Therapeutic antibodies to treat Pneumocystis pneumonia in a nonhuman primate model of HIV infection

在 HIV 感染的非人灵长类动物模型中治疗肺孢子虫肺炎的治疗性抗体

• 批准号: 10001636
• 负责人: Jarrod Mousa
• 金额: $ 34.83万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-10 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001636
• 关键词: AIDS prevention; AIDS/HIV problem; Address; Affect; Affinity; Animals; Antibodies; Antibody Therapy; Antibody titer measurement; Antibody-mediated protection; Antigens; Award; B-Lymphocytes; Binding; Clinical; Clinical Trials; Development; Disease; Dose; Drug resistance; Enzyme-Linked Immunosorbent Assay; Exposure to; Generations; Goals; HIV; HIV Infections; HIV vaccine; Human; Humoral Immunities; Hybridomas; Immunocompromised Host; Immunoglobulin A; Immunoglobulin G; In Vitro; Incidence; Individual; Intravenous; Laboratories; Liquid substance; Lung; Macaca; Macaca mulatta; Measures; Memory B-Lymphocyte; Mentored Research Scientist Development Award; Mentors; Mentorship; Modeling; Monkeys; Monoclonal Antibodies; Morbidity - disease rate; Negative Staining; Opportunistic Infections; Outcome; Pathogenesis; Patients; Peptide Hydrolases; Peripheral Blood Mononuclear Cell; Pharmacotherapy; Phase I Clinical Trials; Pneumocystis; Pneumocystis carinii; Pneumocystis carinii Pneumonia; Prevention; Prophylactic treatment; Protein Fragment; Proteins; Pulmonary Pathology; Recovery; Research; Research Personnel; Resources; SIV; Sampling; Scientist; Serum; Structure; Technology; Testing; Therapeutic; Therapeutic antibodies; Time; Training; Translational Research; Treatment Efficacy; Trimethoprim-Sulfamethoxazole; Universities; Vaccinated; Vaccination; Vaccines; Work; alternative treatment; antiretroviral therapy; base; career development; co-infection; efficacy testing; fungus; human monoclonal antibodies; innovation; lung injury; mortality; nonhuman primate; novel; novel therapeutics; novel vaccines; pathogen; pathogenic virus; polyclonal antibody; prevent; primate development; programs; prophylactic; response; side effect; standard of care; therapeutic development; therapeutic evaluation; treatment strategy; vaccine candidate; AIDS prevention; AIDS/HIV problem; Address; Affect; Affinity; Animals; Antibodies; Antibody Therapy; Antibody titer measurement; Antibody-mediated protection; Antigens; Award; B-Lymphocytes; Binding; Clinical; Clinical Trials; Development; Disease; Dose; Drug resistance; Enzyme-Linked Immunosorbent Assay; Exposure to; Generations; Goals; HIV; HIV Infections; HIV vaccine; Human; Humoral Immunities; Hybridomas; Immunocompromised Host; Immunoglobulin A; Immunoglobulin G; In Vitro; Incidence; Individual; Intravenous; Laboratories; Liquid substance; Lung; Macaca; Macaca mulatta; Measures; Memory B-Lymphocyte; Mentored Research Scientist Development Award; Mentors; Mentorship; Modeling; Monkeys; Monoclonal Antibodies; Morbidity - disease rate; Negative Staining; Opportunistic Infections; Outcome; Pathogenesis; Patients; Peptide Hydrolases; Peripheral Blood Mononuclear Cell; Pharmacotherapy; Phase I Clinical Trials; Pneumocystis; Pneumocystis carinii; Pneumocystis carinii Pneumonia; Prevention; Prophylactic treatment; Protein Fragment; Proteins; Pulmonary Pathology; Recovery; Research; Research Personnel; Resources; SIV; Sampling; Scientist; Serum; Structure; Technology; Testing; Therapeutic; Therapeutic antibodies; Time; Training; Translational Research; Treatment Efficacy; Trimethoprim-Sulfamethoxazole; Universities; Vaccinated; Vaccination; Vaccines; Work; alternative treatment; antiretroviral therapy; base; career development; co-infection; efficacy testing; fungus; human monoclonal antibodies; innovation; lung injury; mortality; nonhuman primate; novel; novel therapeutics; novel vaccines; pathogen; pathogenic virus; polyclonal antibody; prevent; primate development; programs; prophylactic; response; side effect; standard of care; therapeutic development; therapeutic evaluation; treatment strategy; vaccine candidate

Despite tremendous efforts to develop a HIV vaccine, there is currently no vaccine for the prevention of HIV infection. With the advent of highly successful antiretroviral therapy, mortality and morbidity associated with HIV infection has been significantly reduced. Unfortunately, opportunistic infections are commonly observed among HIV-infected patients, and remain a problematic issue that must be urgently addressed. A frequently encountered HIV-associated opportunistic infection is Pneumocystis pneumonia (PCP), which is caused by the ubiquitous fungus Pneumocystis jirovecii. Although antiretroviral therapy has reduced the incidence of PCP, 30% of HIV- infected individuals will develop PCP, which can have unacceptable lethal outcomes despite current drug treatments. PCP is often a defining disease in infected patients who are unaware of their HIV infection. The goal of this K01 award is to support the transition of my research program to develop new therapeutics for opportunistic infections affecting HIV/AIDS patients, and to test these therapeutics in a nonhuman primate (NHP) model of HIV infection. My previous research has primarily focused on structural mechanisms of bacterial pathogenesis and antibody-mediated immunity to viral pathogens. Although I have been very successful in my previous training, I desire additional protected time to transition my research in an exciting and independent direction to study antibody-mediated immunity to opportunistic pathogens affecting HIV/AIDS patients, particularly incorporating NHPs, which represent the best model of HIV infection. To complete my training, I am leveraging the excellent resources at the University of Georgia NHP core, which my primary mentor Dr. Karen Norris recently established during her move to UGA. The proposed work in this application will focus on the development of therapeutic antibodies to treat PCP in a NHP model of HIV-infection. My overall hypothesis is that antibodies specific to the Pneumocystis kexin protease can effectively treat PCP. Dr. Norris has developed an excellent NHP model of HIV/PCP co-infection, and has identified a protein-based vaccine candidate (KEX1) based on the Pneumocystis kexin protease. The proposed work will combine my current expertise in antibody generation with new training in the HIV field under the guidance of Dr. Norris and my clinical mentor Dr. Alison Morris. In Specific Aim 1 I will determine if antibodies generated in response to KEX1 vaccination can effectively treat PCP. The KEX1 fragment of the Pneumocystis kexin protein was previously shown to protect against development of PCP. I will purify KEX1-specific antibodies and test the antibodies for treatment of PCP in a NHP model of HIV/PCP co-infection. In Specific Aim 2, I will leverage my expertise in human antibody generation to isolate novel human antibodies specific to the KEX1 protein. The antibodies will be characterized to identify the top candidate, and the top candidate will be tested for PCP treatment efficacy in the NHP model. I expect the top candidate will advance to clinical trials, and have high potential to serve as a therapeutic to treat PCP in HIV- infected individuals.

尽管为开发艾滋病毒疫苗而做出了巨大努力，但目前尚无预防艾滋病毒的疫苗 感染。随着非常成功的抗逆转录病毒疗法的出现，与HIV相关的死亡率和发病率 感染已大大减少。不幸的是，通常观察到机会性感染 艾滋病毒感染的患者，仍然是一个有问题的问题，必须紧急解决。经常遇到的 HIV相关的机会感染是肺炎肺炎肺炎（PCP），是由无处不在的 真菌肺炎藻菌。尽管抗逆转录病毒疗法降低了PCP的发生率，但30％的HIV- 受感染的人将开发PCP，尽管目前的药物 治疗。 PCP通常是不知道其HIV感染的受感染患者的定义疾病。目标 这项K01奖是为了支持我的研究计划的过渡，以开发新的治疗剂 影响艾滋病毒/艾滋病患者的机会主义感染，并在非人类灵长类动物（NHP）中测试这些治疗剂 HIV感染的模型。我以前的研究主要集中于细菌的结构机制 发病机理和抗体介导的对病毒病原体的免疫力。虽然我在自己的 以前的培训，我希望额外的受保护时间以令人兴奋且独立的方式过渡我的研究 研究抗体介导的对影响艾滋病毒/艾滋病患者的机会病原体免疫的方向， 特别融合了代表HIV感染最佳模型的NHP。为了完成我的培训，我是 利用佐治亚大学NHP Core的优质资源，我的主要导师Karen博士 诺里斯（Norris）最近搬到UGA期间建立了。本申请中的拟议工作将重点放在 在HIV感染模型中处理治疗PCP的治疗抗体的开发。我的总体假设是 该抗体特有的肺炎藻蛋白酶蛋白酶可以有效治疗PCP。诺里斯博士已经发展 HIV/PCP共感染的出色NHP模型，并确定了基于蛋白质的疫苗候选者（KEX1） 基于肺炎藻蛋白酶。拟议的工作将结合我目前的抗体专业知识 在诺里斯博士和我的临床导师艾莉森博士的指导下，在艾滋病毒领域进行了新的培训。 莫里斯。在特定的目标1中，我将确定响应KEX1疫苗的抗体是否可以有效 治疗PCP。先前显示出肺炎藻蛋白蛋白的Kex1片段 PCP的开发。我将纯化KEX1特异性抗体，并测试NHP中PCP治疗的抗体 HIV/PCP共同感染的模型。在特定目标2中，我将利用我在人类抗体生成方面的专业知识 分离出针对KEX1蛋白的新型人类抗体。抗体将被表征以识别 顶级候选人和最高候选人将在NHP模型中测试PCP治疗功效。我期待 顶级候选人将促进临床试验，并具有很高的潜力，可以作为治疗PCP的治疗方法。 受感染的人。