PA-22-176, SBIR, Phase I, Novel Bispecific Nanotherapeutics as Broad-Spectrum Influenza Antivirals Refractory to Viral Escape

PA-22-176，SBIR，I 期，新型双特异性纳米疗法，作为难以病毒逃逸的广谱流感抗病毒药物

• 批准号: 10698804
• 负责人: Crystal Lee Moyer
• 金额: $ 29.98万
• 依托单位: EITR BIOLOGICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2024-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10698804
• 关键词: PA; 22; 176; SBIR; Phase

Project Summary Influenza A viruses (IAVs) have caused four pandemics since the turn of the 20th century. The 1918-1919 “Spanish Flu” was the most severe and is estimated to have caused more than 50 million deaths worldwide. A rapid response in the face of the next pandemic depends on the availability of pre-positioned medical countermeasures, including vaccines and therapeutics. These medical interventions are in a constant arms race with rapidly evolving IAV strains that use multiple strategies to escape them. The segmented genome of influenza viruses can reassort when two IAV strains infect the same cell, allowing generation of novel strains in a process called antigenic shift. These new strains, most often arising in an avian reservoir, have been to blame for each of the previous pandemics as humans may have no preexisting immunity. Additionally, the viral error-prone polymerase drives antigenic drift, allowing rapid accumulation of mutations in response to selective pressure to effectively escape the host immune response or antiviral medications. Antigenic drift has driven the emergence of multiple strains that are resistant to each of the six FDA-approved antivirals and underscores the need for next-generation therapeutics. Immunotherapeutics are effective antiviral countermeasures and can be carefully designed with flu evasion strategies in mind. First, epitopes that are highly conserved among the many different IAV strains circulating in multiple hosts are less likely to tolerate resistance mutations, making them an appropriate target for antiviral molecules. Second, bispecific molecules that bind to two distinct epitopes can be employed to decrease the likelihood of complete escape, and in some cases can function synergistically. With these ideal properties of a next-generation IAV immunotherapeutic in mind, we propose to develop a novel bispecific molecule targeting the highly conserved hemagglutinin (HA) stalk and the matrix 2 ectodomain (M2e). Our approach leverages a new class of immunotherapeutics—the ODIN (Orthogonal Dual-Interacting Nanotherapeutic) platform—that combines two natural immune sequence repertoires into single-domain bispecific molecule. ODIN molecules seamlessly merge camelid VHHs with the ultra-long CDR3s (UL-CDR3s) found in a subset of bovine immunoglobulin heavy chains to create a “small with a long reach” bispecific. The small size allows ODIN molecules to access epitopes like the HA stalk and M2e that IAV shields from immune surveillance with glycosylation and spatial localization near the viral membrane. ODINs can also be tailored to provide different mechanisms of action. To generate IAV ODIN molecules, we will immunize cattle with a combination of divergent IAV strains and recombinant proteins to elicit broad-spectrum UL-CDR3s. The lead UL- CDR3s will be combined with complimentary VHHs, yielding a subset of ODIN candidates that will be evaluated for IAV neutralization breadth and potency and the ability to resist the generation of viral escapes. The lead candidate emerging from these studies will be pursued as a next-generation IAV immunotherapeutic and pre- positioned for deployment in the next influenza pandemic.

项目摘要 自20世纪初以来，流感病毒（IAV）引起了四个大流行。 1918- 1919年 “西班牙流感”是最严重的，据估计在全球造成超过5000万人死亡。一个 面对下一个大流行的快速反应取决于预位医学的可用性 对策，包括疫苗和治疗。这些医疗干预措施处于持续的武器竞赛中 随着使用多种策略逃避它们的快速发展的IAV菌株。影响力的分段基因组 当两个IAV菌株感染了同一细胞时，病毒可以重新升级，从而在过程中产生新型菌株 称为抗原转移。这些新的菌株最常在禽类水库中产生，这是每个人都应该归咎于每一个 以前的大流行者作为人类可能没有先前的免疫力。此外，容易发生误差 聚合酶驱动抗原漂移，从而使突变迅速积累，以响应选择性压力 抗原驱动器驱动了宿主免疫反应或抗病毒药物的出现。 对六种FDA批准的抗病毒药中每一种都具有抗性的多种菌株的需求 下一代疗法。免疫治疗药是有效的抗病毒对策，可以谨慎 考虑到流感进化策略。首先，在许多不同的不同的表位 在多个宿主中循环的IAV菌株忍受耐药突变的可能性较小，使其成为 抗病毒分子的适当靶标。其次，与两个不同表位结合的双特异性分子可以是 用于降低完全逃脱的可能性，在某些情况下可以协同起作用。和 下一代IAV免疫治疗的这些理想特性，我们建议开发一种新颖 靶向高度保守的血凝素（HA）茎和基质2胞外域（M2E）的双特异性分子。 我们的方法利用了新的免疫治疗剂 - ODIN（正交双相互作用） 纳米疗法）平台 - 将两个天然免疫试剂组合为单域 双特异性分子。 Odin分子无缝将Camelid VHH与超长的CDR3S（UL-CDR3S）合并 在牛免疫球蛋白重链的一部分中发现，创建了一个“长距离的小”双特异性。这 小尺寸使Odin分子可以访问诸如HA茎和M2E之类的表位，而IAV屏蔽了免疫 病毒膜附近的糖基化和空间定位的监测。奥德斯也可以量身定制 提供不同的作用机制。为了产生IAV ODIN分子，我们将用A免疫牛 发散的IAV菌株和重组蛋白的结合，可引起广谱UL-CDR3。铅ul- CDR3将与免费的VHHS结合，产生将评估的Odin候选者的子集 对于IAV神经化的广度和效能，以及抵抗病毒逃生产生的能力。领先 从这些研究中出现的候选人将被作为下一代IAV免疫治疗和预性 定位在下一个影响力大流行中。