HIV/AIDS Vaccine and Antibody Development

在过去的一年中，我们已经创建并测试了几种候选疫苗，包括包膜三聚体蛋白和载体蛋白上展示的融合肽。此外，我们继续测试不同的给药方法和途径以及初免/加强组合，以进一步优化艾滋病毒疫苗策略。还测试了具有不同佐剂和纳米颗粒形式的蛋白质免疫原。正在进一步测试在初步研究中引起有希望的免疫原性数据的几种候选疫苗。在多种疫苗试验动物模型（包括小鼠、豚鼠和非人灵长类动物（NHP））中，广泛诱导了针对融合肽（FP）的HIV-1中和活性，FP是HIV融合机制的重要组分。基于这些临床前数据，两种新的HIV免疫原（与载体蛋白缀合的FP和进化枝C共有三聚体）被鉴定为候选疫苗，并且已经启动了GMP生产。这些研究中使用的佐剂Adjuplex的GMP生产也已开始。 使用不同的人免疫球蛋白基因敲入小鼠来了解广泛中和抗体的开发的研究也在进行中。这些研究正在测试新的免疫原，旨在产生针对多个HIV-1脆弱位点的中和抗体：CD 4结合位点，V2顶点和膜近端外部区域（MPER）。 对于抗体开发，我们已将靶向突变应用于从HIV+供体中分离的几种广泛中和抗HIV-1抗体（bNAb）。这些突变被设计为增加宽度、效力和半衰期，以改善治疗应用的潜在功效，并降低免疫原性，以允许更有效和更持久的体内功能。也有基于结构的突变，旨在提高亲和力和中和效力。此外，与Just Biotherapeutics合作设计了改善生物物理特性和可制造性的突变，并计划进一步开发和用于临床试验。 我们还与合作者合作开发三特异性抗HIV-1抗体，将三种不同的抗HIV-1特异性结合在一个IgG样分子中，用于HIV-1预防和治疗，其中一种已进入I期临床试验。 在另一项合作努力中，我们正在开发用于HIV-1治疗的改进的N6样抗体。 艾滋病的联合抗逆转录病毒疗法（cART）仍然是终身的，主要是因为病毒在潜伏的水库持续存在。因此，消除潜伏感染的细胞可以缩短治疗时间并促进免疫重建。我们已经开发了被称为T细胞粘附分子（TCE）的免疫调节蛋白，其结合了HIV-1广泛中和抗体的特异性和针对T细胞受体的CD 3组分的抗体的特异性。这些TCE可能有助于消除潜伏感染的细胞，并耗尽HIV-1感染者的病毒库。此外，我们已经开始合作开发TCE，激活T细胞裂解HIV-1感染的细胞。

During the past year, we have created and tested several vaccine candidates including envelope trimer proteins and fusion peptides displayed on carrier proteins. In addition, we have continued our work testing different methods and routes of administration as well as prime/boost combinations to further optimize HIV vaccine strategies. Protein immunogens with different adjuvants and in the form of nanoparticles were also tested. Several candidate vaccines that elicited promising immunogenicity data in preliminary studies are being tested further. Broadly HIV-1 neutralizing activity directed to fusion peptide (FP), which is an essential component of HIV fusion machinery, was elicited in multiple vaccine-test animal models including mouse, guinea pig and non-human primate (NHP). Based on these preclinical data, two new HIV immunogens (FP conjugated to a carrier protein and a clade C consensus trimer) were identified as vaccine candidates and GMP manufactures have been initiated. GMP manufacture of the adjuvant used in these studies, Adjuplex, has also started. Studies to understand the development of broadly neutralizing antibodies using different human immunoglobulin knock-in mice are also ongoing. These studies are testing novel immunogens designed to generate neutralizing antibodies to multiple HIV-1 vulnerable sites: the CD4 binding site, V2 apex and membrane-proximal external region (MPER). For antibody development, we have applied targeted mutations to several broadly neutralizing anti-HIV-1 antibodies (bNAbs) that have been isolated from HIV+ donors. The mutations are designed to increase breadth, potency and half-life to improve potential efficacy for therapeutic application and to decrease immunogenicity to allow for more effective and longer lasting in vivo function. There are also structure-based mutations designed to improve affinity and neutralization potency. Additionally, mutations to improve biophysical properties and manufacturability have been designed in collaboration with Just Biotherapeutics, with plans for further development and use in clinical trials. We are also working with collaborators to develop tri-specific anti-HIV-1 antibodies that combine three different anti-HIV-1 specificities in one IgG-like molecule for both HIV-1 prevention and therapy, one of which has advanced to phase I clinical trials. In another collaborative effort, we are developing improved N6-like antibodies for use in HIV-1 therapy. The treatment of AIDS with combination antiretroviral therapy (cART) remains lifelong largely because the virus persists in latent reservoirs. Elimination of latently infected cells could therefore reduce treatment duration and facilitate immune reconstitution. We have developed immunomodulatory proteins referred to as T cell engagers (TCEs) that combines the specificity of a HIV-1 broadly neutralizing antibody with that of an antibody to the CD3 component of the T-cell receptor. These TCEs could potentially help to eliminate latently infected cells and deplete the viral reservoir in HIV-1-infected individuals. In addition, we have started collaborative work to develop TCEs that activate T cells to lyse HIV-1 infected cells.