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.

Design and Synthesis of A PD-1 Binding Peptide and Evaluation of Its Anti-Tumor Activity

“…Many studies have been concerned with the design, synthesis, extraction, and evaluation of the effectiveness of such molecules. In recent years, peptide therapy has become one of the promise candidates for drug development in cancer treatment and other diseases [24,25,26,27,28,29,30,31,32]. Jolene L. Lau and Michael K. Dunn said that peptides represent one of the greatest areas of pharmaceutical development, particularly for tumor treatment, metabolic disease, and cardiovascular disease [33].…”

Shedding New Light on The Role of ανβ3 and α5β1 Integrins in Rheumatoid Arthritis

“…RA is described as a vicious disease characterized by joints inflammation and angiogenesis [25]. From this standpoint, the following sections present involvement of αvβ3 and α5β1 with facilitating ECM protein-rheumatoid cells communication during RA pathogenesis as well as angiogenesis-regulated factors.…”

“…The arthritic medium involves a large number of inflammatory cells and angiogenic effector molecules. VEGF and angiopoietins are main types of angiogenic factors that regulate angiogenesis process [25]. During RA inflammation, the synovial tissue expands, therefore, the supply of blood becomes inadequate, resulting in hypoxia.…”

“…In vivo , inhibition of VEGF reduced joint destruction through preventing endothelial cells migration, differentiation and tube formation [66]. Likewise, αvβ3 and α5β1 antagonists recover inflammation by inducing apoptosis of undesirable sprouting blood vessels [25]. The role of αvβ3 and α5β1 in RA joint angiogenesis was summarized in Figure 3.…”

“…It is shows anti-angiogenic activity through inhibition of inflammatory factors, VEGF and PDGF-A in endothelial cells. Phase I clinical trials are currently underway [25].…”