Project 2: Limiting anti-drug antibodies

项目2：限制抗药物抗体

基本信息

批准号：
10381478
负责人：
Ronald C Desrosiers
金额：
$ 31.62万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-15 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10381478
关键词：
Address Animals Antibodies Antibody Response Antibody Therapy Antigen Targeting Antigens Antiviral Agents Binding Bispecific Antibodies Blood specimen Capsid Cells Collection CpG dinucleotide Data Development Dose Ensure Erythrocytes Funding Goals HIV HIV-1 Human Immune Tolerance Immunity Immunization Immunoglobulin Constant Region Individual Infection Ingestion Injections Intramuscular Injections Light Literature Macaca Macaca mulatta Mediating Monitor Monkeys Monoclonal Antibodies Mus Mutation Oral Paper Persons Pharmaceutical Preparations Pharmacotherapy Program Research Project Grants Prophylactic treatment Protocols documentation Publications Publishing Regimen Resistance Rhesus Safety Technology Testing Therapy trial Transgenes United States National Institutes of Health Viral Load result Virus Replication adeno-associated viral vector arm base design efficacy evaluation expectation experimental study human monoclonal antibodies immunogenic oral tolerance oral tolerization promoter simian human immunodeficiency virus vector

项目摘要

PROJECT SUMMARY (Project 2 – Limiting anti-drug antibodies against AAV-delivered bNAbs) Given the remarkable collection of human monoclonal antibodies with potent neutralizing activity against a broad range of HIV-1 isolates (bNAbs), it has become possible to envision long-term delivery of a combination of such antibodies as a means for achieving stringent, long-term virological control in the absence of continuing antiviral drug therapy. In preliminary data and recently published paper in Immunity, we shown that sustained AAV-mediated expression of two bNAbs, 10-1074 and 3BNC117, introduced 86 weeks after an untreated SHIV-AD8 infection resulted in robust long-term suppression of viral replication for over three years. This monkey has been referred to as “the Miami monkey”. We also nonetheless show that consistent delivery of bNAbs using AAV has been severely hampered by anti-drug antibody (ADA) responses to the bNAb in the majority of macaques. Although the broad antibody-like immunoadhesin eCD4-Ig is less immunogenic, it also raises ADA that could potentially limit its efficacy or its safety in humans. This project is therefore committed to finding approaches that can effectively and practically suppress ADA responses to an antibody, using the immunogenic bNAb 3BCN117 as our primary test case. In this project we will evaluate three approaches for doing so: (1) elimination of CpG motifs in the transgene, (2) oral tolerization, and (3) tolerization with a bispecific antibody that coordinates bNAb binding to erythrocytes. In addition, we will assist in evaluating the ADA responses from different capsids and promoters (Project 1), and those from an AAV transgene whose expression has been delayed by four months (Project 4). We will then use the best combination of these approaches and AAV- expressed bNAbs to establish and characterize functional cures in ART-treated and untreated rhesus macaques. This project will therefore address a central challenge to the use AAV-expressed bNAbs for HIV-1 prophylaxis and therapy.

项目摘要（项目2 - 限制抗药物抗体针对AAV提供的BNABS）鉴于人类单克隆抗体的显着收集，具有潜在的中和活性针对A 广泛的HIV-1分离株（BNABS），已经有可能设想长期交付这种抗体作为在实现严格的长期病毒学控制的手段的结合缺乏持续的抗病毒药物治疗。在初步数据中，最近发表的论文免疫力，我们表明两个BNAB的持续AAV介导的表达，10-1074和3bnc117，未经治疗的SHIV-AD8感染后86周引入，导致了强大的长期抑制病毒复制超过三年。这只猴子被称为“迈阿密猴子”。我们也是尽管如此表明，使用AAV持续交付的BNAB已受到反毒品的严重阻碍大多数猕猴中对BNAB的抗体（ADA）反应。虽然宽抗体状免疫粘附素ECD4-Ig的免疫原性较低，它也会提高ADA，可能会限制其有效性或它在人类中的安全。因此，该项目致力于寻找可以有效的方法实际上，使用免疫原性BNAB 3BCN117抑制ADA对抗体的反应主要测试用例。在这个项目中，我们将评估三种方法：（1）消除CPG 转化中的基序，（2）口服耐受性，（3）用双特异性抗体的耐受性，该抗体坐标 BNAB与红细胞结合。此外，我们将协助评估来自不同的ADA响应衣壳和启动子（项目1），以及来自AAV转换的人的表达方式延迟四个月（项目4）。然后，我们将使用这些方法的最佳组合和AAV- 表达的bnabs以建立和表征艺术治疗和未经处理的恒河猴中的功能疗法猕猴。因此，该项目将解决使用AAV表达的BNAB的核心挑战 HIV-1预防和治疗。