A novel and effective nanobody to prevent and treat Zika virus infection

一种预防和治疗寨卡病毒感染的新型有效纳米抗体

• 批准号: 9920081
• 负责人: Lanying Du
• 金额: $ 26.7万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-23 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920081
• 关键词: Affect; Affinity; Animal Model; Antibodies; Antibody-Dependent Enhancement; Attention; Behavior; Binding; Biological Assay; Blood; Brain; Brain Injuries; Cessation of life; Characteristics; Chemicals; Chlorides; Clinical; Communicable Diseases; Congenital neurologic anomalies; Country; Development; Disease; Drug or chemical Tissue Distribution; Engineering; Evaluation; Fetal Death; Fetus; Flavivirus; Generations; Goals; Grant; Guidelines; Half-Life; High temperature of physical object; Human; Immunoglobulin G; In Vitro; Microcephaly; Middle East Respiratory Syndrome Coronavirus; Monoclonal Antibodies; Mus; Mutation; Nervous system structure; Neuraxis; Neurologic; Neurons; Newborn Infant; Organ; Pathogenicity; Penetration; Peptide Hydrolases; Permeability; Placenta; Pregnant Women; Property; Reproductive system; Research; Specificity; Structure; Testing; Therapeutic; Therapeutic Agents; Therapeutic antibodies; Time; Tissues; Toxic effect; Urea; Vaccines; Vertical Disease Transmission; Viral Pathogenesis; Virus; ZIKV infection; Zika Virus; base; brain abnormalities; congenital zika syndrome; design; env Gene Products; experience; fetal; fight against; guanidinium; human disease; immunogenicity; improved; in vivo; malformation; mouse model; nanobodies; neutralizing monoclonal antibodies; novel; pandemic disease; pre-clinical; pregnant; prevent; pup; reproductive; reproductive organ; success; therapeutic vaccine; tool; type I interferon receptor; virus envelope

Abstract Zika virus (ZIKV) is the latest emerging infectious virus raising worldwide attention. ZIKV infection has led to severe diseases, including neurological and congenital Zika syndromes, as represented by microcephaly with fetal damage, fetal and pup death, brain abnormalities, and other malformations. ZIKV may infect pregnant fetuses and persistently exist in neuronal and reproductive tissues for months, resulting in severe tissue damage. Currently, there are no therapeutic agents available to prevent and treat ZIKV-caused severe diseases in humans, calling for the development of novel anti-ZIKV therapeutics for human use. ZIKV envelope (E) protein is a key therapeutic and vaccine target. ZIKV E-specific neutralizing monoclonal antibodies (mAbs) are being developed preclinically and/or tested clinically, but some of them have failed to fully stop vertical transmission of ZIKV. Moreover, the conventional mAbs usually have relatively large size, complicated structure, unstable behavior, and/or poor tissue penetration. In contrast, a nanobody (Nb) is a single-domain antibody of the variable domain of Camelid heavy-chain antibody, and it presents such unique properties as strong stability and specificity, high binding affinity, and good tissue penetration based on its small size (~15 kDa), making it an attractive therapeutic tool to prevent and treat human diseases. Our previous studies have established the technological platform for designing and developing novel and effective Nbs against Middle East respiratory syndrome coronavirus (MERS-CoV). Compared to conventional mAbs, these anti-MERS-CoV Nbs showed significantly enhanced stability and half-life. We have also demonstrated the ability of ZIKV E protein-based vaccines and therapeutics to protect against ZIKV infection in our established animal models. In the proposed study, we hypothesize that ZIKV E-specific Nbs, after appropriate engineering, will present extended half-life, excellent stability, good tissue penetration without toxicity, and improved efficacy against ZIKV infection. The specific aims are to (1) engineer ZIKV E-specific Nbs for generation of humanized Nbs with extended half-life and enhanced efficacy, (2) characterize these Nbs for stability and broad tissue permeability without toxicity, and (3) evaluate in vitro cross-neutralizing activity and in vivo efficacy of ZIKV E- specific Nbs against ZIKV infection. Within the tenure of this grant, the overall goal is to rapidly generate a novel and effective anti-ZIKV Nb with extended half-life, strong stability, excellent tissue penetration, and increased efficacy to prevent ZIKV infection. Even though ZIKV causes severe fetal damage and demise, and persists in neuronal and reproductive tissues for up to months with severe damage, the properties and characteristics of the final and fully developed Nb is expected to contribute to its efficacy in completely preventing the vertical transmission of ZIKV and clear it from infected tissues, leading to a significant reduction of ZIKV-associated microcephaly, brain abnormalities, other malformations and tissue damage. !

抽象的 寨卡病毒（ZIKV）是最新出现的传染性病毒，引起了全世界的关注。 ZIKV 感染导致 严重疾病，包括神经系统疾病和先天性寨卡综合征，以小头畸形为代表 胎儿损伤、胎儿和幼崽死亡、大脑异常和其他畸形。 ZIKV 可能感染孕妇 胎儿并在神经元和生殖组织中持续存在数月，导致严重的组织损伤 损害。目前，尚无治疗药物可用于预防和治疗 ZIKV 引起的重症 人类疾病，呼吁开发供人类使用的新型抗 ZIKV 疗法。 ZIKV 信封 (E) 蛋白质是关键的治疗和疫苗靶点。 ZIKV E 特异性中和单克隆抗体 (mAb) 正在临床前开发和/或临床测试，但其中一些未能完全阻止垂直 ZIKV 的传播。此外，传统的单克隆抗体通常尺寸较大、结构复杂 结构、不稳定的行为和/或组织渗透性差。相比之下，纳米抗体 (Nb) 是单域 骆驼重链抗体可变域的抗体，它具有以下独特的特性： 稳定性和特异性强，结合亲和力高，因其尺寸小（~15）而具有良好的组织渗透性 kDa），使其成为预防和治疗人类疾病的有吸引力的治疗工具。我们之前的研究有 建立了针对中小型企业设计和开发新颖有效的Nbs的技术平台 东呼吸综合征冠状病毒（MERS-CoV）。与传统的单克隆抗体相比，这些抗中东呼吸综合征冠状病毒 Nbs 的稳定性和半衰期显着增强。我们还展示了ZIKV E的能力 基于蛋白质的疫苗和疗法，可在我们建立的动物模型中预防 ZIKV 感染。在 在拟议的研究中，我们假设 ZIKV E 特异性 Nbs 经过适当的工程设计后，将呈现 半衰期延长，稳定性优异，组织渗透性好，无毒性，提高抗病毒功效 ZIKV 感染。具体目标是 (1) 设计 ZIKV E 特异性 Nbs 以生成人源化 Nbs 具有延长的半衰期和增强的功效，(2) 表征这些 Nb 的稳定性和广泛的组织 渗透性且无毒性，(3) 评估 ZIKV E-的体外交叉中和活性和体内功效 针对 ZIKV 感染的特定 Nbs。在这笔赠款的任期内，总体目标是快速产生 新型有效的抗ZIKV Nb，半衰期长，稳定性强，组织渗透性好， 提高预防 ZIKV 感染的功效。尽管 ZIKV 会导致严重的胎儿损伤和死亡，并且 在神经元和生殖组织中持续存在长达数月，并造成严重损害，其特性和 最终和完全开发的铌的特性预计将有助于其完全发挥功效 防止 ZIKV 的垂直传播并将其从受感染的组织中清除，从而显着减少 寨卡病毒相关的小头畸形、大脑异常、其他畸形和组织损伤。 ！

项目成果

A vaccine inducing solely cytotoxic T lymphocytes fully prevents Zika virus infection and fetal damage.

仅诱导细胞毒性 T 淋巴细胞的疫苗可完全预防寨卡病毒感染和胎儿损伤。

• 发表时间: 2021-05-11
• 影响因子: 8.8
• 作者: Gambino Jr, Frank;Tai, Wanbo;Voronin, Denis;Zhang, Yi;Zhang, Xiujuan;Shi, Juan;Wang, Xinyi;Wang, Ning;Du, Lanying;Qiao, Liang
• 通讯作者: Qiao, Liang

Effects of Adjuvants on the Immunogenicity and Efficacy of a Zika Virus Envelope Domain III Subunit Vaccine.

佐剂对寨卡病毒包膜结构域 III 亚基疫苗免疫原性和功效的影响。

• 发表时间: 2019-10-27
• 影响因子: 7.8
• 作者: Wang, Xinyi;Tai, Wanbo;Zhang, Xiaolu;Zhou, Yusen;Du, Lanying;Shen, Chuanlai
• 通讯作者: Shen, Chuanlai