Neutralizing Nanobodies Targeting Diverse Chemokines Effectively Inhibit Chemokine Function
Neutralizing Nanobodies Targeting Diverse Chemokines Effectively Inhibit Chemokine Function
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DOI：
10.1074/jbc.m113.467969
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发表时间：
2013-08-30
影响因子：
4.8
通讯作者：
Smit, Martine J.
中科院分区：
文献类型：
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作者：
Blanchetot, Christophe;Verzijl, Dennis;Smit, Martine J.
趋化因子受体及其配体在免疫调节中起重要作用，但许多也与炎性疾病如多发性硬化、类风湿性关节炎、移植后同种异体移植物排斥以及癌症转移有关。治疗靶向趋化因子系统的大多数方法涉及用低分子量拮抗剂靶向趋化因子受体。在这里，我们描述了针对几种趋化因子的前所未有的大而多样的中和纳米抗体（单域骆驼抗体片段）的选择和表征。我们表明，针对CCL 2（MCP-1）、CCL 5（RANTES）、CXCL 11（I-TAC）和CXCL 12（SDF-1 α）的纳米抗体以高亲和力（纳摩尔浓度）结合趋化因子，从而阻断受体结合，抑制趋化因子诱导的受体活化以及趋化性。总之，我们表明，可以有效地选择中和纳米抗体，用于针对广泛的免疫和炎症疾病的有效和特异性治疗。
Chemokine receptors and their ligands play a prominent role in immune regulation but many have also been implicated in inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, allograft rejection after transplantation, and also in cancer metastasis. Most approaches to therapeutically target the chemokine system involve targeting of chemokine receptors with low molecular weight antagonists. Here we describe the selection and characterization of an unprecedented large and diverse panel of neutralizing Nanobodies (single domain camelid antibodies fragment) directed against several chemokines. We show that the Nanobodies directed against CCL2 (MCP-1), CCL5 (RANTES), CXCL11 (I-TAC), and CXCL12 (SDF-1 alpha) bind the chemokines with high affinity (at nanomolar concentration), thereby blocking receptor binding, inhibiting chemokine-induced receptor activation as well as chemotaxis. Together, we show that neutralizing Nanobodies can be selected efficiently for effective and specific therapeutic treatment against a wide range of immune and inflammatory diseases.