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

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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.

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          Fc-fusion proteins: new developments and future perspectives

          Since the first description in 1989 of CD4-Fc-fusion antagonists that inhibit human immune deficiency virus entry into T cells, Fc-fusion proteins have been intensely investigated for their effectiveness to curb a range of pathologies, with several notable recent successes coming to market. These promising outcomes have stimulated the development of novel approaches to improve their efficacy and safety, while also broadening their clinical remit to other uses such as vaccines and intravenous immunoglobulin therapy. This increased attention has also led to non-clinical applications of Fc-fusions, such as affinity reagents in microarray devices. Here we discuss recent results and more generally applicable strategies to improve Fc-fusion proteins for each application, with particular attention to the newer, less charted areas.
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            The codependence of angiogenesis and chronic inflammation.

            Angiogenesis is the growth of new blood vessels from existing ones. It is an important aspect of new tissue development, growth, and tissue repair. It is also a component of many diseases including cancer, blindness, and chronic inflammation such as rheumatoid arthritis (RA) and psoriasis. There is considerable evidence to suggest that angiogenesis and chronic inflammation are codependent; recent studies have begun to reveal the nature of this link, which involves both augmentation of cellular infiltration and proliferation and overlapping roles of regulatory growth factors and cytokines. Through these studies, we have begun to understand the codependence of chronic inflammation and angiogenesis, the potential benefits of targeting angiogenesis in the treatment of chronic inflammation, and of targeting chronic inflammation to affect angiogenesis.
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              Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins

              Liming Liu (2017)
              There are many factors that can influence the pharmacokinetics (PK) of a mAb or Fc-fusion molecule with the primary determinant being FcRn-mediated recycling. Through Fab or Fc engineering, IgG-FcRn interaction can be used to generate a variety of therapeutic antibodies with significantly enhanced half-life or ability to remove unwanted antigen from circulation. Glycosylation of a mAb or Fc-fusion protein can have a significant impact on the PK of these molecules. mAb charge can be important and variants with pI values of 1–2 unit difference are likely to impact PK with lower pI values being favorable for a longer half-life. Most mAbs display target mediated drug disposition (TMDD), which can have significant consequences on the study designs of preclinical and clinical studies. The PK of mAb can also be influenced by anti-drug antibody (ADA) response and off-target binding, which require careful consideration during the discovery stage. mAbs are primarily absorbed through the lymphatics via convection and can be conveniently administered by the subcutaneous (sc) route in large doses/volumes with co-formulation of hyaluronidase. The human PK of a mAb can be reasonably estimated using cynomolgus monkey data and allometric scaling methods.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                10 September 2018
                September 2018
                : 19
                : 9
                : 2683
                Affiliations
                [1 ]State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China; huangruijing1981@ 123456sina.com
                [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; lijian16@ 123456tasly.com (J.L.); wangyibo@ 123456tasly.com (Y.W.); maxiaohui@ 123456tasly.com (X.M.); wanghongyu@ 123456tasly.com (H.W.); liwenlei@ 123456tasly.com (W.L.); caoxd@ 123456tasly.com (X.C.)
                [4 ]Tasly Academy, Tasly Holding Group Co., Ltd., Tianjin 300410, China; zhanglihua@ 123456tasly.com
                Author notes
                [* ]Correspondence: 13913925346@ 123456126.com (H.X.); jialiang_hu51@ 123456aliyun.com (J.H.); Tel.: +86-139-1392-5346 (H.X.); +86-150-0516-1104 (J.H.)
                Author information
                https://orcid.org/0000-0002-4989-1997
                Article
                ijms-19-02683
                10.3390/ijms19092683
                6163367
                30201867
                5883fed0-2bfd-4b96-89dc-be254f6052f6
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 17 July 2018
                : 05 September 2018
                Categories
                Article

                Molecular biology
                rheumatoid arthritis,hm-3,fc-domain of immunoglobulin g4,synovial angiogenesis,inflammatory response,tnf-α,half-life,pharmacodynamics

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