State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China.
The Engineering Research Center of Peptide Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China.
Int J Mol Sci. 2018 Sep 10;19(9):2683. doi: 10.3390/ijms19092683.
Current treatment of rheumatoid arthritis (RA) is limited by relative shortage of treatment targets. HM-3 is a novel anti-RA polypeptide consisting of 18 amino acids with integrin αVβ3 and α5β1 as targets. Previous studies confirmed that HM-3 effectively inhibited the synovial angiogenesis and the inflammatory response. However, due to its short half-life, the anti-RA activity was achieved by frequent administration. To extend the half-life of HM-3, we designed a fusion protein with name HM-3-Fc, by combination of modified Fc segment of immunoglobulin 4 (IgG4) with HM-3 polypeptide. In vitro cell experiments demonstrated that HM-3-Fc inhibited the proliferation of splenic lymphocytes and reduced the release of TNF-α from macrophages. The pharmacodynamics studies on mice paw in Collagen-Induced Arthritis (CIA) model demonstrated that HM-3-Fc administered once in 5 days in the 50 and 25 mg/kg groups, or once in 7 days in the 25 mg/kg group showed a better protective effect within two weeks than the positive control adalimumab and HM-3 group. Preliminary pharmacokinetic studies in cynomolgus confirmed that the in vivo half-life of HM-3-Fc was 15.24 h in comparison with 1.32 min that of HM-3, which demonstrated that an Fc fusion can effectively increase the half-life of HM-3 and make it possible for further reduction of subcutaneous injection frequency. Fc-HM-3 is a long-acting active molecule for RA treatment.
目前类风湿关节炎（RA）的治疗方法受到治疗靶点相对缺乏的限制。HM-3 是一种新型的抗 RA 多肽，由 18 个氨基酸组成，以整合素 αVβ3 和 α5β1 为靶点。先前的研究证实，HM-3 能有效抑制滑膜血管生成和炎症反应。然而，由于其半衰期较短，需要频繁给药才能发挥抗 RA 活性。为了延长 HM-3 的半衰期，我们设计了一种融合蛋白，命名为 HM-3-Fc，它由免疫球蛋白 4（IgG4）的修饰 Fc 片段与 HM-3 多肽结合而成。体外细胞实验表明，HM-3-Fc 抑制脾淋巴细胞的增殖，并减少巨噬细胞释放 TNF-α。胶原诱导关节炎（CIA）模型小鼠爪的药效学研究表明，在 50 和 25mg/kg 组中，HM-3-Fc 每 5 天给药 1 次，或在 25mg/kg 组中每 7 天给药 1 次，在两周内的保护效果优于阳性对照阿达木单抗和 HM-3 组。在食蟹猴中的初步药代动力学研究证实，HM-3-Fc 的体内半衰期为 15.24 小时，而 HM-3 的半衰期为 1.32 分钟，这表明 Fc 融合可以有效延长 HM-3 的半衰期，并有可能进一步减少皮下注射频率。Fc-HM-3 是一种长效活性分子，可用于治疗 RA。
