Llama Antibody Fragments Have Good Potential for Application as HIV Type 1 Topical Microbicides
Llama Antibody Fragments Have Good Potential for Application as HIV Type 1 Topical Microbicides
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DOI：
10.1089/aid.2011.0133
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发表时间：
2012-02-01
影响因子：
1.5
通讯作者：
Verrips, Theo
中科院分区：
文献类型：
--
作者：
Gorlani, Andrea;Brouwers, Joachim;Verrips, Theo
全球迫切需要预防艾滋病毒-1感染的战略。骆驼重链抗体片段(VHH)是最近被描述为有效的跨分支HIV-1进入抑制剂的一类分子。我们以一种面向应用的方式研究了基于VHH的杀微生物剂的潜力。我们发现，VHH可以在GRAS生物体酿酒酵母中廉价地大量生产，从而产生非常纯净和不含内毒素的产品。VHH在运输、储存或妇女使用过程中可能遇到的条件下非常稳定。我们开发了VHH水凝胶和压缩冻干片的活性配方，用于阴道内装置的控制释放。VHH从例如阴道环的释放情况表明，在感染时刻，该分子在粘膜部位有足够的生物利用度和保护性浓度。体外人体组织的渗透动力学表明，VHH扩散到粘膜层，通过阻断HIV受体结合部位或通过阻断粘膜中免疫细胞的受体，打开了创建第二防护层的可能性。综上所述，我们的数据表明，VHH具有生产成本低、稳定性高以及良好的释放和组织渗透特性，因此在HIV-1杀微生物剂应用中具有很高的潜力。
There is an urgent global need for preventive strategies against HIV-1 infections. Llama heavy-chain antibody fragments (VHH) are a class of molecules recently described as potent cross-clade HIV-1 entry inhibitors. We studied the potential of a VHH-based microbicide in an application-oriented fashion. We show that VHH can be inexpensively produced in high amounts in the GRAS organism Saccharomyces cerevisiae, resulting in a very pure and endotoxin free product. VHH are very stable under conditions they might encounter during transport, storage, or use by women. We developed active formulations of VHH in aqueous gel and compressed and lyophilized tablets for controlled release from an intravaginal device. The release profile of the VHH from, e. g., a vaginal ring suggests sufficient bioavailability and protective concentration of the molecule at the mucosal site at the moment of the infection. The ex vivo penetration kinetics through human tissues show that the VHH diffuse into the mucosal layer and open the possibility to create a second defense layer either by blocking the HIV receptor binding sites or by blocking the receptors of immune cells in the mucosa. In conclusion, our data show that VHH have a high potential for HIV-1 microbicide application because of their low production costs, their high stability, and their favorable release and tissue penetration properties.