Arming Neutrophils for the Destruction of HIV by Anti-HIV Antibody

通过抗 HIV 抗体武装中性粒细胞来破坏 HIV

• 批准号: 7667733
• 负责人: Lisa A Cavacini
• 金额: $ 39.51万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7667733
• 关键词: Address; Anti-Retroviral Agents; Antibodies; Antibody Formation; Binding; Binding Sites; Bispecific Antibodies; Blood Circulation; Cell-Mediated Cytolysis; Cells; Chronic; Combined Modality Therapy; Drug Kinetics; Effectiveness; Effector Cell; Engineering; Ensure; Epitopes; Evolution; Fc domain; HIV; HIV Antibodies; HIV Envelope Protein gp120; HIV Infections; Half-Life; Human; IgA receptor; Immune system; Immunoglobulin G; Immunotherapeutic agent; Immunotherapy; Improve Access; In Vitro; Individual; Infection; Infection prevention; Leukocytes; Link; Measures; Mediating; Modeling; Modification; Monoclonal Antibodies; Pathogenesis; Prevention; Production; Property; Recycling; Resistance; Structure; Structure-Activity Relationship; Testing; Tissues; Upper arm; V3 Loop; Viral; Viral Load result; Virus; Virus Diseases; anti-IgA; antigen binding; base; design; disorder control; effective therapy; human monoclonal antibodies; immunoreactivity; improved; in vivo; innovation; killings; neonatal Fc receptor; neutralizing antibody; neutrophil; nonhuman primate; novel; public health relevance; success; transmission process

DESCRIPTION (provided by applicant): Despite a robust antibody response to HIV following infection, the neutralizing antibody response is poor and ineffective at controlling disease; however, specific antibodies have been shown effective at preventing infection in non-human primate models. Thus, novel immunotherapeutic approaches are necessary for antibodies to be useful in treating HIV infection. In addition to the direct neutralization of virus by antibodies, there is a broader potential for antibody mediated inhibition of HIV by targeting HIV to effector cells. We hypothesize that directing HIV, using bispecific antibodies incorporating select anti-HIV antibodies and anti-IgA receptor (CD89) antibody, to neutrophils will effectively destroy HIV and HIV infected cells. Neutrophils, which are the most predominant type of white blood cells, are very efficient at mediating cell cytotoxicity as well as relatively resistant to infection with HIV. Therefore, they represent a significant arsenal against infection if they can be directed and armed to destroy HIV and infected cells. Based on structure-function relationships, we propose to study bispecific antibodies generated using three different human anti-HIV monoclonal antibodies. IgG1b12 is a neutralizing antibody with a unique structure giving it improved access to the CD4 binding site of virus. F425B4e8 is also a potent neutralizing antibody, to the V3 loop, which is relatively accessible on virus and infected cells. Finally, given the exposure of the well-conserved cluster I epitope on gp41, recognized by the antibody F240, we also propose to determine the ability of a bispecific antibody, with broad anti-HIV reactivity, to destroy HIV. The use of F240 allows clear differentiation between inherent neutralization activity from neutrophil directed killing. Bispecific antibodies will be tested for the ability to stimulate neutrophil effector functions and the destruction of HIV. Bispecific antibody constructs will be prepared as single chain Fv (scFv) antibodies. However, since the short half-life of scFv antibodies in vivo may be limiting, we also propose to generate constructs with a modified Fc domain. It is expected that some constructs will be more effective than others based in part on epitope exposure. Constructs will also be tested for bystander killing of uninfected cells with bound gp120. Identification of constructs active in vitro at inhibiting viral production, with minimal bystander killing, will allow for further testing in non-human primate models of infection. These studies represent an important advance in treating chronic HIV infection. D PUBLIC HEALTH RELEVANCE: espite the success of combination therapy with anti-retroviral agents, additional means of therapy are required for the treatment of HIV infection. Since antibodies that directly inhibit virus are either ineffective or rare in vivo, we propose to design antibodies to target HIV to cells for destruction. These studies represent an important advance in treating chronic HIV infection.

描述（由申请人提供）：尽管在感染后对HIV有强大的抗体反应，但中和抗体反应较差，在控制疾病方面无效；然而，在非人类灵长类动物模型中，特异性抗体已被证明在预防感染方面有效。因此，新的免疫治疗方法对于抗体治疗HIV感染是必要的。除了通过抗体直接中和病毒外，通过将HIV靶向效应细胞，抗体介导的HIV抑制具有更广泛的潜力。我们假设，使用双特异性抗体（包括选定的抗HIV抗体和抗iga受体（CD89）抗体）将HIV引导到中性粒细胞将有效地破坏HIV和HIV感染细胞。中性粒细胞是最主要的白细胞类型，在介导细胞毒性方面非常有效，并且对HIV感染具有相对的抵抗力。因此，如果它们能够被引导和武装起来摧毁HIV和被感染的细胞，它们就代表了对抗感染的重要武器库。基于结构-功能关系，我们建议研究用三种不同的人抗hiv单克隆抗体生成的双特异性抗体。igg1112是一种具有独特结构的中和抗体，使其能够更好地进入病毒的CD4结合位点。F425B4e8也是一种有效的中和抗体，针对V3环，V3环在病毒和感染细胞上相对容易接近。最后，鉴于暴露在gp41上保守的簇I表位，被抗体F240识别，我们也提出确定具有广泛抗HIV反应性的双特异性抗体破坏HIV的能力。使用F240可以明确区分固有中和活性和中性粒细胞定向杀伤。将测试双特异性抗体刺激中性粒细胞效应功能和破坏艾滋病毒的能力。双特异性抗体构建体将被制备为单链Fv抗体。然而，由于scFv抗体在体内的半衰期较短，因此我们也建议产生具有修饰Fc结构域的构建体。预计一些结构将比其他结构更有效，部分基于表位暴露。构建体也将测试用结合的gp120杀死未感染细胞的旁观者。鉴定出体外抑制病毒产生的活性构建体，并使旁观者死亡最小，将允许在非人类灵长类动物感染模型中进行进一步测试。这些研究在治疗慢性HIV感染方面取得了重要进展。D