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.
Highlights
Rheumatoid arthritis (RA), a multi-systemic autoimmune disease, is characterized by joint synovitis, pannus formation and symmetrical destructive joint disease [1]
HM-3 is an anti-angiogenic polypeptide with 18 amino acid residues, which is generated by the connection of an integrin-targeting RGD (Arg-Gly-Asp) sequence to the C-terminus of an endostatin fragment (IVRRADRAAVP)
Several studies have shown that as an integrin inhibitor, HM-3 directly reduced the expression of vascular endothelial growth factor (VEGF) and platelet derived growth factor A (PDGF-A) in endothelial cells and down-regulated the corresponding signal transduction pathways [8]
Summary
Rheumatoid arthritis (RA), a multi-systemic autoimmune disease, is characterized by joint synovitis, pannus formation and symmetrical destructive joint disease [1]. In order to extend the in vivo half-life of peptides, various pharmaceutical technologies have been developed, such as fusion protein formation, chemical modification and glycosylation modification, among which PEG modification and fusion protein technology represented by Fc-fusion are the most prominent [13,14]. Both methods are applied in many successfully listed drugs. The half-life of the Fc fusion protein has been greatly improved in drugs listed in the market [22,23].
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