定向进化具有广谱交叉反应性的趋化因子阻断抗体在关节炎中的疗效。

Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis.

机构信息

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA.

Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA.

出版信息

Nat Commun. 2018 Apr 13;9(1):1461. doi: 10.1038/s41467-018-03687-x.

Chemokine receptors typically have multiple ligands. Consequently, treatment with a blocking antibody against a single chemokine is expected to be insufficient for efficacy. Here we show single-chain antibodies can be engineered for broad crossreactivity toward multiple human and mouse proinflammatory ELR CXC chemokines. The engineered molecules recognize functional epitopes of ELR CXC chemokines and inhibit neutrophil activation ex vivo. Furthermore, an albumin fusion of the most crossreactive single-chain antibody prevents and reverses inflammation in the K/BxN mouse model of arthritis. Thus, we report an approach for the molecular evolution and selection of broadly crossreactive antibodies towards a family of structurally related, yet sequence-diverse protein targets, with general implications for the development of novel therapeutics.

趋化因子受体通常具有多种配体。因此，预计用针对单一趋化因子的阻断抗体进行治疗对于疗效来说是不够的。在这里，我们展示了可以对单链抗体进行工程改造，使其对多种人和小鼠促炎性 ELR CXC 趋化因子具有广泛的交叉反应性。这些工程化的分子识别 ELR CXC 趋化因子的功能表位，并在体外抑制中性粒细胞的激活。此外，最具交叉反应性的单链抗体的白蛋白融合物可预防和逆转关节炎 K/BxN 小鼠模型中的炎症。因此，我们报告了一种针对结构相关但序列多样的蛋白质靶家族的广泛交叉反应性抗体的分子进化和选择方法，这对新型治疗药物的开发具有普遍意义。