Chen Weizao, Dimitrov Dimiter S
Protein Interactions Group, CCRNP, CCR, NCI-Frederick, NIH, Frederick, MD 21702-1201, USA.
Curr Opin HIV AIDS. 2009 Mar;4(2):112-7. doi: 10.1097/COH.0b013e328322f95e.
To summarize the in-vivo efficacy of neutralizing human monoclonal antibodies against HIV-1, to discuss the recent finding that an engineered human antibody VH domain, domain antibody (dAb), exhibits exceptionally potent and broadly cross-reactive neutralizing activity against HIV-1 primary isolates by targeting a hidden conserved epitope that is not accessible by larger antibodies and to suggest the possibility of developing a novel class of potent HIV-1 inhibitors based on human dAbs.
HIV-1 has evolved a number of strategies to evade humoral immunity, including protecting highly conserved and important structures from the access of antibodies generated by the immune system. We have recently demonstrated that a human dAb (size approximately 15 kDa), m36, targets a highly protected structure on the HIV-1 envelope glycoprotein (Env), gp120, and exhibits exceptionally potent neutralizing activity against HIV-1 primary isolates, with potency on average higher than those of the broadly cross-reactive neutralizing human monoclonal antibody, scFv m9, and the inhibitory peptide, C34.
The efficacy of the anti-HIV-1 therapy is significantly compromised by resistance to the currently used US Food and Drug Administration-approved antiretroviral drugs, which suggests an urgent need to develop novel classes of potent inhibitors. Several broadly cross-reactive neutralizing human monoclonal antibodies are highly effective against HIV-1 infection in vitro, but their administration to HIV-1-infected humans has only resulted in modest antiviral effects. Engineered human antibody fragments, dAbs, could be more potent because of their small size (about 10-fold smaller than that of an IgG), which allows targeting of highly conserved structures on the HIV-1 envelope glycoprotein that are not accessible by full-size antibodies and relatively efficient penetration into the densely packed lymphoid environment in which HIV-1 mostly replicates and spreads.
总结针对HIV-1的人源中和单克隆抗体的体内疗效，讨论一项最新发现，即一种经过工程改造的人源抗体VH结构域，即结构域抗体（dAb），通过靶向一种较大抗体无法触及的隐蔽保守表位，对HIV-1原始分离株表现出异常强效且广泛交叉反应的中和活性，并提出基于人源dAb开发新型强效HIV-1抑制剂的可能性。
HIV-1已进化出多种逃避体液免疫的策略，包括保护高度保守且重要的结构不被免疫系统产生的抗体接触。我们最近证明，一种人源dAb（大小约为15 kDa），即m36，靶向HIV-1包膜糖蛋白（Env）gp120上一个高度受保护的结构，并对HIV-1原始分离株表现出异常强效的中和活性，其效力平均高于广泛交叉反应的中和人源单克隆抗体scFv m9和抑制肽C34。
目前美国食品药品监督管理局批准的抗逆转录病毒药物产生的耐药性严重损害了抗HIV-1治疗的疗效，这表明迫切需要开发新型强效抑制剂。几种广泛交叉反应的中和人源单克隆抗体在体外对HIV-1感染具有高效性，但将它们施用于HIV-1感染的人类仅产生了适度的抗病毒效果。经过工程改造的人源抗体片段dAb可能因其小尺寸（比IgG小约10倍）而更具效力，这使得它们能够靶向HIV-1包膜糖蛋白上全尺寸抗体无法触及的高度保守结构，并相对有效地穿透HIV-1主要复制和传播的密集淋巴环境。
