Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA.
Department of Applied Chemistry, Osaka Prefecture University, Osaka 599-8531, Japan.
Sci Adv. 2019 Nov 6;5(11):eaay1971. doi: 10.1126/sciadv.aay1971. eCollection 2019 Nov.
Enhancing the therapeutic efficacy of drugs for inflammatory diseases is of high demand. One possible approach is targeting drugs to the extracellular matrix of the inflamed area. Here, we target collagens in the matrix, which are inaccessible in most tissues yet are exposed to the bloodstream in the inflamed area because of vascular hyperpermeability. We conferred collagen affinity to anti-tumor necrosis factor-α (α-TNF) antibody by conjugating a collagen-binding peptide (CBP) derived from the sequence of decorin. CBP-α-TNF accumulated in the inflamed paw of the arthritis model, and arthritis development was significantly suppressed by treatment with CBP-α-TNF compared with the unmodified antibody. Similarly, CBP-anti-transforming growth factor-β (α-TGF-β) accumulated in the inflamed lung of pulmonary fibrosis model and significantly suppressed pulmonary fibrosis compared with the unmodified antibody. Together, collagen affinity enables the anticytokine antibodies to target arthritis and pulmonary fibrosis accompanied by inflammation, demonstrating a clinically translational approach to treat inflammatory diseases.
提高治疗炎症性疾病的药物疗效是当务之急。一种可能的方法是将药物靶向到炎症区域的细胞外基质。在这里，我们将靶向基质中的胶原蛋白，由于血管通透性增加，胶原蛋白在大多数组织中无法到达，但在炎症区域暴露于血液中。我们通过将源自 decorin 序列的胶原蛋白结合肽 (CBP) 缀合到抗肿瘤坏死因子-α (α-TNF) 抗体上来赋予其胶原蛋白亲和力。CBP-α-TNF 在关节炎模型的发炎爪子中积累，与未修饰的抗体相比，用 CBP-α-TNF 治疗可显著抑制关节炎的发展。同样，CBP-抗转化生长因子-β (α-TGF-β) 在肺纤维化模型的发炎肺中积累，并与未修饰的抗体相比显著抑制肺纤维化。总之，胶原蛋白亲和力使抗细胞因子抗体能够靶向伴有炎症的关节炎和肺纤维化，为治疗炎症性疾病提供了一种具有临床转化潜力的方法。
