Application of anti-CXCR6 antibody in treatment of allergic asthma disease
The anti-CXCR6 antibody targets the removal of pathogenic CXCR6+CD4+ T cells in lung tissues of allergic asthma, which solves the problem of difficulty in curing allergic asthma in the prior art and achieves a safer and more effective treatment effect.
Patent Information
- Application Number
- CN202510670240.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-23
- Publication Date
- 2025-07-18
AI Technical Summary
The prior art is difficult to effectively target the removal of pathogenic CXCR6+CD4+ T cells, which makes it difficult to cure allergic asthma airway inflammation, and there are adverse reactions in the long-term use of commonly used drugs such as dexamethasone.
Anti-CXCR6 antibodies were used to target the proportion of pathogenic CXCR6+CD4+ T cells in lung tissues with allergic asthma, downregulate the expression of CXCR6 and ligand CXCL16 protein, and eliminate pathogenic T cells.
It significantly reduces airway inflammation in allergic asthma and has better therapeutic effects than dexamethasone, providing new targets and strategies for treating allergic asthma and reducing the risk of drug toxicity.
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Figure CN120324601A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of new uses of drugs, specifically the application of anti-CXCR6 antibody in the treatment of allergic asthma diseases. Background Art
[0002] Allergic asthma is a chronic inflammatory disease of the airway, and its pathological features are airway inflammation, airway hyperresponsiveness and airway remodeling, which can cause clinical symptoms such as shortness of breath, wheezing, chest tightness and coughing. In the past few decades, the prevalence of asthma has increased significantly, affecting about 300 million people globally. The prevalence of asthma in people over 20 years old in China is 4.2%, and the total number of patients is 45.7 million. At present, dexamethasone is a key drug widely used clinically in the treatment of acute asthma or when the condition deteriorates rapidly. It belongs to the class of adrenal cortical hormones and has pharmacological effects such as anti-inflammatory, anti-allergic and immunosuppressive, and is inexpensive. Although dexamethasone is usually very effective in reducing asthma symptoms, preventing acute attacks and improving lung function in patients with mild to moderate asthma, long-term or excessive use of the drug in patients with severe asthma will cause various adverse reactions, including hypothalamic-pituitary-adrenal axis suppression, reduced growth rate, osteoporosis, diabetes and respiratory tract infections, etc., and seriously affect the quality of life of asthma patients.
[0003] Although significant progress has been made in the treatment strategies of asthma in the past few decades, it is still difficult to achieve a radical cure for asthma. Therefore, conducting research on the pathogenesis of asthma, exploring new therapeutic targets and more effective specific treatment methods has become the trend of asthma treatment.
[0004] The pathogenesis of allergic asthma is mainly related to the abnormal activation of type 2 immune responses induced by allergens. In the airways of patients with allergic asthma, the number of allergen-specific CD4 + T cells increases significantly, producing a variety of mediators that cause airway inflammation, such as IL-4, IL-5, IL-13, IL-17 and IFN-γ, etc., activating the body's adaptive immune response and playing a key role in type 2 inflammatory responses. More and more studies have confirmed that a variety of chemokines play an important role in the recruitment and invasion of airway inflammatory cells, including CXCL1, CXCL5, CXCL8, etc., and promote the chemotaxis of granulocytes, monocytes, T lymphocytes and B lymphocytes by binding to the corresponding chemokine receptors, aggravating inflammatory damage.
[0005] CXCR6 is a G protein-coupled receptor, a transmembrane protein belonging to the CXC chemokine receptor family, and is expressed on a variety of T cell subsets, such as CD4 +T cells (such as Th1 and Th17) and natural killer (NK) cells, etc. The only known ligand of CXCR6 is CXCL16, and their interaction regulates processes such as immune cell migration, proliferation, and activation, triggering downstream signaling pathways (such as the ERK / MAPK and Akt / mTOR pathways). It has been reported that in experimental autoimmune encephalomyelitis (EAE), CXCR6 is preferentially expressed on pathogenic CD4 + T cell subsets. Treatment with anti-CXCR6 antibody significantly depletes CXCR6+ T cells and reduces the accumulation of helper T cells in the spinal cord, improving the symptoms of EAE, demonstrating that CXCR6-labeled pathogenic CD4 + T cells are key pathogenic factors in EAE. Studies have shown that CXCR6 is highly enriched on CD4 + T cells present in the synovium of patients with rheumatoid arthritis and collagen-induced arthritis mice, and CXCR6 knockout can reduce the severity of arthritis. Although CXCR6, as a key molecule in immune regulation, exhibits extensive functions in various immune-related disease processes (such as immune overactivation, tumor immune escape, etc.), its role in the pathological mechanism of asthmatic airway inflammation and the therapeutic effect of anti-CXCR6 monoclonal antibody intervention on allergic asthma are currently unclear. Therefore, there is an urgent need to explore immune intervention strategies targeting CXCR6 and develop a new therapy for allergic asthma with low toxicity, high efficiency, and specificity. Summary of the Invention
[0006] The present invention aims to provide an application of an anti-CXCR6 antibody in the treatment of allergic asthma. The chemokine receptor CXCR6 is highly expressed in the lung tissue of allergic asthma.
[0007] The anti-CXCR6 antibody strategy targets and reduces the proportion of pathogenic CXCR6 + CD4 + T cells in the lung tissue of allergic asthma, and downregulates the expression of CXCR6 and its ligand CXCL16 proteins.
[0008] The anti-CXCR6 antibody mediates a therapeutic effect on allergic asthmatic airway inflammation by targeting CXCR6-labeled CD4 + T cells.
[0009] The beneficial effects of the present invention are as follows:
[0010] CXCR6, as a chemokine receptor, is significantly highly expressed in CD4 + T cells infiltrating the lung tissue of allergic asthma mice. Through treatment with anti-CXCR6 antibody, pathogenic CXCR6 + CD4 +T cells, compared with the prior art, can significantly reduce the proportion of pathogenic cells; at the same time, they can effectively alleviate the airway inflammation symptoms of allergic asthma. Through experimental verification, their therapeutic effect is significantly better than that of the marketed therapeutic drug dexamethasone. The present invention provides a new target and treatment idea for the treatment of allergic asthma by targeting and clearing pathogenic CXCR6 + CD4 + The innovative strategy of T cells provides a new target and treatment idea for the treatment of allergic asthma, is expected to overcome the limitations of existing drugs, and has significant clinical application value and innovation. BRIEF DESCRIPTION OF THE DRAWINGS
[0011] The drawings are used to provide a further understanding of the present invention, and constitute a part of the specification. Together with the embodiments of the present invention, they are used to explain the present invention, and do not constitute a limitation to the present invention.
[0012] Figure 1 It is a schematic diagram showing the high expression of CXCR6 in the lung tissue of mice with allergic asthma;
[0013] Figure 2 It is a schematic diagram showing that the anti-CXCR6 antibody targets and inhibits the infiltration of pathogenic CXCR6+CD4+T cells and the expression of CXCR6 protein in the lung tissue of mice with allergic asthma;
[0014] Figure 3 It is a schematic diagram showing that the treatment with anti-CXCR6 antibody significantly alleviates airway inflammation in mice with allergic asthma. DETAILED DESCRIPTION OF THE EMBODIMENTS
[0015] The technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative work shall fall within the protection scope of the present invention.
[0016] Example 1: CXCR6 is highly expressed in CD4 + T cells infiltrating the lung tissue of mice with allergic asthma
[0017] (1) Establish a mouse model of allergic asthma induced by OVA. Figure 1 The results of flow cytometry show that compared with the normal control group, the proportion of CXCR6 + CD4 + T cells has no significant difference in the spleen and lymph nodes of mice in the allergic asthma model group (P>0.05), but is significantly increased in the lung tissue, and the difference is statistically significant (P<0.01, see Table 1). In addition, as Figure 1As shown in Table 2, Western blot analysis confirmed that the protein expression levels of CXCR6 and its chemokine ligand CXCL16 were also significantly increased in the lungs of mice in the model group, with a significant difference (P<0.001).
[0018] Table 1 CXCR6 in the lungs, spleens and lymph nodes of control and model group mice + CD4 + Proportion of T cells ( n = 4)
[0019]
[0020] Note: Compared with the control group, **P<0.01.
[0021] Table 2 Protein expression levels of CXCR6 and CXCL16 in the lungs of control and model group mice( n = 3)
[0022]
[0023] Note: Compared with the control group, ***P<0.001.
[0024] As shown in Table 1 and Table 2, CXCR6 + CD4 + T cells and CXCR6 were highly expressed in the lung tissues of mice with allergic asthma. CXCR6 played a key role in the pathological mechanism of allergic asthma. Targeted clearance of pathogenic CXCR6 + CD4 + T cells may have a therapeutic effect.
[0025] Example 2: Efficacy of anti-CXCR6 antibody in treating mice with allergic asthma model (1) To explore the pathological mechanism of CXCR6-labeled CD4 + T cells in the progression of allergic asthma, and to clarify whether the strategy of using anti-CXCR6 antibody can down-regulate the pathogenic CXCR6 + CD4 + T cell ratio and the expression of CXCR6 and CXCL16 proteins in the lung tissues of mice with allergic asthma. Therefore, anti-CXCR6 antibody was used for targeted intervention in mice with allergic asthma model. Flow cytometry results showed that compared with the normal control group, the CXCR6 + CD4 + T cell ratio in the lungs of mice in the model group was significantly increased (P<0.001), while the CXCR6 + CD4 + T cell ratios in the lungs, spleens and lymph nodes of mice treated with anti-CXCR6 antibody were all significantly reduced, with a significant difference (P<0.01, see Figure 2A and Table 3). Figure 2 The results of Group B and Table 4 showed that the protein expression levels of CXCR6 and CXCL16 in the lungs of mice in the model group were significantly higher than those in the normal control group (P<0.05). However, compared with the model group, the anti-CXCR6 antibody group and the dexamethasone group significantly reduced the expression of CXCR6 and CXCL16 proteins, and the differences were statistically significant (P<0.05, see Table 4), and the anti-CXCR6 antibody group had a more obvious effect than the marketed therapeutic drug dexamethasone. It indicated that the anti-CXCR6 antibody successfully targeted pathogenic CXCR6 + CD4 + T cells, significantly reduced the proportion and number of this group of pathogenic T cells, and down-regulated the protein expression of CXCR6 and CXCL16.
[0026] Table 3 Effects of anti-CXCR6 antibody on the expression of CXCR6+CD4+T cells in the lungs, spleens and lymph nodes of asthmatic mice( n = 5)
[0027]
[0028] Note: Compared with the control group, ***P<0.001; compared with the model group, ## P<0.01.
[0029] Table 4 Protein expression levels of CXCR6 and CXCL16 in the lung tissues of mice in each group( n = 3)
[0030]
[0031] Note: Compared with the control group, *P<0.05 and **P<0.01; compared with the model group, # P<0.05 and ## P<0.01.
[0032] (2) This study further explored the therapeutic effect of anti-CXCR6 antibody on allergic asthma airway inflammation mediated by targeting CD4 + T cells labeled with CXCR6.
[0033] As shown in Table 5, during the three sensitization stages on days 0 - 7, 7 - 14, and 14 - 21 respectively, the body weights of mice in each group gradually increased. During the aerosol challenge stage on days 21 - 28, the body weights of mice in the normal group and the anti - CXCR6 antibody group continued to increase, while the body weights of mice in the model group and the dexamethasone group decreased to varying degrees. Compared with the normal group, the body weights of mice in the model group were significantly reduced on days 21 - 28, and the difference was statistically significant (P < 0.01). The body weights of mice in the anti - CXCR6 antibody group were significantly increased on days 21 - 28, compared with the model group (P < 0.05), and the anti - CXCR6 antibody group had a significant alleviation of the body weight loss in mice compared with the marketed therapeutic drug dexamethasone, and the difference was statistically significant (P < 0.05).
[0034] As Figure 3 As shown in Figures A and Table 6, the results of H&E and AB - PAS staining showed that in the lung tissues of mice in the asthma model group, alveolar wall thickening was visible, accompanied by a large number of inflammatory cell infiltrations around bronchi and blood vessels, and a large amount of eosinophilic mucus was secreted by goblet cells in the bronchial mucosal epithelium. Also, the inflammation score of H&E staining and the percentage of eosinophilic mucus - positive areas of AB - PAS staining were significantly higher than those of the normal control group (P < 0.01). Compared with the model group, the inflammatory cell infiltration and eosinophilic mucus secretion in the lung tissues of mice in the anti - CXCR6 antibody group were significantly reduced, and the inflammation score of H&E staining was significantly decreased and the proportion of positive areas of AB - PAS staining was significantly decreased, and the difference was significant (P < 0.05). In addition, the anti - CXCR6 antibody group had a more obvious effect on improving the pathological changes of lung tissue inflammation than the marketed therapeutic drug dexamethasone, and the inflammation score of H&E staining was significantly decreased, and the difference was significant (P < 0.05).
[0035] Table 7 results showed that the numbers of white blood cells, monocytes, lymphocytes in the bronchoalveolar lavage fluid and eosinophils in the lung of mice in the model group were significantly increased compared with those in the normal control group (P<0.05). Compared with the model group, the numbers of white blood cells, lymphocytes, monocytes and eosinophils infiltrating the lung in the bronchoalveolar lavage fluid of the anti-CXCR6 antibody group and the dexamethasone group were significantly down-regulated, and the difference was statistically significant (P<0.05). In addition, the anti-CXCR6 antibody group significantly reduced the numbers of white blood cells, monocytes and lymphocytes infiltrating the lung compared with the dexamethasone group (P<0.05), indicating that the anti-CXCR6 antibody group had a more obvious effect on reducing inflammatory cells than the marketed therapeutic drug dexamethasone group. ELISA test results showed (see Table 8) that compared with the normal control group, the expression levels of specific OVA-IgE, pro-inflammatory cytokines IL-17A and IL-4 in the serum of mice in the model group were significantly increased (P<0.05), suggesting that the allergic asthma mouse model was in a highly sensitized state. Compared with the model group, anti-CXCR6 antibody treatment significantly reduced the contents of specific OVA-IgE, IL-17A and IFN-γ, and the difference was significant (P<0.05), and the CXCR6 antibody group more significantly reduced the content of specific OVA-IgE than the marketed therapeutic drug dexamethasone group (P<0.05). The above research results indicate that anti-CXCR6 antibody can improve airway inflammation in allergic asthma mice, and the therapeutic effect is significantly better than the marketed therapeutic drug dexamethasone.
[0036] Table 5 Changes in body weight differences of mice in each group from day 0 to day 28 ( n = 5)
[0037]
[0038] Note: Compared with the control group, **P<0.01; compared with the model group, # P<0.05; compared with the dexamethasone group, △ P < 0.05.
[0039] Table 6 Quantitative analysis of H&E and AB-PAS pathological staining of lung tissues of mice in each group ( n = 5)
[0040]
[0041] Note: Compared with the control group, **P<0.01 and ***P<0.001; compared with the model group, # P<0.05 and ## P<0.01; compared with the dexamethasone group, △ P < 0.05.
[0042] Table 7 Inflammatory cell infiltration levels in lung tissues of mice in each group ( n = 5)
[0043]
[0044]
[0045] Note: Compared with the control group, *P < 0.05 and ***P < 0.001; compared with the model group, # P < 0.05 and ## P < 0.01; compared with the dexamethasone group, △ P < 0.05.
[0046] Table 8 Expression levels of inflammatory cytokines and IgE in the sera of mice in each group ( n = 5)
[0047]
[0048] Note: Compared with the control group, *P < 0.05, **P < 0.01 and ***P < 0.001; compared with the model group, # P < 0.05 and ## P < 0.01; compared with the dexamethasone group, △ P < 0.05.
[0049] Therefore, as can be seen from Table 3, Table 4, Table 5, Table 6, Table 7 and Table 8, the anti-CXCR6 antibody effectively alleviated airway inflammation in OVA-induced allergic asthma mice, indicating that the high expression of CXCR6 and CXCR6+CD4+ T cells in lung tissue is related to airway inflammatory responses. Therefore, a therapeutic strategy targeting CXCR6 is expected to delay the progression of allergic asthma.
[0050] As described above, it is only a partial specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention should be covered within the protection scope of the present invention.
Claims
1. Use of an anti-CXCR6 antibody in the treatment of allergic asthma.
2. Use of the anti-CXCR6 antibody according to claim 1 in the treatment of allergic asthma, characterized in that: The chemokine receptor CXCR6 is highly expressed in the lung tissue of allergic asthma.
3. Use of the anti-CXCR6 antibody according to claim 1 in the treatment of allergic asthma, characterized in that: The anti-CXCR6 antibody strategy targeted to reduce pathogenic CXCR6 in the lung tissue of allergic asthma + CD4 + T cell ratio and down-regulated the expression of CXCR6 and its ligand CXCL16 proteins.
4. Use of the anti-CXCR6 antibody according to claim 1 in the treatment of allergic asthma, characterized in that: The anti-CXCR6 antibody mediates the treatment of allergic asthma airway inflammation by targeting CXCR6-labeled CD4 + T cells.