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

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.

• Authors: Ruijing Huang, Jian Li, Yibo Wang, Lihua Zhang, Xiaohui Ma, Hongyu Wang, Wenlei Li, Xiaodan Cao, Hanmei Xu, Jialiang Hu
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 19 Issue 9 (Sep 10 2018) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 30201867 (Publication Type: Journal Article)

Chemical References

• Immunoglobulin Fc Fragments
• Integrin alpha5beta1
• Integrin alphaVbeta3
• Integrins
• Peptides
• Recombinant Fusion Proteins
• TNF protein, human
• Tumor Necrosis Factor-alpha
• Adalimumab

Topics

• Adalimumab (administration & dosage, pharmacology)
• Animals
• Arthritis, Experimental (prevention & control)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Half-Life
• Humans
• Immunoglobulin Fc Fragments (administration & dosage, pharmacology)
• Integrin alpha5beta1 (antagonists & inhibitors)
• Integrin alphaVbeta3 (antagonists & inhibitors)
• Integrins (antagonists & inhibitors)
• Lymphocytes (cytology, drug effects)
• Mice
• Peptides (administration & dosage, pharmacology)
• Recombinant Fusion Proteins (administration & dosage, pharmacology)
• Spleen (immunology)
• Tumor Necrosis Factor-alpha (metabolism)
• Zebrafish