Addendum to HIV Active and Passive Clinical Material Manufacturing

HIV 主动和被动临床材料制造附录

• 批准号: 8947161
• 负责人: DAVID HEIMBROOK
• 金额: $ 1000万
• 依托单位: LEIDOS BIOMEDICAL RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-26 至 2018-09-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8947161
• 关键词: Addendum; Advanced Development; Antibodies; Antigens; Area; Binding; Breast Feeding; Characteristics; Cleaved cell; Clinical; Clinical Trials; Cyclic GMP; Data; Development; Epitopes; Generations; HIV; HIV Infections; HIV vaccine; HIV-1; Half-Life; Immune; Individual; Infant; Methods; Mothers; Newborn Infant; Prevention; Prevention therapy; Process; Production; Prophylactic treatment; Recombinants; Sexual Transmission; Structure; Technology; Technology Transfer; Therapeutic; TimeLine; Vaccines; clinical material; efficacy trial; improved; neutralizing antibody; novel; prevent; product development; research clinical testing; success; transmission process; vaccine candidate; vaccine development; vaccine efficacy

PROJECT ABSTRACT The VRC's highest priority remains development of a vaccine or other immune modulator that prevents HIV acquisition. The overarching objectives of this task include activities to produce HIV candidate vaccines or broadly neutralizing antibodies for passive prevention trials and to develop novel product development technologies to enable faster timelines to clinical trial for HIV vaccine candidates. OBJECTIVE 1: HIV VACCINE DEVELOPMENT BACKGROUND No vaccine is currently available to prevent HIV infection. The moderate protection afforded in one vaccine efficacy trial was associated with the induction of antibodies to the V1V2 region of HIV envelope. A stabilized soluble HIV env trimer is antigenically preferable to current un­cleaved trimers and should serve as an improved immunogen to stimulate antibodies to the major neutralization epitopes, including V1V2 antibodies. Thus, the ability to manufacture a stabilized trimer will advance the development of HIV vaccines, used alone or in combination with existing vaccine platforms, by accelerating clinical testing of multiple vaccine strategies that are currently stalled for lack of an appropriate HIV env immunogen. PROJECT REQUIREMENTS Despite the development and structural determination of a soluble trimer of HIV Env gp140 (BGSOS SOSIP664) difficulties in manufacturability and stability hamper its clinical development. Using data from new atomic level crystal structures, the VRC has determined a method for creating a gp140 trimer with improved stability and manufacturability. This trimer binds all classes of broadly neutralizing antibodies, but not non-neutralizing antibodies. In addition, we have determined optimal sequence characteristics for the potential to elicit VlV2 antibodies. 1/ The VRC requests cGMP manufacturing and technology transfer* support for a recombinant stabilized gp140 trimer vaccine candidate for the VRC to advance to clinical trials. OBJECTIVE 2: HIV MPER BNABS FOR PREVENTION, THERAPY, OR CURE BACKGROUND Production and clinical testing of long half-life bNAbs targeting multiple neutralizing epitopes will improve the coverage and likely success of bNAbs for prophylaxis, therapy, and cure strategies. Advances in this area will broadly impact strategies for: 1) prevention of transmission from HIV-1 infected mothers to newborn and breastfeeding infants; 2) prevention of HIV infection by sexual transmission; and 3) therapeutic application in HIV-1 infected individuals (including elimination of the latent reservoir). PROJECT REQUIREMENTS 1/ The VRC requests cGMP manufacturing and technology transfer support for 1st generation MPER bNAb candidates for the VRC to advance to clinical trials. 2/ The VRC requests cGMP manufacturing and technology transfer* support for 2nd generation MPER bNAb candidates, and for additional novel broadly neutralizing candidates, potentially including bi-specific or other antibody approaches, for the VRC to advance to clinical trials *All process development activity will be independently undertaken by the VRC. However, general technology transfer activities, involving potential process transfer to the VCMP, are included in the request for support.

项目摘要 VRC 的首要任务仍然是开发疫苗或其他免疫调节剂来预防艾滋病毒感染。该任务的总体目标包括生产用于被动预防试验的艾滋病毒候选疫苗或广泛中和抗体的活动，以及开发新颖的产品开发技术，以加快艾滋病毒候选疫苗临床试验的时间表。 目标 1：艾滋病毒疫苗的开发 背景 目前没有疫苗可以预防艾滋病毒感染。一项疫苗功效试验中提供的适度保护与 HIV 包膜 V1V2 区域抗体的诱导有关。稳定的可溶性 HIV 包膜三聚体在抗原性上优于目前未切割的三聚体，并且应作为改进的免疫原来刺激针对主要中和表位的抗体，包括 V1V2 抗体。因此，制造稳定三聚体的能力将通过加速目前因缺乏适当的 HIV 包膜免疫原而陷入停滞的多种疫苗策略的临床测试，从而促进单独使用或与现有疫苗平台组合使用的 HIV 疫苗的开发。 项目要求 尽管 HIV Env gp140 (BGSOS SOSIP664) 的可溶性三聚体已得到开发和结构测定，但可制造性和稳定性方面的困难阻碍了其临床开发。利用新原子级晶体结构的数据，VRC 确定了一种创建 gp140 三聚体的方法，该三聚体具有更高的稳定性和可制造性。该三聚体结合所有类别的广泛中和抗体，但不结合非中和抗体。此外，我们还确定了可能引发 VIV2 抗体的最佳序列特征。 1/ VRC 要求为 VRC 的重组稳定 gp140 三聚体候选疫苗提供 cGMP 制造和技术转让*支持，以推进临床试验。 目标 2：用于预防、治疗或治愈的 HIV MPER BNABS 背景 针对多个中和表位的长半衰期 bNAb 的生产和临床测试将提高 bNAb 在预防、治疗和治愈策略中的覆盖范围和可能的成功率。该领域的进展将广泛影响以下策略：1）预防 HIV-1 感染母亲向新生儿和母乳喂养婴儿传播； 2）预防通过性传播感染艾滋病毒； 3) HIV-1感染者的治疗应用（包括消除潜伏病毒库）。 项目要求 1/ VRC 请求为 VRC 推进临床试验的第一代 MPER bNAb 候选药物提供 cGMP 生产和技术转让支持。 2/ VRC 要求为第二代 MPER bNAb 候选药物以及其他新型广泛中和候选药物（可能包括双特异性或其他抗体方法）提供 cGMP 制造和技术转让*支持，以便 VRC 进入临床试验 *所有工艺开发活动将由 VRC 独立承担。然而，一般技术转让活动，包括可能向 VCMP 转让工艺，都包含在支持请求中。