Deimmunized Griffithsin Microbicide

甘露糖结合凝集素格里菲辛(GRFT)代表了一种令人兴奋的预防感染的新方法 由HIV-1和单纯疱疹病毒2(HSV-2)感染。GRFT结合HIV-1和HSV-2上致密的多糖保护膜 包膜，其寡聚注释结构是高度保守的特征。在预防艾滋病毒方面，GRFT 对不同的病毒株具有很强的中和活性，并与化学物质协同作用 抗菌剂，甚至广谱中和抗体。在预防HSV-2方面，GRFT已被证明是 在体外和临床前动物模型中，防止感染和阻止细胞间的传播。重要的是，HSV-2 在普通人群中，感染艾滋病毒-1的风险增加3-5倍，至少增加一倍 高危人群中的HIV-1风险。因此，GRFT抵御这两种病毒感染的能力 提示它是一种很有前途的暴露前预防(PrEP)药物，我们建议基于GRFT的 Prep杀微生物剂可以帮助大幅减少新的HIV-1感染病例。事实上，在NIAID下- 资助的预防计划，我们最近获得了FDA的批准，对我们的Q-GRFT进行了首次人体研究 局部杀微生物剂(Q-GRFT是一种为增强氧化稳定性而设计的变体)。值得注意的是，作为普洛斯的一部分 毒理学研究对于这一研究性新药(IND)的应用，我们观察到了一种强大的抗药抗体 (ADA)兔的反应。这促使了临床上对Q-GRFT免疫原性的更仔细的检查 相关模型：人外周血单个核细胞(PBMC)免疫检测和人源化的人类白细胞抗原 转基因小鼠。我们发现Q-GRFT在人类白细胞抗原转基因中重复给药后可引起高滴度的ADA滴度 类似地，它被证明可以激活几个健康的人类捐赠者的PBMC中的辅助T细胞。因此， 虽然Q-GRFT在抗击新的HIV-1感染方面前景光明，但我们的临床前数据强烈 建议如果要长期使用Q-GRFT作为PrEP，就必须解决免疫原性问题 探员。我们建议设计和开发下一代去免疫GRFT(DGRFT)杀微生物剂 这保留了野生型和Q-GRFT的有效和广谱的抗病毒活性，但避免了有害的 人类的抗药免疫反应。为了实现这一目标，我们将结合隐形生物公司的先进技术 拥有深厚专业知识和开发团队经验的蛋白质设计和去免疫平台， 这已经将Q-GRFT推向临床试验。在此快速通道SBIR计划的第一阶段中，我们将 开发dGRFT候选药物，并使用初步的免疫学和功能检测进行验证。在……里面 在这个快速通道提案的第二阶段，我们将确认dGRFT的抗病毒活性的广度，展示减少 在大型和多样化的PBMC捐赠者面板中具有免疫原性潜力，开发可扩展的制造系统， 在标准动物模型和人源化动物模型中评估dGRFT的毒性，并测试该制剂的预防性 在临床相关的HSV-2和HIV感染动物模型中的疗效。完成这笔拨款后，我们将 手头有一位高性能的dGRFT首席候选人，该候选人定位于支持IND的研究。

The mannose binding lectin Griffithsin (GRFT) represents an exciting new approach to preventing infection by HIV-1 and herpes simplex virus 2 (HSV-2). GRFT binds the dense glycan shield on the HIV-1 and HSV-2 envelopes, for which oligomannose structures are a highly conserved feature. In protecting against HIV, GRFT possesses potent neutralizing activity towards diverse viral strains, and it acts synergistically with chemical antimicrobials and even broadly neutralizing antibodies. In protecting against HSV-2, GRFT has been shown to prevent infection and stop cell-to-cell spread both in vitro and in pre-clinical animal models. Importantly, HSV-2 infection increases the risk of HIV-1 acquisition by 3- to 5-fold in the general population and at least doubles the HIV-1 risk in high risk populations. Thus, GRFT’s capacity to protect against infection by both viruses suggests it is a promising agent for Pre-exposure Prophylaxis (PrEP), and we propose that a GRFT-based PrEP microbicide could help dramatically reduce new cases of HIV-1 infection. Indeed, under the NIAID- funded PREVENT Program, we recently received FDA approval for a first-in-human study of our Q-GRFT topical microbicide (Q-GRFT is a variant engineered for enhanced oxidative stability). Notably, as part of GLP toxicology studies for this Investigational New Drug (IND) application, we observed a potent anti-drug antibody (ADA) response in rabbits. This prompted a closer examination of Q-GRFT immunogenicity in two clinically relevant models: human peripheral blood mononuclear cell (PBMC) immunoassays and humanized HLA transgenic mice. We found that Q-GRFT elicited high ADA titers following repeated dosing in HLA transgenic mice, and it was similarly shown to activate helper T cells in PBMC from several healthy human donors. Thus, while Q-GRFT holds great promise in the fight against new HIV-1 infections, our preclinical data strongly suggests that the immunogenicity issue must be addressed if Q-GRFT is to be employed, long-term, as a PrEP agent. We propose here to design and develop a next-generation deimmunized GRFT (dGRFT) microbicide that retains the potent and broad-spectrum antiviral activity of wild type and Q-GRFT but evades detrimental anti-drug immune responses in humans. To achieve this goal, we will combine Stealth Biologics’ advanced protein design and deimmunization platform with the deep expertise and experience of the development team, which has already pushed Q-GRFT into clinical trials. In Phase I of this Fast-track SBIR proposal, we will develop a dGRFT lead candidate and validate it using preliminary immunological and functional assays. In Phase II of this Fast-track proposal, we will confirm dGRFT’s breadth of antiviral activity, demonstrate reduced immunogenic potential in large and diverse PBMC donor panels, develop a scalable manufacturing system, assess dGRFT toxicity in both standard and humanized animal models, and test the agent’s prophylactic efficacy in clinically-relevant animal models of HSV-2 and HIV infection. Upon completion of this grant, we will have in hand a high-performance dGRFT lead candidate that is positioned for IND-enabling studies.