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Int. J. Mol. Sci. 2018, 19(9), 2683; https://doi.org/10.3390/ijms19092683

The Protective Effect of a Long-Acting and Multi-Target HM-3-Fc Fusion Protein in Rheumatoid Arthritis

1
State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
2
The Engineering Research Center of Peptide Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China
3
Centre for Biopharmaceutical Products, Tasly Pharmaceuticals Co., Ltd., Tianjin 300410, China
4
Tasly Academy, Tasly Holding Group Co., Ltd., Tianjin 300410, China
*
Authors to whom correspondence should be addressed.
Received: 17 July 2018 / Revised: 5 September 2018 / Accepted: 5 September 2018 / Published: 10 September 2018
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Abstract

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. View Full-Text
Keywords: rheumatoid arthritis; HM-3; Fc-domain of immunoglobulin G4; synovial angiogenesis; inflammatory response; TNF-α; half-life; pharmacodynamics rheumatoid arthritis; HM-3; Fc-domain of immunoglobulin G4; synovial angiogenesis; inflammatory response; TNF-α; half-life; pharmacodynamics
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Huang, R.; Li, J.; Wang, Y.; Zhang, L.; Ma, X.; Wang, H.; Li, W.; Cao, X.; Xu, H.; Hu, J. The Protective Effect of a Long-Acting and Multi-Target HM-3-Fc Fusion Protein in Rheumatoid Arthritis. Int. J. Mol. Sci. 2018, 19, 2683.

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