Next Generation Broadly Neutralizing Antibodies to Clear HIV-1 Reservoir

下一代广泛中和抗体可清除 HIV-1 病毒库

• 批准号: 10515649
• 负责人: Qingsheng Li
• 金额: $ 77.84万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-09 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10515649
• 关键词: Acquired Immunodeficiency Syndrome; Affinity; Antibodies; Antibody Therapy; Antigen-Antibody Complex; Antigens; Antiviral Therapy; Avidity; BLT mice; Binding; Biological; Biological Assay; CD3 Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cell surface; Cells; Clinical Trials; Competence; Cytotoxic T-Lymphocytes; Development; Disease remission; Effector Cell; Engineering; Ensure; Epitopes; Exhibits; Fc domain; Glycoproteins; Goals; HIV; HIV Antibodies; HIV antiretroviral; HIV envelope protein; HIV-1; Human; IgA2; Immune; Immunity; Immunoglobulin G; Immunotherapeutic agent; In Vitro; Individual; Infection; Interleukin-15; Intervention; Investigation; Knowledge; Lead; Mediating; Modeling; Modification; Mus; Mutation; Natural Killer Cells; Outcome; Outcome Study; Role; Structure; Synapses; Testing; Therapeutic Agents; Transgenic Organisms; Transplantation; Viral; Virus; Virus Diseases; Virus Replication; antibody engineering; antibody-dependent cell cytotoxicity; antiretroviral therapy; cytotoxic; cytotoxicity; design; effective intervention; humanized mouse; improved; in vivo; manufacture; mouse model; neutralizing antibody; next generation; nonhuman primate; novel; protective efficacy; rational design; recruit; targeted agent; viral rebound; virtual

Project summary HIV-1 curing is one of the top priorities for AIDS interventions. The recent isolation of many potent and broadly neutralizing antibodies (bNAbs) against HIV envelope glycoproteins (Env) offers great opportunities for exploring their potential as passively administered agents to treat established infections. The protective efficacy of bNAbs is primarily mediated by their extremely high capacity to inhibit virus infectivity and cell-cell virus spread (neutralization), as well as their ability to facilitate the killing of infected cells that express the cognate Env antigens on the cell surface through antibody-dependent cell-mediated cytotoxicity (ADCC) and to form antibody-virus immune complexes leading to viral clearance. Unfortunately, the outcome of the most recent clinical trials with bNAb as therapeutic agent demonstrated that the antigenically diverse and persistently evolving HIV-1 Env can rapidly acquire mutations that evade bNAbs administered as single agents. While simultaneously targeting distinct cognate epitopes by physically combining multiple bNAbs can result in virtually 100% virus coverage, the use of a “single” agent consisting of these multiple functional binding moieties is preferred for both regulatory and manufacturing purposes, in addition to the potential of augmented potency resulting from the increased avidity through bi- or multi- valence Env binding and possible synergistic effect between bNAbs. In addition, a recent study demonstrated in non-human primate model that in conjunction with bNAb therapy, CD8+ cytolytic T cells can effectively control virus rebound after the cessation of anti-viral therapy. Therefore, it is timely to engineer therapeutic agent that can effectively bridge the infected cells and the cytolytic T cells to mediate the killing of infected cells. Furthermore, previous studies established that modifications in the antibody Fc regions that increase their abilities to mediate cytotoxicity and extend their half-lives. However, such modifications have not been well applied to bNAbs for HIV treatment. This study aims to fill in the tremendous knowledge gap in the field by investigations with the following specific aims: 1) To generate HIV Env bNAbs with multiple epitope binding moieties possessing improved potency, avidity and breadth by structure-based design; 2) To engineer bNAbs that will efficiently recruit CD8+ cytolytic T cells to latently infected CD4+ T cells and kill the infected cells; and 3) To improve Fc region effector function (ADCC). The overall outcome of this study will advance our basic understanding of protective immunity against persistent virus infection and contribute to the development of safe and effective intervention strategies for HIV remission and eradication.

项目概要 HIV-1 治疗是艾滋病干预措施的首要任务之一，最近隔离了许多有效药物。 和针对 HIV 包膜糖蛋白 (Env) 的广泛中和抗体 (bNAb) 提供 探索其作为被动给药药物治疗的潜力的绝佳机会 bNAb 的保护功效主要是由它们的极端介导的。 抑制病毒感染性和细胞间病毒传播（中和）的高能力及其 促进杀死细胞上表达同源 Env 抗原的受感染细胞的能力 通过抗体依赖性细胞介导的细胞毒性（ADCC）表面并形成抗体病毒 不幸的是，最近的结果是免疫复合物导致病毒清除。 以 bNAb 作为治疗剂的临床试验表明，抗原多样性和 持续进化的 HIV-1 Env 可以快速获得突变，从而逃避 bNAb 的注射 同时通过物理方式不同地靶向同源表位。 结合多种 bNAb 可以实现几乎 100% 的病毒覆盖，使用“单一”试剂 由这些多功能结合部分组成的结构对于调节和 制造目的，除了增强效力的潜力之外 通过双价或多价 Env 结合增加亲和力以及之间可能的协同效应 此外，最近的一项研究在非人类灵长类动物模型中证明了这一点。 通过bNAb治疗，CD8+溶细胞T细胞可以有效控制停药后病毒反弹 因此，现在是时候设计能够有效桥接的治疗剂了。 受感染的细胞和溶细胞 T 细胞介导对受感染细胞的杀伤。此外， 先前的研究证实，抗体 Fc 区的修饰可增加其 然而，这种修饰并没有介导细胞毒性并延长其半衰期。 已被很好地应用于 HIV 治疗的 bNAbs。这项研究旨在填补大量知识。 通过具有以下具体目标的调查来弥补该领域的空白：1) 产生 HIV 包膜 bNAb 具有多个表位结合部分，具有改进的效力、亲合力和广度 基于结构的设计；2) 设计可有效招募 CD8+ 溶细胞 T 细胞的 bNAb 潜伏感染的CD4+T细胞并杀死被感染的细胞；3)提高Fc区效应子； 这项研究的总体结果将增进我们对功能（ADCC）的基本理解。 针对持续病毒感染的保护性免疫力，有助于安全性的发展 缓解和根除艾滋病毒的有效干预策略。

项目成果

Identification of the predominant human NK cell effector subset mediating ADCC against HIV-infected targets coated with BNAbs or plasma from PLWH.

鉴定介导针对涂有 BNAb 或 PLWH 血浆的 HIV 感染靶标的 ADCC 的主要人类 NK 细胞效应器子集。

• 发表时间: 2021
• 影响因子: 5.4
• 作者: Tomescu, Costin;Kroll, Kyle;Colon, Krystal;Papasavvas, Emmanouil;Frank, Ian;Tebas, Pablo;Mounzer, Karam;Reeves, Roger Keith;Montaner, Luis J
• 通讯作者: Montaner, Luis J

Structural Features of Antibody-Peptide Recognition.

抗体-肽识别的结构特征。

• 发表时间: 2022
• 作者: Lee, Jessica H;Yin, Rui;Ofek, Gilad;Pierce, Brian G
• 通讯作者: Pierce, Brian G

Tracking B cell responses to the SARS-CoV-2 mRNA-1273 vaccine.

追踪 B 细胞对 SARS-CoV-2 mRNA-1273 疫苗的反应。

• 发表时间: 2023-07-25
• 影响因子: 8.8
• 作者: Lopes de Assis, Felipe;Hoehn, Kenneth B;Zhang, Xiaozhen;Kardava, Lela;Smith, Connor D;El Merhebi, Omar;Buckner, Clarisa M;Trihemasava, Krittin;Wang, Wei;Seamon, Catherine A;Chen, Vicky;Schaughency, Paul;Cheung, Foo;Martins, Andrew J;Chiang
• 通讯作者: Chiang

One dose of COVID-19 nanoparticle vaccine REVC-128 protects against SARS-CoV-2 challenge at two weeks post-immunization.

一剂 COVID-19 纳米颗粒疫苗 REVC-128 可在免疫后两周预防 SARS-CoV-2 攻击。

• 发表时间: 2021-12
• 影响因子: 13.2
• 作者: Gu, Maggie;Torres, Jonathan L;Li, Yijia;Van Ry, Ale;Greenhouse, Jack;Wallace, Shannon;Chiang, Chi;Pessaint, Laurent;Jackson, Abigail M;Porto, Maciel;Kar, Swagata;Li, Yuxing;Ward, Andrew B;Wang, Yimeng
• 通讯作者: Wang, Yimeng

Broadly neutralizing antibodies target the coronavirus fusion peptide.

广泛中和抗体靶向冠状病毒融合肽。

• 发表时间: 2022-08-12
• 作者: Dacon, Cherrelle;Tucker, Courtney;Peng, Linghang;Lee, Chang;Lin, Ting;Yuan, Meng;Cong, Yu;Wang, Lingshu;Purser, Lauren;Williams, Jazmean K;Pyo, Chul;Kosik, Ivan;Hu, Zhe;Zhao, Ming;Mohan, Divya;Cooper, Andrew J R;Peterson, Ma
• 通讯作者: Peterson, Ma