表达模式的基础科学 (3) 晶体；新型 MHC/HPV 肽复合物的结构；以及 (4) 一组经过生化验证的 HPV mTCR 抗体用于直接基础科学应用和临床治疗诊断学的未来发展。