Refinement of DNA-Launched NanoParticles decorated with Apex and CD4bs B cell lineage targeting Envs (DLNP-ACEs)

用 Apex 和 CD4bs B 细胞谱系靶向 Envs (DLNP-ACE) 修饰的 DNA 启动纳米粒子的精制

基本信息

批准号：
10589588
负责人：
Daniel Kulp
金额：
$ 116.34万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-08 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10589588
关键词：
Address Adjuvant Adoptive Transfer Affinity Animal Model Animals Antibodies Antibody Repertoire Antigens Apical Artificial nanoparticles B-Lymphocytes Benchmarking Binding Binding Sites Cell Lineage Clinic Complex Cryoelectron Microscopy Cyclic GMP DNA DNA Structure Development Directed Molecular Evolution Electron Microscopy Engineering Epitope Mapping Epitopes Formulation Frequencies Genes Genetic Glycoproteins Goals HIV HIV vaccine HIV-1 HIV-1 vaccine Human Immune Immunity Immunization In Vitro Individual Investigation Knock-in Mouse Laboratories Maps Measures Methods Modality Modeling Modification Molecular Monitor Mus Mutation Pathway interactions Pattern Plasma Primates Process Production Protein Subunits Protocols documentation Publications Recombinants Recurrence Reporting Rhesus Somatic Mutation Structure Structure of germinal center of lymph node Subunit Vaccines Surface Techniques Testing Time Vaccine Design Vaccines Variant Virus Virus Diseases acronyms cell type clinical development design global health immunogenic immunogenicity improved in vivo innovation lead candidate lead optimization lead series mouse model nanoparticle neutralizing antibody nonhuman primate novel pre-clinical programs prophylactic response simian human immunodeficiency virus synthetic construct trafficking vaccine candidate vaccine strategy vaccine trial

项目摘要

Project 2 - Project Summary In order to protect against HIV-1 acquisition, antibody-based vaccines must be able to consistently elicit broadly neutralizing antibodies (bnAbs). bnAb elicitation has proven difficult in humans and non-human primates (NHPs), in part because of the complex developmental pathways bnAbs require to mature, competition from off-target responses to the HIV-1 envelope glycoprotein (Env), and rare precursor B cell frequency. In this project we will develop candidate immunogens to address each of these problems through a variety of approaches. First, we will use structure-based and mammalian display techniques to further enhance the germline targeting ability of our lead candidate, Q23.17 MD39. Using these approaches, we will develop native-like trimers capable of targeting the V2-apex and CD4 binding site bnAb epitopes. These trimer immunogens will additionally be engineered to limit off-target responses by minimizing competition from highly immunodominant non-neutralizing antibody lineages. Furthermore, we will use these constructs to develop novel “germline targeting SHIVs”, and through SHIV-infection will identify boosting immunogens that can guide the development of breadth. Additionally, through structural analysis of the process of Env- Ab coevolution, we aim to identify determinants of bnAb development in infected primates, that will further inform our immunogen design process. Finally, we will complex these with genetic adjuvants developed in project 1 and platform advances in project 3, as well as with our novel DNA-Launched NanoParticle (DLNP) platform. We have shown DLNPs improve the immunogenicity while not requiring the complex cGMP processes that hamper the pace of clinical development for traditional nanoparticle vaccines. We will then down-select immunogens using a variety of innovative mouse models that harbor human B cell lineages, recapitulate human B cell competition and have tunable bnAb precursor frequencies. These mice will provide a benchmark for our lead candidates to be advanced into GMP production. We will test them in a NHP model for heterologous challenge, and through these combined approaches, we aim to demonstrate, for the first time, protection from heterologous tier-2 challenge in NHPs.

项目 2 - 项目概要为了防止 HIV-1 感染，基于抗体的疫苗必须始终能够引发广泛中和抗体 (bnAb) 已被证明在人类和非人类中很难诱导。灵长类动物 (NHP)，部分原因是 bnAb 成熟所需的复杂发育途径，来自对 HIV-1 包膜糖蛋白 (Env) 和罕见前体 B 细胞的脱靶反应的竞争在这个项目中，我们将开发候选免疫原来解决这些问题。首先，我们将使用基于结构和哺乳动物的展示技术来进一步。使用这些方法，我们增强了我们的主要候选物 Q23.17 MD39 的种系靶向能力。将开发能够靶向 V2-apex 和 CD4 结合位点 bnAb 表位的天然三聚体。三聚体免疫原还将被设计为通过最大限度地减少竞争来限制脱靶反应来自高度免疫显性的非中和抗体谱系此外，我们将使用这些构建体。开发新型“针对 SHIV 的种系”，并通过 SHIV 感染识别增强免疫原另外，通过对环境过程的结构分析，可以指导广度的发展。 Ab 共同进化，我们的目标是确定受感染灵长类动物 bnAb 发育的决定因素，这将进一步最后，我们将把它们与开发的遗传佐剂复合。项目 1 和项目 3 的平台进展，以及我们的新型 DNA 发射纳米粒子 (DLNP) 我们已经证明 DLNP 可以提高免疫原性，同时不需要复杂的 cGMP。然后我们将讨论阻碍传统纳米颗粒疫苗临床开发步伐的过程。使用含有人类 B 细胞谱系的各种创新小鼠模型下调免疫原，这些小鼠将重现人类 B 细胞竞争并具有可调节的 bnAb 前体频率。为我们的主要候选人进入 GMP 生产提供基准，我们将在一个环境中对其进行测试。针对异源挑战的 NHP 模型，通过这些组合方法，我们的目标是证明，首次在 NHP 中免受异源 2 级挑战。