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Neutralizing antibody of follistatin-like 1 and application thereof

An antibody and neutralization technology, applied in the direction of antibodies, immunoglobulins, anti-animal/human immunoglobulins, etc., can solve the problem that the role of FSTL1 has not been elucidated

Active Publication Date: 2021-01-05
NANKAI UNIV
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

This gene encodes a small molecule glycoprotein (38kD) that can be secreted. Existing studies have shown that FSTL1 plays an important role in the development of the lung as an inhibitor of BMP4. In addition, FSTL1 is considered to be an important factor in lung cancer and ovarian cancer cells. A possible tumor suppressor gene, an immunomodulator in rheumatoid arthritis, also plays a role in lung fibrotic disease by promoting TGF-β signaling activation, but the role of FSTL1 in skin fibrosis has not been elucidated

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  • Neutralizing antibody of follistatin-like 1 and application thereof
  • Neutralizing antibody of follistatin-like 1 and application thereof
  • Neutralizing antibody of follistatin-like 1 and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0053] Example 1. FSTL1 has a key facilitative role in skin fibrosis disease progression.

[0054] Skin fibrosis mainly occurs in the dermis, manifested by the proliferation of support cells such as fibroblasts and the expression of a large number of extracellular matrix proteins, accompanied by the infiltration of inflammatory factors and the production of a large number of cytokines. Current studies have shown that TGF-β1 is a key factor regulating the activation and proliferation of fibroblasts in the process of skin fibrosis. The research results released by our laboratory have confirmed that FSTL1 can promote the activation of myofibroblasts and the expression of extracellular matrix by promoting the TGF-β1 signaling pathway in the pathogenesis of pulmonary fibrosis. We speculate that FSTL1 is involved in the process of skin fibrosis, regulates the proliferation and activation of fibroblasts, the synthesis and deposition of extracellular matrix, and used experiments to st...

Embodiment 2

[0060] Example 2. Murine FSTL1 monoclonal antibody 2K6 can specifically bind to FSTL1 protein, and can antagonize the binding of FSTL1 to TGF-β1 or TGF-β1 receptor.

[0061] In order to confirm that the 2K6 monoclonal antibody is a neutralizing antibody to FSTL1, we first tested whether the 2K6 antibody can specifically bind to the FSTL1 protein. figure 2 The results of A microcalorimetric heat surge experiment showed that 2K6 monoclonal antibody can bind to FSTL1 protein, and the binding constant (Kd) is 106.8nM, but cannot bind to FSTL1 family protein FS; figure 2 As shown in the results of immunoprecipitation experiments in B, 2K6 monoclonal antibody can bind to FSTL1 protein, but cannot bind to TGF-β1 or FS, which shows that the binding of 2K6 monoclonal antibody to FSTL1 is very specific. Studies have proved that FSTL1 exerts its biological function mainly by promoting the activity of TGF-β1 signaling pathway. The specific mechanism is that FSTL1 can simultaneously bind...

Embodiment 3

[0064] Example 3. Murine FSTL1 monoclonal antibody 2K6 can neutralize the biological function of FSTL1.

[0065] After confirming the specificity of 2K6 mAb by co-immunoprecipitation experiments, we tested the biological activity of FSTL1 mAb 2K6 using two in vitro cell models. In previous reports on rheumatoid arthritis, it was found that Fstl1 can promote the expression of IL-6 inflammatory cytokines in Cos7 cells, so we constructed a cell model in which Fstl1 plasmid was transfected in Cos7 cells, and detected the expression of Cos7 after overexpressing Fstl1 by ELISA experiments. The expression level of the inflammatory factor IL-6 secreted by the cells. After transfecting pc-Fstl1 plasmid and control pc-DNA3.1 plasmid in Cos7 cells for 24 hours, exogenously added 2K6 monoclonal antibody and control antibody IgG2b for 48 hours, it was found that Fstl1 promoted the inflammatory response under the action of monoclonal antibody The effect was significantly reversed ( image...

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Abstract

The invention relates to a neutralizing antibody of follistatin-like 1 and an application thereof. The antibody is a murine FSTL1 neutralizing antibody 2K6. The invention also discloses a heavy chainvariable region and a light chain variable region of the antibody or an antigen binding fragment thereof. The invention also relates to an application of the FSTL1 in promoting the treatment of skin fibrosis diseases, the application of the murine FSTL1 neutralizing antibody 2K6 in treating or remitting pulmonary fibrosis, skin fibrosis and arthritis diseases or symptoms, and a pharmaceutical composition prepared from the murine FSTL1 neutralizing antibody 2K6. Research results show that the murine FSTL1 neutralizing antibody 2K6 can treat or remit pulmonary fibrosis, skin fibrosis and arthritis diseases; and compared with an antibody 22B6 which is researched and developed by the research and development team in the earlier stage and used for treating pulmonary fibrosis, the antibody 2K6 has better prevention and treatment effects on mouse pulmonary fibrosis than the antibody 22B6, that is to say, the prevention and treatment remission rates of a 2K6 experimental group on pulmonary fibrosis key indexes including the hydroxyproline content and the pulmonary fibrosis area proportion are higher than those of a 22B6 experimental group.

Description

technical field [0001] The present invention relates to the function of follistatin-like protein 1 (FSTL1) in promoting the disease process of skin fibrosis, and the murine FSTL1 neutralizing antibody as an active ingredient of the pharmaceutical composition is used to treat, alleviate or improve pulmonary fibrosis, skin fibrosis Use in chemical and arthritic diseases or conditions. Background technique [0002] The essence of organ fibrosis is the repair response after tissue damage to protect the relative integrity of tissues and organs. Organ fibrosis can occur in various parts including the lung, skin, heart, liver, kidney, etc., and has similar pathological features. It is a pathological change in which fibrous connective tissue increases and parenchymal cells decrease in organ tissues caused by various acute and chronic diseases. , can lead to organ structural damage and functional decline. The main pathological changes of organ fibrosis are the increase of fibrous c...

Claims

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Application Information

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IPC IPC(8): C07K16/18A61K39/395A61P11/00A61P17/00A61P19/02A61P17/02
CPCC07K16/18A61P11/00A61P17/00A61P19/02A61P17/02C07K2317/56C07K2317/565C07K2317/76C07K2317/20C07K2317/51C07K2317/515A61K2039/505
Inventor 宁文周红刚李霄鹤
Owner NANKAI UNIV
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