HIV/AIDS Vaccine and Antibody Development

在过去的一年里，我们创造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显示的融合肽。此外，我们继续测试不同的给药方法和途径以及优质/强化组合，以进一步优化艾滋病毒疫苗策略。含有不同佐剂和纳米颗粒形式的蛋白质免疫原也进行了测试。在初步研究中获得了有希望的免疫原性数据的几种候选疫苗正在进行进一步的测试。广泛地说，针对HIV融合机制的重要组成部分融合肽(FP)的HIV-1中和活性在包括小鼠、豚鼠和非人灵长类动物(NHP)在内的多种疫苗试验动物模型中被激发。基于这些临床前数据，两种新的HIV免疫原(FP连接到载体蛋白和C分支共识三聚体)被确定为候选疫苗，GMP制造商已经启动。这些研究中使用的佐剂Adjuplex的GMP生产也已经开始。 使用不同的人类免疫球蛋白敲入小鼠来开发广谱中和抗体的研究也在进行中。这些研究正在测试新的免疫原，旨在针对多个HIV-1脆弱部位产生中和抗体：CD4结合部位、V2顶点和膜近端外部区域(MPER)。 为了开发抗体，我们将靶向突变应用于从HIV+捐赠者分离的几种广泛中和的抗HIV-1抗体(BNAbs)。这些突变旨在增加广度、效力和半衰期，以提高治疗应用的潜在疗效，并降低免疫原性，以实现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，还与Just BioTreatetics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在临床试验中使用。 我们还在与合作者合作开发三种不同的抗HIV-1抗体，这种抗体将三种不同的抗HIV-1特异性结合在一个类免疫球蛋白分子中，用于HIV-1预防和治疗，其中一种已经进入I期临床试验。 在另一项合作中，我们正在开发用于HIV-1治疗的改进的N6样抗体。 艾滋病联合抗逆转录病毒疗法(CART)的治疗仍然是终生的，这主要是因为病毒持续存在于潜伏的蓄水池中。因此，消除潜伏感染细胞可以缩短治疗时间，促进免疫重建。我们已经开发出被称为T细胞结合蛋白(TCES)的免疫调节蛋白，它结合了HIV-1广谱中和抗体和针对T细胞受体CD3成分的抗体的特异性。这些TCEs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能够激活T细胞来裂解HIV-1感染细胞的TCES。

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.