Tuning Fc-effector functions of HIV-specific antibodies

说明(申请人提供)：除了中和作用外，抗体(Abs)还是适应性免疫系统和先天免疫系统之间的重要桥梁，因为它们通过控制和指示先天免疫系统如何清除它们所结合的抗原来调节它们的活动。抗体为天然免疫系统提供特异性的能力受到以下因素的严格调控：a)抗体的同种类型，b)抗体重链CH2区内天冬酰胺297处的糖链结构。虽然抗体工程通过优化抗体多糖结构来治疗恶性肿瘤和自身免疫性疾病，彻底改变了单抗的疗效，但关于如何在体内通过疫苗接种抗体糖基化来增强对传染病的保护作用，人们知之甚少。越来越多的证据表明，抗体-葡聚糖的自然调节发生在炎症条件下，显著改变抗体的活性。然而，关于调节抗体糖基化的机制(S)，免疫系统如何自然地利用这种体液活动，以及如何利用它来增强抗体抗病毒活性，人们知之甚少。鉴于先天免疫招募抗体可在早期艾滋病毒感染中检测到，富含长期非进展性抗体，并与增强的艾滋病毒控制相关，PI假设，通过体内特定的糖链，可以从自然感染中学习诱发先天免疫招募抗体的“规则”。因此，在这项建议中，私人投资公司将 钻研糖基化的B细胞生物学，以确定a)在自发控制者中抗体糖基化被自然调节的机制，b)调控B细胞糖基化的机制，以及c)确定免疫后抗体糖基化是否被“记住”。总之，从这些研究中获得的知识将为调节抗体效应器功能的机制提供关键的见解，并将导致产生新的策略来增强疫苗诱导的抗体的抗病毒活性。

DESCRIPTION (provided by applicant): In addition to neutralization, antibodies (Abs) represent a critical bridge between the adaptive and innate immune system, as they mediate their activity by harnessing and instructing the innate immune system on how to clear the antigen to which they are bound. The ability of Abs to provide specificity to the innate immune system is tightly regulated by: a) the isotype of the antibody (Ab), and b) the glycan structure attached at the asparagine 297 within the CH2-domain of the Ab heavy chain. While Ab engineering has revolutionized the efficacy of monoclonal Abs through the optimization of Ab glycan structures for the treatment of malignancies and autoimmune disorders, little is known about how Ab glycosylation may be harnessed in vivo through vaccination to provide enhanced protection against infectious diseases. Accumulating evidence suggests that natural modulation of the Ab-glycan occurs under inflammatory conditions, dramatically altering the activity of an Ab. However, little is known about the mechanism(s) that regulates Ab-glycosylation, how the immune system naturally exploits this humoral activity, and how it may be harnessed to potentiate Ab-antiviral activity. Given that innate immune recruiting Abs are detectable in early HIV infection, are enriched in long-term non-progressors, and correlate with enhanced HIV control, the PI hypothesizes that the "rules" for eliciting innate immune recruiting Abs, with specific glycans in vivo, can be learned from natural infection. Thus in this proposal, the PI will hone in on the B cell biology of glycosylation to define a) the mechanism by which Ab-glycosylation is tuned naturally in spontaneous controllers, b) define the mechanism by which glycosylation in B cells is regulated, and c) determine whether Ab-glycosylation is "remembered" following immunization. Together, knowledge gained from these studies will provide critical insights into the mechanism by which Ab-effector functions are regulated, and will lead to the generation of new strategies to potentiate the antiviral activity of vaccine inducd Abs.