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Optimizing AAV delivery of bNAbs for HIV prevention

优化 AAV 的 bNAb 递送以预防 HIV

基本信息

批准号：
10403278
负责人：
Matthew Ryan Gardner
金额：
$ 90.67万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-11-24 至 2026-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10403278
关键词：
AIDS prevention Address Antibodies Antibody Formation Antibody Response Antibody-Producing Cells Area Binding CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CTLA4-Ig Capsid Clinical Clinical Trials Combined Modality Therapy DNA cassette Data Dependovirus Development Disease Dose Effectiveness Engineering Evaluation Foundations Future Gene Transduction Agent Goals HIV-1 HIV-1 vaccine Immune Immune Targeting Immune response Immune system Immunity Individual Infection Infusion procedures Intramuscular Investigation Lead Macaca Macaca mulatta Measurement Mediating Monoclonal Antibodies Mus Muscle Muscle Cells Ovalbumin Participant Pathway interactions Patients Pharmaceutical Preparations Pilot Projects Plasma Populations at Risk Production Recombinants Regulatory T-Lymphocyte SIV Serum System T-Lymphocyte Therapeutic Time Transgenes Update Vaccines Variant adeno-associated viral vector antiretroviral therapy cellular transduction cost detection limit gene therapy immune checkpoint improved inhibitor neutralizing antibody nonhuman primate novel novel strategies prevent prevention clinical trial programmed cell death ligand 1 programmed cell death protein 1 promoter protective efficacy research clinical testing simian human immunodeficiency virus transgene expression transmission process vector

项目摘要

PROJECT SUMMARY HIV-1 broadly neutralizing antibodies (bNAbs) are currently under clinical evaluation for their ability to prevent transmission. Until a conventional vaccine is realized, repetitive dosing of a bNAb would be necessary to maintain protective antibody concentrations. An alternative to passive infusion of bNAbs is to use adeno- associated virus (AAV) vectors that can turn muscles into antibody production factories. This one-time treatment would have clear cost advantages over the continuous production, purification, and administration of recombinant monoclonal antibodies. However, host immune responses limit the efficacy of AAV vectors. CD8+ T cell clearance of AAV transduced muscle cells limits the total number of cells producing the antibody, and pre-existing immunity to AAV capsids limit the number of possible individuals that can receive AAV vectors. We and others have previously shown that host immune responses are detrimental to AAV-delivered HIV-1 antibodies resulting in low to no detectable serum concentrations. Thus, overcoming the host immune response to the AAV vector and expressed transgene is critical for future evaluation of AAV-delivered antibody studies in non-human primates. One area of investigation for limiting a host immune response would be to utilize immune checkpoints that regulate immune system pathways. To this end, in a pilot study, we have observed about a 21-fold increase in concentrations of an HIV-1 antibody in rhesus macaques when macaques were co-inoculated with an AAV vector encoding rhesus macaque PD-L1. PD-L1 functions in binding T cell expressed PD-1 to inhibit the cytolytic and degranulation functions. It also helps in the development of regulatory T cells. Thus, we hypothesize that expression of PD-L1 on muscle cells transduced by AAV vectors to express antibodies will avoid T cell clearance and maintain expression of the antibody. Here we seek to demonstrate that co-inoculation of vectors encoding PD-L1 will result in serum concentrations of a bNAb that will protect rhesus macaques from repetitive, low-dose SHIV challenges. Additionally, we will develop this system by evaluating strategies to reduce the dose of AAV vector. Furthermore, we will engineer AAV transgene cassettes and assess novel a novel AAV capsid for increasing expression from intramuscular inoculation. Together, the results from these studies will provide a foundation for AAV gene therapy studies in non-human primates as well as lead to the development of novel AAV vectors for expressing HIV-1 bNAbs.

项目总结