CN116173199A - Application of Deshu monoclonal antibody in preparation of medicine for treating gonarthromeningitis - Google Patents
Application of Deshu monoclonal antibody in preparation of medicine for treating gonarthromeningitis Download PDFInfo
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- CN116173199A CN116173199A CN202211310193.1A CN202211310193A CN116173199A CN 116173199 A CN116173199 A CN 116173199A CN 202211310193 A CN202211310193 A CN 202211310193A CN 116173199 A CN116173199 A CN 116173199A
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- C—CHEMISTRY; METALLURGY
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2875—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
The invention discloses application of Deshu monoclonal antibody in preparing a medicament for treating gonarthromeningitis, and belongs to the technical field of biological pharmacy. The invention discovers that the Desulzumab can obviously improve the knee joint pain threshold of mice with synovitis, relieve pain caused by inflammation, and effectively relieve joint injury so as to delay the progress of synovitis.
Description
Technical Field
The invention belongs to the technical field of biological pharmacy, and particularly relates to application of Desulzumab in preparation of a medicament for treating gonarthromeningitis.
Background
Synovium is a soft tissue attached to the inner wall of the joint cavity and its main function is to secrete synovial fluid, i.e. to secrete lubricant to the joint while protecting the joint cartilage. Gonarthromeningitis is a common joint disorder in life, and refers to inflammation generated after synovitis is stimulated, and the disorder can lead to secretion imbalance, thereby forming effusion and aggravating symptoms of bone joints. Previous studies on gonarthromeningitis have been few, particularly on the progression of chronic synovitis to the development of arthritis. In recent years, damage to bone and cartilage with respect to synovial inflammatory mediators has been increasingly emphasized.
At present, the knee joint synovitis treatment medicine mainly adopts non-steroidal anti-inflammatory analgesic drugs, and mainly comprises two main types of oral administration and external use (closed needle and sodium hyaluronate injection). The external medicines are anti-inflammatory analgesics, and have limited therapeutic effects on chronic inflammation of synovium or acute phase of severe wound. The oral medicine has similar action mechanism with the external medicine, and can relieve uncomfortable symptoms such as pain. However, these methods cannot be fundamentally and effectively used for treating gonarthromeningitis, and the nonsteroidal analgesic has the problems of large adverse reactions such as gastrointestinal tract and the like, has poor long-term treatment effect, and cannot be used for patients suffering from respiratory tract and acute cardiovascular diseases such as asthma and the like. The medicine is injected into the joint cavity, which mainly plays a role in lubrication, but needs to be injected into the joint cavity for multiple times, so that the risk of infection of the joint cavity is greatly increased. These treatment regimens have poor effect on some patients, probably because the current drug has a single target site, and cannot cover multiple pathogenesis of gonarthromeningitis, so finding the core pathogenesis of each tissue is a key for treating gonarthromeningitis.
Currently, deshumab is commonly used clinically in the treatment of osteoporosis, but may also be used in the treatment of other diseases such as multiple myeloma, bone fracture and cone tumors.
Disclosure of Invention
In view of the above, the present invention aims at providing the application of the Deshu monoclonal antibody in preparing the medicine for treating gonarthromeningitis, aiming at the defects and disadvantages of the existing medicine for treating gonarthromeningitis.
Deshumab is a fully humanized monoclonal IgG2 antibody to RANKL, found by study: the Deshu monoclonal antibody can obviously improve the knee joint pain threshold of mice with synovitis, relieve pain caused by inflammation, and effectively relieve joint injury so as to delay the progress of synovitis. Deshu monoclonal antibody can obviously reduce the expression of DNA injury signal related genes (p 16INK4a and p 21) of knee joint cartilage cells, increase the expression of cytokinesin, and simultaneously obviously reduce the expression of synovial cell inflammation related genes (TNF-alpha, IL-6, IL-1 beta, MMP3 and MMP 13).
In order to solve the problems, the invention adopts the following technical scheme: application of Deshu monoclonal antibody in preparing medicine for treating gonarthromeningitis.
The other technical scheme of the invention is realized as follows: application of composition containing Deshu monoclonal antibody in preparing medicine for treating gonarthromeningitis.
Preferably, the composition containing the Deshu monoclonal antibody contains the Deshu monoclonal antibody and a pharmaceutically acceptable carrier or auxiliary material thereof.
The third technical scheme of the invention is realized as follows: a medicament for treating gonarthromeningitis, which comprises Deshu monoclonal antibody.
Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or auxiliary material of the Deshumazumab.
Compared with the prior art, the Deshuzumab can obviously improve the knee joint pain threshold of mice with synovitis, relieve pain caused by inflammation, and effectively relieve joint injury so as to delay the progress of synovitis. Deshu monoclonal antibody can obviously reduce knee joint cartilage cell DNA damage signal related gene (p 16) INK4a P 21), increases the expression of cytoskeletal Vimentin (Vimentin), and simultaneously can remarkably reduce the expression of synovial cell inflammation related genes (TNF-alpha, IL-6, IL-1 beta, MMP3 and MMP 13); deshuzumab can improve knee joint function of patients with gonarthromeningitis and life treatment of patients. These findings indicate that desipramab is effective in treating gonarthromeningitis.
Drawings
The above features and characteristics of the present invention will become more apparent from the following detailed description taken in conjunction with the accompanying drawings, in which:
FIG. 1 modeling using C57BL/6J mice, cutting off anterior cruciate ligaments, medial collateral ligaments to construct a medial meniscus instability model, and performing drug intervention to evaluate pain-related behavior of synovial mice by gait walking and von Frey pain threshold experiments;
FIG. 2 modeling was performed using C57BL/6J mice, and a medial meniscus instability model was constructed by cutting off the anterior cruciate ligament and the medial collateral ligament, inducing the mice knee synovitis phenotype, histologically observing the histological improvement of the knee synovitis by desiumab;
figure 3 shows that the in vivo significant decrease of Deshumab induces synovitis in the knee joint of miceChondrocyte DNA damage signal related gene (p 16) INK4a P 21), increases the expression of cytoskeletal Vimentin (Vimentin). Deshuzumab significantly improves the expression of induced synovitis mouse knee joint chondrocyte inflammation-related genes (TNF-alpha, IL-6, IL-1β, MMP3, and MMP 13) in vivo.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Examples: application of Deshu monoclonal antibody in preparation of medicine for treating gonarthromeningitis
1) Experimental protocol:
c57BL/6J mice (20-25 g) were randomized: normal (n=3), injured (n=3), synovitis+Deshumab (DS) (0.1-fold dose (1 mg/kg)) (n=3), synovitis+Deshumab (1-fold dose (10 mg/kg)) (n=3), synovitis+Deshumab (2-fold dose (20 mg/kg)) (n=3), synovitis+Deshumab (5-fold dose (50 mg/kg)) (n=3).
2) Experiment design:
the mice knee synovitis phenotype was induced by severing the anterior cruciate ligament and constructing a medial meniscus instability model by medial collateral ligament.
After one week of injury modeling, the synovitis + Deshu monoclonal antibody group (0.1-fold dose, 1-fold dose, 2-fold dose, and 5-fold dose) was subcutaneously injected every other week with Deshu monoclonal antibody injections of 1mg/kg, 10mg/kg, 20mg/kg, and 50 mg/kg. Meanwhile, mice were tested for pain threshold with von frey every two weeks. Mice were sacrificed 6 weeks after injection of Desmozumab, knee specimens were collected for each group, stained for safranin and synovial tissue mRNA and protein analysis.
3) Results of Deshuzumab on treatment of gonarthromeningitis:
pain-related behavior of synovial mice was assessed using gait walking and von Frey experiments. The CatWalk system is a video-based automated gait analysis system for assessing rodent footprint and gait changes. It can record static and dynamic parameters such as paw pressure, imprint area, stance phase duration, swing phase duration, step size and coordination between limbs. The ability of mice to crawl was assessed by the ratio of left and right hind limb measurements. We found that mice receiving the highest dose of Deshumab (DS 5.0 group) had significantly reduced pain on days 14, 28 and 42, such as reduced swing (FIG. 1A), increased stance time (FIG. 1B), increased footprint area (FIG. 1C), increased pressure (intensity) on foot plate contact (FIG. 1D), increased locomotor speed (FIG. 1E) and increased paw withdrawal threshold (FIG. 1F) (p < 0.05)
4) Observed histological improvement of the knee joint synovitis by the Deshuzumab:
the knee joints of mice after 6 weeks of intervention were collected. Safranin O staining showed abnormal joint surface structure in synovitis groups, with significant loss of proteoglycans (fig. 2A), and early synovitis characterized by superficial destruction of articular cartilage, including collagen destruction and proteoglycan loss, resulting in "mechanical softening" of the extracellular matrix. Proteoglycan levels of groups 1.0, 2.0 and 5.0 of Deshumab were significantly improved in a dose-dependent manner. Furthermore, we found that the thickness of osteophytes on the medial tibial plateau of synovitis mice was gradually increased, and that groups 1.0, 2.0 and 5.0 of Deshuzumab inhibited osteophyte formation (FIG. 2B). In addition, synovitis group mice showed increased thickening of the proximal subchondral bone of the tibia, resulting in increased subchondral bone scores (reference OARSI scoring system), groups 1.0, 2.0 and 5.0 partially alleviating pathological changes in subchondral bone (fig. 2C).
Finally we quantified joint pathology by OARSI scores, suggesting that groups 1.0, 2.0 and 5.0 of desquamation partially alleviated joint pathology of subchondral bone (fig. 2D) (p < 0.05).
5) Mechanism of release of dimesunab against synovitis:
synovial cells were isolated from normal and synovial mouse knee joint tissue and cultured in medium containing 5mM of Desmozumab for 3 days. Then, we performed real-time fluorescent quantitative PCR and Western blot to quantify the expression levels of cell senescence-associated mRNA and protein. We found that mRNA and protein expression levels of p16.sup.ink 4a and p21 were significantly higher in mice with cell senescence-associated synovitis than in normal mice (p < 0.05), whereas treatment with the population of desquamation significantly reduced their expression (p < 0.05) (fig. 3A-C). P16INK4a and Vimentin in synovial tissue were stained using immunofluorescence dual labeling. As a result, it was found that synovial cells of synovitis group exhibited severe senescence phenotype, and that desipramab significantly improved senescence phenotype of synovial cells (fig. 3D, E). Inflammatory index marker of synovitis group: TNF-alpha, IL-6, IL-1 beta, MMP3 and MMP13 were all significantly increased, and Deshuzumab significantly reduced the expression of inflammatory indicators (FIG. 3F). The primer sequences are shown in Table 1 and the sequence listing.
In conclusion, the Deshu monoclonal antibody can obviously improve the knee joint pain threshold of mice with synovitis, relieve pain caused by inflammation, and effectively relieve joint injury so as to delay the progress of synovitis. Deshu monoclonal antibody can obviously reduce knee joint cartilage cell DNA damage signal related gene (p 16) INK4a P 21), increases the expression of cytoskeletal Vimentin (Vimentin), and simultaneously can remarkably reduce the expression of synovial cell inflammation related genes (TNF-alpha, IL-6, IL-1 beta, MMP3 and MMP 13); deshuzumab can improve knee joint function and quality of life of patients with gonarthromeningitis. These findings indicate that desipramab is effective in treating gonarthromeningitis.
The present invention is not limited to the above-mentioned embodiments, and any changes or substitutions that can be easily understood by those skilled in the art within the technical scope of the present invention are intended to be included in the scope of the present invention. Therefore, the protection scope of the present invention should be subject to the protection scope of the claims.
Claims (5)
1. Application of Deshu monoclonal antibody in preparing medicine for treating gonarthromeningitis.
2. Application of composition containing Deshu monoclonal antibody in preparing medicine for treating gonarthromeningitis.
3. The use of a composition comprising Deshumab according to claim 2 in the manufacture of a medicament for the treatment of gonarthromeningitis, wherein said composition comprising Deshumab comprises Deshumab and a pharmaceutically acceptable carrier or adjuvant therefor.
4. A medicament for treating gonarthromeningitis, which is characterized by comprising Deshu monoclonal antibody.
5. The medicament for treating gonarthromeningitis according to claim 4, further comprising a pharmaceutically acceptable carrier or adjuvant for the Deshumazumab.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211310193.1A CN116173199A (en) | 2022-10-25 | 2022-10-25 | Application of Deshu monoclonal antibody in preparation of medicine for treating gonarthromeningitis |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202211310193.1A CN116173199A (en) | 2022-10-25 | 2022-10-25 | Application of Deshu monoclonal antibody in preparation of medicine for treating gonarthromeningitis |
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| Publication Number | Publication Date |
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| CN116173199A true CN116173199A (en) | 2023-05-30 |
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| CN202211310193.1A Pending CN116173199A (en) | 2022-10-25 | 2022-10-25 | Application of Deshu monoclonal antibody in preparation of medicine for treating gonarthromeningitis |
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- 2022-10-25 CN CN202211310193.1A patent/CN116173199A/en active Pending
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