Application of Glembumumab vedotin in preparation of medicine for preventing and treating interstitial lung diseases
By using Glembatumumab vedotin to target GPNMB, the problem of limited treatment options for interstitial lung disease has been solved, and the effect of effectively alleviating disease progression, improving lung function and reducing inflammation has been achieved, providing a new treatment plan for interstitial lung disease.
Patent Information
- Application Number
- CN202411639565.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-15
- Publication Date
- 2025-02-25
AI Technical Summary
The treatment options for interstitial lung disease are limited, and existing treatment methods cannot effectively alleviate disease progression, especially in terminal patients, lung transplantation has challenges such as lack of donors, high costs and complications.
Glembatumumab vedotin is used as a therapeutic drug to prevent and treat interstitial lung diseases by targeting GPNMB, which specifically includes administration by laryngoscopy in a mouse model, administered once every other day for 3 weeks, with a dose of 2.5 mg/kg; administration in humans by oral administration, administered once every other day for 3 weeks, with a dose of 0.28 mg/kg.
Glembatumumab vedotin significantly alleviates the progress of interstitial lung disease, improves lung function, reduces the exudation of lung inflammation, reduces the lesions and lesions of lung fibrosis, and delays the progress of the disease.
Smart Images
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of biomedicine, and specifically relates to the application of Glembatumumab vedotin in preparing medicines for preventing and treating interstitial lung diseases. Background Art
[0002] Interstitial lung diseases (ILDs) are a group of heterogeneous diseases characterized by involvement of the lung interstitium. Its main pathological features include inflammatory cell infiltration, destruction of alveolar structure, proliferation and differentiation of fibroblasts, and abnormal deposition of a large amount of extracellular matrix (ECM). There are many specific types of interstitial lung diseases, mainly including idiopathic pulmonary fibrosis (IPF) of unknown cause and pneumoconiosis of known cause. In recent years, the incidence of interstitial lung diseases has shown a clear upward trend at home and abroad, and has become a health problem of widespread concern worldwide. Studies have found that the incidence and prevalence of interstitial lung diseases increase with age, especially in elderly patients over 60 years old, with a prevalence as high as 3%. Even more regrettable is that the prognosis of patients with interstitial lung diseases is extremely poor. Once diagnosed, the average survival period is only 3-5 years, and the 5-year survival rate is only 20%.
[0003] Currently, treatment options for interstitial lung disease are limited, mainly symptomatic treatment, such as antitussive and antiasthmatic, anti-inflammatory and anti-infective. For patients with terminal interstitial lung disease, lung transplantation is considered the most effective treatment method, which can improve patients' lung function, improve their quality of life, and delay disease progression. However, due to challenges such as donor shortage, high cost, immune rejection, infection, and complications, the application of lung transplantation is subject to certain limitations. Therefore, in order to find more effective treatment options, the field needs to actively develop new therapeutic drugs for interstitial lung disease. Summary of the invention
[0004] The purpose of the present invention is to provide an application of Glembatumumab vedotin in the preparation of a drug for preventing and treating interstitial lung disease. The Glembatumumab vedotin can effectively prevent and treat interstitial lung disease, thereby increasing the medical use of Glembatumumab vedotin.
[0005] The present invention provides application of Glembatumumab vedotin in preparing medicine for preventing and treating interstitial lung disease.
[0006] Preferably, the interstitial lung disease includes idiopathic pulmonary fibrosis and / or pneumoconiosis.
[0007] Preferably, the drug includes a drug for preventing and treating human interstitial lung disease or a mouse interstitial lung disease model.
[0008] Preferably, when the drug is used to prevent and treat an interstitial lung disease model in mice, the dosage of Glembatumumab vedotin is 2.5 mg / kg, and the method of using Glembatumumab vedotin is to administer the drug via laryngoscope, once every other day, for 3 weeks;
[0009] When the drug is used to prevent and treat human interstitial lung disease, the dosage of Glembatumumab vedotin is 0.28 mg / kg, and the method of using Glembatumumab vedotin is oral administration, once every other day, for 3 weeks.
[0010] Preferably, the medicament comprises a medicament for alleviating the progression of interstitial lung disease.
[0011] Preferably, the drug includes drugs having one or more functions of improving lung function, reducing lung inflammation and exudation, reducing pulmonary fibrosis lesions, and reducing the degree of pulmonary fibrosis lesions.
[0012] Preferably, the Glembatumumab vedotin is used in the form of a Glembatumumab vedotin solution, the concentration of the Glembatumumab vedotin solution is 1.25 mg / mL, and the solvent is normal saline.
[0013] The present invention also provides a medicine for preventing and treating interstitial lung disease, wherein the effective component of the medicine comprises Glembatumumab vedotin.
[0014] Preferably, the dosage form of the drug includes one or more of powder, tablet and solution.
[0015] Beneficial effects:
[0016] The present invention provides the use of Glembatumumab vedotin in the preparation of drugs for preventing and treating interstitial lung diseases. The GV of the present invention treats interstitial lung diseases with GPNMB as a target, and has a good effect and can effectively alleviate the progression of interstitial lung diseases. Specifically, after administration of GV, the lung function of mice with pulmonary fibrosis is significantly improved, including lung volume indicators such as inspiratory capacity (IC), pulmonary ventilation function tests such as airway resistance (RI), dynamic compliance (Cdyn) and quasi-static compliance (Cchord); the concentrations of inflammatory factors IL-1β and Il-6 in the alveolar lavage fluid of mice with pulmonary fibrosis are reduced, the transcription levels of inflammatory factors Il-1β, Il-6 and Tnf-α in lung tissue are reduced, and pulmonary inflammatory exudation is alleviated; the transcription levels of fibrosis factors Fn-1 and Col-I are reduced, the protein level of FN-1 is reduced, the collagen-specific amino acid hydroxyproline Hydroxyproline is reduced, the fibrosis lesions are reduced, and the degree of lesions is alleviated. Therefore, GV can be used as a new solution for the prevention and treatment of interstitial lung disease. BRIEF DESCRIPTION OF THE DRAWINGS
[0017] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required to be used in the embodiments are briefly introduced below.
[0018] Figure 1 The GV administration intervention scheme was performed for the pulmonary fibrosis mouse model in Example 1;
[0019] Figure 2 This is a graph showing the results of lung function testing in the pulmonary fibrosis mouse model after GV administration in Example 1;
[0020] Figure 3 This is a picture showing the pathological staining results of the pulmonary fibrosis mouse model after GV administration in Example 1;
[0021] Figure 4 This is a graph showing the results of the ELISA kit in Example 1 detecting the concentration of IL-1β inflammatory factor in the bronchoalveolar lavage fluid of a mouse model of pulmonary fibrosis;
[0022] Figure 5 This is a graph showing the results of the ELISA kit in Example 1 detecting the concentration of Il-6 inflammatory factor in the bronchoalveolar lavage fluid of a mouse model of pulmonary fibrosis;
[0023] Figure 6 The results of the Western blot experiment in Example 1 for detecting the protein level of FN-1 in the lung tissue of the pulmonary fibrosis mouse model;
[0024] Figure 7 The mRNA level of Fn-1 in lung tissue of the pulmonary fibrosis mouse model detected by QPCR experiment in Example 1;
[0025] Figure 8 The mRNA level of Col-I in lung tissue of the pulmonary fibrosis mouse model detected by QPCR experiment in Example 1;
[0026] Fig. 9 The mRNA level of Il-1β in lung tissue of the pulmonary fibrosis mouse model detected by QPCR experiment in Example 1;
[0027] Fig.10 The mRNA level of Il-6 in the lung tissue of the pulmonary fibrosis mouse model detected by QPCR experiment in Example 1;
[0028] Fig.11 The mRNA level of Tnf-α in lung tissue of the pulmonary fibrosis mouse model detected by QPCR experiment in Example 1;
[0029] Fig.12 is the content of hydroxyproline in the lung tissue of the mouse model of pulmonary fibrosis in Example 1;
[0030] Among them, Figures 3 to 12 In the middle, **P<0.01, ***P<0.001. DETAILED DESCRIPTION
[0031] The present invention provides application of Glembatumumab vedotin in preparing medicine for preventing and treating interstitial lung disease.
[0032] Glembatumumab vedotin (GV), whose Chinese name is Glembatumumab vedotin, has a CAS number of 1182215-65-1.
[0033] As an embodiment, the interstitial lung disease of the present invention includes idiopathic pulmonary fibrosis and / or pneumoconiosis. As an embodiment, the medicine of the present invention includes a medicine for relieving the progression of interstitial lung disease; as another embodiment, the medicine for relieving the progression of interstitial lung disease of the present invention includes a medicine having one or more functions of improving lung function, reducing lung inflammation exudation, reducing lung fibrosis lesions, and reducing the degree of lung fibrosis lesions.
[0034] As an embodiment, the drug of the present invention includes a drug for preventing and treating human interstitial lung disease or a mouse interstitial lung disease model. As another embodiment, when the drug is used to prevent and treat a mouse interstitial lung disease model, the dosage of the Glembatumumab vedotin is 2.5 mg / kg, and the Glembatumumab vedotin is administered through a laryngoscope, once every other day, for 3 weeks; as another embodiment, when the drug is used to prevent and treat human interstitial lung disease, the dosage of the Glembatumumab vedotin is 0.28 mg / kg, and the Glembatumumab vedotin is administered orally, once every other day, for 3 weeks. As an embodiment, when the drug is used to prevent and treat a mouse interstitial lung disease model or when the drug is used to prevent and treat human interstitial lung disease, it is for non-diagnostic or therapeutic purposes.
[0035] As an embodiment, the Glembatumumab vedotin of the present invention is used in the form of a Glembatumumab vedotin solution, the concentration of the Glembatumumab vedotin solution is 1.25 mg / mL, and the solvent is normal saline.
[0036] The present invention also provides a medicine for preventing and treating interstitial lung disease, wherein the effective component of the medicine comprises Glembatumumab vedotin.
[0037] As an embodiment, the dosage form of the drug of the present invention includes one or more of powder, tablet and solution. As an embodiment, the drug also includes pharmaceutically acceptable excipients. The present invention does not specifically limit the type of the excipient, and it can be selected according to the conventional dosage form of the drug.
[0038] In order to further illustrate the present invention, the technical solution provided by the present invention is described in detail below in conjunction with the accompanying drawings and embodiments, but they should not be construed as limiting the protection scope of the present invention.
[0039] Example 1
[0040] To evaluate GV administration for the treatment of interstitial lung disease, the following steps are performed:
[0041] 1.1 Construction of idiopathic pulmonary fibrosis (IPF) mouse model and pneumoconiosis mouse model and GV administration treatment, the technical process is as follows Figure 1 As shown, the left figure is a schematic diagram of GV action, and the right figure is the dosing regimen for IPF mouse model and pneumoconiosis mouse model.
[0042] 1.1.1 Construction of IPF Mouse Model and GV Administration
[0043] Male C57BL / 6J mice (8 weeks old, 25-30 g) were selected and raised in an SPF-grade experimental animal room. IPF model was established by a one-time tracheal instillation of bleomycin (BLM). The mice were divided into 3 groups (n=6-9), namely:
[0044] ①PBS+vehicle group: The same volume of PBS solution as BLM solution was given for one tracheal instillation, and the same dose of normal saline as GV was given for laryngoscope instillation on the next day. Normal saline was instilled once every other day for 3 weeks.
[0045] ②BLM+vehicle group: BLM solution (1.5-2U / kg) was administered by tracheal instillation once, and the next day, normal saline with the same dose as GV was administered by laryngoscopic instillation. Normal saline was instilled once every other day for 3 weeks.
[0046] ③BLM+GV group: BLM solution (1.5-2U / kg) was administered by tracheal instillation once, and GV 2.5mg / kg was administered by laryngoscopy on the second day. The drug was administered once every other day for 3 weeks.
[0047] 1.1.2 Construction of pneumoconiosis mouse model and GV administration
[0048] Male C57BL / 6J mice (8 weeks old, 25-30 g) were selected and raised in an SPF-grade experimental animal room. The pneumoconiosis model was established by a one-time tracheal instillation of silica. The mice were divided into 3 groups (n=6), namely:
[0049] ①PBS+vehicle group: The same volume of PBS solution as the silica suspension was administered for one tracheal instillation. From the third week, the same dose of saline as the GV was administered for laryngoscope instillation, once every other day for 3 weeks.
[0050] ② Si+vehicle group: A silica suspension solution (300 mg / kg, 40 μL) was administered by tracheal instillation once. From the third week, the same dose of saline as that of GV was administered by laryngoscope instillation once every other day for 3 weeks.
[0051] ③ Si+GV group: A silica suspension solution (300 mg / kg, 40 μL) was administered by tracheal instillation once, and GV 2.5 mg / kg was administered by laryngoscopy starting from the third week, once every other day for 3 weeks.
[0052] 1.2 Pulmonary function test
[0053] After 3 weeks of administration, the anesthetized mice were fixed on the experimental table, and the lung function of the mice was tested using a lung function testing system (DSI Buxco, USA). Before the experiment, 0.4 mL / 100 g of 2% pentobarbital was injected intraperitoneally into the mice for anesthesia, and then the trachea was incised, a endotracheal tube was inserted, and the ventilator was connected. Next, the PFT system automatically detected the FRC test, PV test, FV test, and RC test. This example selects indicators that are closely related to changes in lung function in pulmonary fibrosis for statistical analysis, including lung volume indicators such as inspiratory capacity (IC), airway resistance (RI), dynamic compliance (Cdyn), and quasi-static compliance (Cchord). The results are as follows: Figure 2 shown.
[0054] 1.3 Pathological staining
[0055] The left lung of the mouse was fixed in 4% paraformaldehyde for 72 hours, and then dehydrated and embedded in paraffin for sections (5 μm), which were then stained with HE and Masson staining. HE staining was used to score inflammation according to Szapiel's score, which included no inflammation (grade 0), mild (grade 1), moderate (grade 2), and severe (grade 3); Masson staining of the pneumoconiosis mouse model was used to evaluate the degree of fibrosis according to the King score, and Masson staining of the IPF mouse model was used to evaluate the degree of fibrosis using the modified Ashcroft score. The sections were scanned, filmed, and counted using a 3D HISTECH digital biopsy scanner. The results are shown in the figure. Figure 3 As shown, A is a typical picture of HE and Masson staining of mouse lung tissue sections; B is the inflammation score of HE staining; C is the fibrosis score of Masson staining.
[0056] 1.4ELISA experiment
[0057] The concentrations of IL-1β and Il-6 inflammatory factors in mouse bronchoalveolar lavage fluid (BALF) were detected using ELISA kits. Figures 4-5 shown.
[0058] 1.5 Western blot experiment
[0059] Extract all mouse lung tissue proteins. Prepare 10% polyacrylamide gel, load 10μg protein, and then perform electrophoresis at 80V for 20min; adjust the voltage to 120V and continue electrophoresis until the end. Use PVDF membrane for transfer, transfer current 260mA 1.5h, 5% skim milk powder blocking for 1h, incubate with primary antibody FN-1 (abcam, ab2413, 1:1000) at 4℃ overnight, secondary antibody at room temperature for 1h, and finally develop using chemiluminescence. The above bands were incubated with β-actin primary antibody as an internal reference, and the remaining steps were the same as above. The results are as follows Figure 6 shown.
[0060] 1.6 QPCR experiments
[0061] RNA was extracted from lung tissues of all mice, and cDNA was obtained using a reverse transcription kit (KR103, Tiangen Biotechnology, Beijing, China). QPCR experiments were performed using a SYBR Green I Q-PCR kit (TransGen Biotech, Beijing, China). The primer sequences are shown in Table 1. Data collection and analysis were performed using the Bio-Rad IQ5 system. Figures 7 to 11 shown.
[0062] Table 1 Primer sequences (5'-3')
[0063]
[0064] 1.7 Detection of collagen-specific amino acid hydroxyproline content
[0065] Hydroxyproline content in mouse lung tissue was assessed using a hydroxyproline assay kit (NBP2-59747, Novus Biologicals, Littleton, CO, USA). The procedure was performed according to the instructions, and approximately 30 mg of lung tissue from each mouse was taken for analysis. The absorbance at 560 nm was determined using a standard curve, and the final content analysis was performed. The results are shown in Table 1. Fig.12 shown.
[0066] 1.8 Results Analysis
[0067] GV administration to mice with pulmonary fibrosis can effectively alleviate the progression of interstitial lung disease, and the lung function of mice with interstitial lung disease is significantly improved, including lung volume indicators such as inspiratory capacity IC ( Figure 2 A), pulmonary ventilation function test such as airway resistance RI ( Figure 2 (B), quasi-static compliance Cchord ( Figure 2 C) and dynamic compliance Cdyn( Figure 2 Middle D). Inflammatory factor Il-1β ( Fig. 9 )、Il-6( Fig.10 ) and Tnf-α( Fig.11 ) mRNA levels decreased, and the inflammatory factor IL-1β ( Figure 4 ) and Il-6( Figure 5 ) concentration also decreased. HE staining showed that pulmonary inflammatory exudation was alleviated ( Figure 3 Masson staining showed that the fibrosis foci were reduced and the degree of fibrosis was alleviated ( Figure 3 A and C). Fibrosis factor Fn-1 ( Figure 7 ) and Col-Ⅰ( Figure 8 ) transcription level decreased, and the protein level of FN-1 also decreased ( Figure 6 ; Collagen-specific amino acid hydroxyproline content ( Fig.12 )reduce.
[0068] It can be concluded from the above examples that the Glembatumumab vedotin of the present invention can effectively prevent and treat interstitial lung diseases, thereby increasing the medical uses of Glembatumumab vedotin.
[0069] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. People can also obtain other embodiments based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.
Claims
1. Application of Glembatumumab vedotin in the preparation of drugs for preventing and treating interstitial lung diseases.
2. The use according to claim 1, characterized in that: The interstitial lung diseases include idiopathic pulmonary fibrosis and / or pneumoconiosis.
3. The use according to claim 1 or 2, characterized in that: The drugs include drugs for preventing and treating human interstitial lung disease or mouse interstitial lung disease models.
4. The use according to claim 3, characterized in that: When the drug is used to prevent and treat an interstitial lung disease model in mice, the dosage of Glembatumumab vedotin is 2.5 mg / kg, and the method of using Glembatumumab vedotin is to administer the drug through a laryngoscope, once every other day, for 3 weeks; When the drug is used to prevent and treat human interstitial lung disease, the dosage of Glembatumumab vedotin is 0.28 mg / kg, and the method of using Glembatumumab vedotin is oral administration, once every other day, for 3 weeks.
5. The use according to claim 4, characterized in that: The Glembatumumab vedotin is used in the form of a Glembatumumab vedotin solution, the concentration of the Glembatumumab vedotin solution is 1.25 mg / mL, and the solvent is normal saline.
6. The use according to claim 1, characterized in that: The drugs include drugs that slow the progression of interstitial lung disease.
7. The use according to claim 6, characterized in that: The medicine includes medicines having one or more functions of improving lung function, reducing lung inflammation exudation, reducing lung fibrosis lesions and reducing the degree of lung fibrosis lesions.
8. A drug for preventing and treating interstitial lung disease, characterized in that: The active ingredient of the drug includes Glembatumumab vedotin.
9. The drug according to claim 8, characterized in that The dosage form of the drug includes one or more of powder, tablet and solution.