Overcoming the Constraints of Anti-HIV/CD89 Bispecific Antibodies That Limit Viral Inhibition.
Overcoming the Constraints of Anti-HIV/CD89 Bispecific Antibodies That Limit Viral Inhibition.
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DOI：
10.1155/2016/9425172
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发表时间：
2016
影响因子：
4.1
通讯作者：
Cavacini LA
中科院分区：
文献类型：
--
作者：
Yu X;Duval M;Gawron M;Posner MR;Cavacini LA
创新策略是必要的，以最大限度地提高艾滋病毒中和抗体的临床应用。为此，构建了人抗体F240和抗体14 A8的双特异性构建体，所述人抗体F240与效应细胞上的高度保守的gp 41表位反应，所述抗体14 A8与效应细胞上的伊加受体（CD 89）反应。采用GGGGS连接子将两条单链抗体连接起来，构建了F240 × 14 A8双特异性单链抗体分子。尽管与HIV gp 41和中性粒细胞具有免疫反应性，但这种双特异性scFv未能抑制HIV感染。这与使用这两种抗体的Fab的化学缀合物的病毒抑制形成鲜明对比。因此，我们构建了两种新型Fab样双特异性抗体分子，其中心是IgG 1 CH 1结构域或CH 1铰链结构域与F240 scFv的C-末端的融合以及κ链CL结构域与14 A8 scFv的C-末端的融合。两种Bi-FaB抗体通过武装嗜中性粒细胞以抑制HIV感染，对多个进化枝B和进化枝C分离株显示出显著的ADCVI活性。本研究中提出的方法对于HIV免疫治疗是独特的，因为中和的动力是武装和动员PMN来破坏HIV和HIV感染的细胞。
Innovative strategies are necessary to maximize the clinical application of HIV neutralizing antibodies. To this end, bispecific constructs of human antibody F240, reactive with well-conserved gp41 epitope and antibody 14A8, reactive with the IgA receptor (CD89) on effector cells, were constructed. A F240 × 14A8 bispecific single chain variable region (scFv) molecule was constructed by linking two scFvs using a conventional GGGGS linker. Despite immunoreactivity with HIV gp41 and neutrophils, this bispecific scFv failed to inhibit HIV infection. This is in sharp contrast to viral inhibition using a chemical conjugate of the Fab of these two antibodies. Therefore, we constructed two novel Fab-like bispecific antibody molecules centered on fusion of the IgG1 CH1 domain or CH1-hinge domain to the C-terminus of F240scFv and fusion of the kappa chain CL domain to the C-terminus of 14A8scFv. Both Bi-Fab antibodies showed significant ADCVI activity for multiple clade B and clade C isolates by arming the neutrophils to inhibit HIV infection. The approach presented in this study is unique for HIV immunotherapy in that the impetus of neutralization is to arm and mobilize PMN to destroy HIV and HIV infected cells.