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Antibody-based eradication of HIV from the CNS reservoirs

基于抗体的中枢神经系统病毒库消除艾滋病毒

基本信息

批准号：
9570099
负责人：
Chen Sabrina Tan
金额：
$ 42.44万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-26 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9570099
关键词：
Animals Antibodies Binding Bispecific Antibodies Blood Blood - brain barrier anatomy Brain Cells Clinical Trials Collaborations Data Detection Development Engineering Environment Evolution Funding Generations Goals HIV HIV-associated neurocognitive disorder Human Immune response Immunoglobulin G Immunoglobulins Immunology In Vitro Incidence Infection Inflammation Inflammatory Response Intravenous Intravenous infusion procedures Knowledge Macaca mulatta Mediating Methods Monkeys Monoclonal Antibodies Neuraxis Neurosciences Outcome Patients Penetration Phase Plasma Primary Infection Production Public Health Research Risk SIV Safety Seeds TFRC gene Technology Testing Toxic effect Treatment-related toxicity Viral Viral Load result Viral reservoir Virus Virus Replication Work antiretroviral therapy arm base brain parenchyma brain tissue cohort efficacy testing experimental study improved neutralizing antibody neutralizing monoclonal antibodies nonhuman primate novel novel therapeutic intervention novel therapeutics receptor receptor binding response safety testing side effect simian human immunodeficiency virus tool transcytosis

项目摘要

Despite successful control of HIV with combined antiretroviral therapy (cART), HIV-infected patients continue to harbor HIV in their brain and are at risk for HIV-associated neurocognitive disorders (HAND). This is in part due to the incomplete CNS penetrations by cART. However, cART toxicity to the brain tissue is also associated with HAND. Therefore, novel therapy is necessary to treat HIV in the CNS without causing toxicity. Recently, a new broadly neutralizing monoclonal antibody (mAb) against HIV, PGT121, was shown to achieve control of viral replication in the blood of simian human immunodeficiency virus (SHIV)-infected Rhesus monkeys. However, only limited quantity of PGT121 penetrates through the blood-brain-barrier (BBB); and it is also not known if PGT121 retains its functions in the CNS environment. Our overall goal is to reduce viral load in the CSN by re-engineer PGT121 for better penetration through the BBB. We will create a bispecific antibody where PGT121 is one arm of the antibody and the other arm binds the human transferrin receptor (HTfR) on the BBB to facilitate active transcytosis (PGT121/anti-HTfR Ab). The central hypothesis is that intravenous infusion with PGT121/anti-HTfR Ab will specifically target HIV in the CNS. Our Preliminary Data demonstrated distinct CSF IgG profile, detection of simian immunodeficiency virus (SIV) in the brain early after intrarectal infection in rhesus monkeys, and that less than 0.2% of intravenously infused PGT121 enters the CSF, which is below the threshold for efficacy. We posit that re-engineering PGT121 as a bispecific antibody (PGT121/anti-HTfR Ab) to efficiently across the BBB will treat HAND by reducing viral load without the cART-associated toxicity. We will test this hypothesis by pursuing three specific aims: 1.) Re-engineer mAb PGT121 as a bispecific Ab for improved CNS penetration. 2.) Determine preliminary efficacy and safety of bispecific PGT121/anti-HTfR Ab in SHIV-infected rhesus monkeys. 3.) Reduce SHIV replication in CNS reservoirs of infected rhesus monkeys with bispecific PGT121/anti- HTfR Ab. To achieve these, the Tan lab will continue our ongoing collaboration with the Reimann lab in generating and testing the bispecific antibody PGT121/anti-HTfR Ab in Aim 1. The non-human primate studies in Aims 2 and 3 were developed and will be carried out in collaboration between the Tan and Barouch labs. The development of novel tools such as the bispecific antibody will pave the way for the discovery of new therapeutics for eradication of HIV from the CNS. This proposed work will expand our understanding of antibody-mediated responses within the CNS, and create new therapeutic interventions targeting HIV in the CNS.

尽管联合抗逆转录病毒疗法（cART）成功地控制了艾滋病毒，但艾滋病毒感染患者仍在继续