Evaluating anti-idiotypic antibodies as novel vaccine candidates against HIV-1

评估抗独特型抗体作为针对 HIV-1 的新型候选疫苗

基本信息

批准号：
10540731
负责人：
Andrew McGuire
金额：
$ 36.91万
依托单位：
FRED HUTCHINSON CANCER CENTER
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：
2018-12-06 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10540731
关键词：
Adoptive Transfer Affinity Amino Acids Animal Model Animals Anti-Idiotypic Antibodies Antibodies Antibody Binding Sites Antibody Formation Antigens B-Cell Activation B-Cell Antigen Receptor B-Lymphocytes Binding Binding Sites Biological Assay CD4 Positive T Lymphocytes Cattle Cell Separation Cloning Collaborations Cross Reactions Data Development Engineering Epitope Mapping Epitopes Failure Frustration Gene Targeting Genes Genetic Glycoproteins Goals Growth HIV Infections HIV-1 HIV-1 vaccine Human Immune response Immunization Immunodominant Epitopes Immunoglobulin Idiotypes In Vitro Individual Infection Infection prevention Knock-in Knock-in Mouse Light Llama Longevity Modeling Monoclonal Antibodies Mus Mutation Peptides Peripheral Blood Mononuclear Cell Process Reaction Reagent Recombinant Antibody Recombinants Research Sampling Sequence Homology Site Specificity Structure of germinal center of lymph node Surface T cell response T-Lymphocyte Testing Transgenic Mice Vaccination Vaccines Viral Virion Work antigen binding design experimental study humanized mouse immunogenic immunogenicity improved in vivo insight knockin animal mouse model neutralizing antibody novel novel vaccines progenitor recruit response tool vaccine candidate

项目摘要

Project Summary/Abstract Broadly neutralizing antibodies (bNAbs) that bind to the HIV-1 Envelope glycoprotein (Env) are expected to be an important component of the immune response elicited by an effective HIV-1 vaccine. However, efforts to elicit bNAbs through vaccination with recombinant Env have not yet been successful. VRC01-class antibodies are among the broadest and most potent bNAbs that have been isolated from infected individuals, and their elicitation would be an ideal goal of a vaccine. VRC01-class antibodies have been isolated from multiple donors, and they all interact with Env in a nearly identical manner; are derived from the same antibody heavy chain gene, VH1-2*02; and have an unusually short third complimentary determining region (CDRL3) on the light chain. During the course of infection, VRC01-class antibodies acquired a number of mutations in their antibody genes that allow them recognize and neutralize diverse HIV-1 viral isolates. Using sequence homology, one can predict the sequence of the B-cell receptor (BCR) on the naive B cell that gave rise to each VRC01-class antibody. Previous work from our group and others has demonstrated that these inferred-germline versions of VRC01-class antibodies fail to recognize diverse recombinant Envs. Thus, conventional Env immunogens are likely ineffective at binding to and activating naive B cells that can give rise to VRC01-class antibodies. The structural similarity and shared genetics of VRC01-class antibodies have led to the proposal that immunogens designed to specifically to engage VRC01-class precursor B cells could, at the very least, start the process of VRC01-class antibody production. Indeed we, and others, have designed Env-based immunogens that can activate B cells expressing VRC01-class precursor BCRs in vitro and in vivo. However, these immunogens also present off-target, potentially immunodominant epitopes that could ultimately frustrate the development of VRC01-class antibodies in competitive germinal center reactions. As an alternative to Env-derived immunogens, we have produced and isolated anti-idiotypic antibodies that are highly specific for the antigen binding site of VRC01-class precursor BCRs. Importantly, because they are non-Env derived, they lack the off-target epitopes present on other germline-targeting immunogens. Our overarching hypothesis is that if used as a vaccine prime, anti-idiotypic antibodies can selectively seek out and expand rare VRC01-class B cells, such that the expanded pool will have a selective advantage over other B cells that respond to off-target epitopes following a boost with germline-targeting Env. This hypothesis will be tested in transgenic mouse models as part of this HIVRAD application, in collaboration with Drs. Stamatatos and Nussenzweig. The focus of this project is to evaluate the ability of these novel immunogens to seek out rare VRC01-class precursor B cells from human PBMC samples and from mice expressing a diverse human-derived BCR repertoire, and to engineer multivalent aiMAb derivatives to improve immunogenicity.

项目概要/摘要与 HIV-1 包膜糖蛋白 (Env) 结合的广泛中和抗体 (bNAb) 有望是有效的 HIV-1 疫苗引发的免疫反应的重要组成部分。然而，努力通过重组 Env 疫苗接种来诱导 bNAb 尚未成功。 VRC01类抗体是从感染个体中分离出的最广泛、最有效的 bNAb 之一，并且它们的诱导将是疫苗的理想目标。 VRC01类抗体已从多个供体中分离出来，它们都以几乎相同的方式与 Env 交互；源自相同的抗体重链基因， VH1-2*02；轻链上有一个异常短的第三互补决定区 (CDRL3)。在感染过程中，VRC01类抗体的抗体发生了许多突变使它们能够识别并中和多种 HIV-1 病毒分离株的基因。利用序列同源性，可以预测产生每个 VRC01 类的初始 B 细胞上的 B 细胞受体 (BCR) 序列抗体。我们小组和其他人之前的工作已经证明，这些推断的种系版本 VRC01 类抗体无法识别多种重组 Env。因此，传统的 Env 免疫原是可能无法有效地结合和激活可产生 VRC01 类抗体的初始 B 细胞。 VRC01 类抗体的结构相似性和共享遗传学导致了这样的提议：专门设计用于接合 VRC01 类前体 B 细胞的免疫原至少可以启动 VRC01类抗体生产过程。事实上，我们和其他人已经设计了基于 Env 的免疫原可以在体外和体内激活表达 VRC01 类前体 BCR 的 B 细胞。然而，这些免疫原还呈现脱靶、潜在的免疫显性表位，最终可能会挫败在竞争性生发中心反应中开发 VRC01 类抗体。作为 Env 衍生免疫原的替代品，我们生产并分离了抗独特型抗体，对 VRC01 类前体 BCR 的抗原结合位点具有高度特异性。重要的是，因为他们是非 Env 衍生的，它们缺乏其他种系靶向免疫原上存在的脱靶表位。我们的总体假设是，如果用作疫苗原药，抗独特型抗体可以选择性地寻找并扩增稀有 VRC01 类 B 细胞，使得扩增的细胞库比其他 B 细胞具有选择性优势在种系靶向环境增强后对脱靶表位做出反应。这个假设将被检验作为 HIVRAD 应用的一部分，与 Drs 合作在转基因小鼠模型中进行了研究。斯塔马塔托斯和努森茨威格。该项目的重点是评估这些新型免疫原寻找稀有免疫原的能力 VRC01 类前体 B 细胞，来自人类 PBMC 样本和表达多种人类来源的小鼠 BCR 库，并设计多价 aiMAb 衍生物以提高免疫原性。