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

• 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
• 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

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.

项目总结/摘要 与HIV-1包膜糖蛋白（Env）结合的广泛中和抗体（bNAb）预期 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 通过用重组Env接种引发bNAb尚未成功。VRC 01类抗体 是从感染个体中分离出的最广泛和最有效的bNAb之一， 激发是疫苗的理想目标。VRC 01类抗体已从多个供体中分离， 并且它们都以几乎相同的方式与Env相互作用;来源于相同的抗体重链基因， VH 1 -2*02;并且在轻链上具有异常短的第三互补决定区（CDRL 3）。 在感染过程中，VRC 01类抗体在其抗体中获得了许多突变 这些基因使它们能够识别并中和各种HIV-1病毒分离株。利用序列同源性，可以 预测初始B细胞上B细胞受体（BCR）的序列，该B细胞受体产生每个VRC 01类 抗体的我们小组和其他人以前的工作已经证明，这些推断的种系版本的 VRC 01类抗体不能识别不同的重组Env。因此，常规Env免疫原是 可能不能有效地结合和激活能产生VRC 01类抗体的幼稚B细胞。 VRC 01类抗体的结构相似性和共有的遗传学导致了以下建议： 被设计为特异性地与VRC 01类前体B细胞结合的免疫原至少可以启动免疫反应。 VRC 01类抗体的生产方法。事实上，我们和其他人已经设计了基于Env的免疫原， 其可以在体外和体内激活表达VRC 01类前体BCR的B细胞。但这些 免疫原还呈现出脱靶的、潜在的免疫显性表位，这些表位可能最终阻碍免疫原的免疫应答。 在竞争性生发中心反应中开发VRC 01类抗体。 作为Env衍生的免疫原的替代物，我们已经产生并分离了抗独特型抗体， 对VRC 01类前体BCR的抗原结合位点高度特异。重要的是，因为它们是 非Env衍生的，它们缺乏存在于其它生殖系靶向免疫原上的脱靶表位。我们 总体假设是，如果用作疫苗初免，抗独特型抗体可以选择性地寻找并 扩增稀有的VRC 01-类B细胞，使得扩增的池将具有优于其他B细胞的选择性优势 其在用生殖系靶向Env加强后对脱靶表位产生应答。这一假设将得到检验 在转基因小鼠模型中，作为HIVRAD应用的一部分，与Stamatatos博士合作， 努森茨韦格。该项目的重点是评估这些新的免疫原的能力，以寻找罕见的 来自人PBMC样品和来自表达多种人源性免疫球蛋白的小鼠的VRC 01类前体B细胞 BCR库，并工程化多价aiMAb衍生物以改善免疫原性。