Project 2: Limiting anti-drug antibodies

项目2：限制抗药物抗体

• 批准号: 10625286
• 负责人: Ronald C Desrosiers
• 金额: $ 40.3万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625286
• 关键词: Acceleration; 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; design; efficacy evaluation; expectation; experimental study; human monoclonal antibodies; immunogenic; oral tolerance; oral tolerization; promoter; simian human immunodeficiency virus; vector

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.

项目总结（项目2-限制针对AAV递送的bNAb的抗药抗体） 考虑到具有有效中和活性的人单克隆抗体的显著集合， 广泛的HIV-1分离株（bNAb），已经有可能设想长期递送 本发明提供了这种抗体的组合作为在感染中实现严格、长期病毒学控制的手段。 没有持续的抗病毒药物治疗。在初步数据和最近发表的论文中， 在免疫方面，我们显示了持续的AAV介导的两种bNAb，10 - 1074和3BNC117的表达， 在未经治疗的SHIV-AD8感染后86周引入， 病毒复制了三年多这只猴子被称为"迈阿密猴"。我们也 然而，这些研究表明，使用AAV的bNAb的一致递送受到抗药物的严重阻碍。 抗体（ADA）对大多数猕猴中的bNAb的应答。虽然广泛的抗体样 免疫粘附素eCD 4-IG免疫原性较低，也会产生ADA，可能会限制其疗效，或 在人类中的安全性。因此，该项目致力于寻找能够有效和 实际上抑制ADA对抗体的反应，使用免疫原性bNAb 3BCN 117作为我们的 主要测试案例在这个项目中，我们将评估三种方法来做到这一点：（1）消除CpG （2）口服耐受化，和（3）用双特异性抗体的耐受化，所述双特异性抗体与转基因中的基序协调， bNAb与红细胞结合。此外，我们还将协助评估来自不同国家的ADA响应。 衣壳和启动子（项目1），以及来自其表达已被逆转录的AAV转基因的那些。 延迟4个月（项目4）。然后，我们将使用这些方法和AAV的最佳组合- 表达bNAb，以确定和表征ART治疗和未治疗恒河猴的功能性治愈 猕猴因此，该项目将解决使用AAV表达的bNAb用于 HIV-1预防和治疗。