Effect of fat factor Chemerin in pulmonary arterial hypertension

Abstract

The invention relates to the technical field of pulmonary arterial hypertension treatment, and discloses an application of a fat factor Chemerin inhibitor in preparation of drugs for treating pulmonary arterial hypertension, the Chemerin inhibitor improves pulmonary vascular remodeling, reduces pulmonary vascular resistance and alleviates right ventricular hypertrophy by inhibiting the activity of Chemerin protein or its receptor CMKLR1; the invention focuses on the key effect of the fat factor Chemerin and the receptor CMKLR1 thereof in pulmonary arterial hypertension, directly blocks the signal channel through the specific inhibitor, inhibits abnormal remodeling of pulmonary blood vessels from the source, reduces vascular resistance and right heart load, overcomes the limitation that the existing vasodilatation drugs cannot reverse vascular structure remodeling, and has a good application prospect. A brand new strategy is provided for disease treatment; a high-selectivity small molecule antagonist and a targeted delivery system are adopted, so that the enrichment efficiency of the medicine in the lung is remarkably improved, and the off-target risk is reduced; aiming at pulmonary arterial hypertension crowds carrying BMPR2 gene mutation or specific imaging characteristics, individualized solutions are provided for patients in different disease course stages.

Description

Technical Field

[0001] The present invention relates to the technical field of pulmonary hypertension treatment, in particular to the role of adipose factor Chemerin in pulmonary hypertension. Background Art

[0002] Pulmonary arterial hypertension (PAH) is a fatal disease characterized by progressive pulmonary vascular remodeling, increased resistance and right heart failure. Its pathological mechanism is complex and involves multiple factors such as inflammatory activation, endothelial dysfunction and abnormal smooth muscle proliferation.

[0003] Current clinical treatments are primarily vasodilators (such as endothelin receptor antagonists and prostacyclin analogs). While these drugs can temporarily relieve vasoconstriction, they are unable to effectively reverse structural lesions such as pulmonary vascular wall thickening and fibrosis, resulting in a five-year survival rate of less than 60%. Recent studies have found that the adipokine Chemerin can activate the downstream MAPK / ERK pathway by binding to the CMKLR1 receptor, promoting the migration and proliferation of vascular smooth muscle cells. However, its specific mechanism of action in pulmonary arterial hypertension remains unclear. Existing treatments lack specific inhibitors for this signaling pathway, and traditional small molecule drugs (such as tyrosine kinase inhibitors) are prone to systemic side effects (such as thrombocytopenia and hepatotoxicity) due to their lack of targeting, which severely limits their clinical application. In addition, there is significant heterogeneity among patients with pulmonary arterial hypertension. Approximately 70% of hereditary cases are associated with BMPR2 gene mutations, but existing therapies have not achieved stratified precision treatment based on biomarkers (such as Chemerin levels). At the same time, conventional oral or intravenous administration has low lung targeting efficiency and requires frequent high-dose administration, which exacerbates poor patient compliance and the risk of systemic exposure. Therefore, the development of new treatment options that combine mechanism innovation, target specificity and dosage form optimization is an urgent need to break through the current treatment dilemma. Summary of the Invention

[0004] The purpose of the present invention is to provide the role of the adipokine Chemerin in pulmonary hypertension, so as to solve the problems raised in the above background technology.

[0005] To achieve the above object, the present invention provides the following technical solutions: A Chemerin inhibitor is used in the preparation of a drug for treating pulmonary hypertension. The Chemerin inhibitor improves pulmonary vascular remodeling, reduces pulmonary vascular resistance, and alleviates right ventricular hypertrophy by inhibiting the activity of Chemerin protein or its receptor CMKLR1.

[0006] As a further embodiment of the present invention, the Chemerin inhibitor is any one of the following: A monoclonal neutralizing antibody or antigen-binding fragment thereof that specifically binds to Chemerin; Highly selective small molecule antagonists targeting CMKLR1; Peptide inhibitors that inhibit the reorganization of the Chemerin-CMKLR1 signaling pathway.

[0007] As a further solution of the present invention: when inhibiting CMKLR1, the small molecule antagonist has a selectivity at least 10 times higher than that of the same family receptors such as CCR2 and CXCR4, and the IC50 value is lower than 100 nM.

[0008] A pharmaceutical composition for treating pulmonary hypertension comprises a Chemerin inhibitor and a pharmaceutically acceptable carrier. The composition is administered in the form of an intravenous injection, a subcutaneous sustained-release implant, or an aerosol inhalation preparation.

[0009] As a further solution of the present invention: the particle size of the aerosol inhalation preparation is 1-3 μm, and polyethylene glycol-modified liposomes are used as delivery vehicles to enhance lung targeting.

[0010] As a further embodiment of the present invention, the drug is used for individuals carrying BMPR2 gene mutations or with imaging features of precapillary pulmonary hypertension, and the administration regimen is a low dose once a week to maintain a steady-state blood drug concentration of 10-100 nM.

[0011] As a further solution of the present invention: the subcutaneous sustained-release implant uses a PLGA carrier, the sustained-release period complies with the zero-order kinetic characteristics, and the in vitro release is maintained for ≥14 days.

[0012] A combined drug kit for treating pulmonary arterial hypertension, comprising: Chemerin inhibitors; at least one drug selected from an endothelin receptor antagonist, a phosphodiesterase type 5 inhibitor, a prostacyclin analogue, or a soluble guanylate cyclase agonist; Package insert describing the combination regimen.

[0013] A detection kit for pulmonary hypertension risk assessment, comprising: Antibodies or probes for detecting Chemerin protein; A reference substance with a concentration threshold of 20 ng / mL and instructions for determining the results.

[0014] Compared with the prior art, the present invention has the following beneficial effects: 1. This invention focuses on the key role of the adipokine Chemerin and its receptor CMKLR1 in pulmonary hypertension. By directly blocking the signaling pathway through specific inhibitors, it inhibits abnormal pulmonary vascular remodeling from the source, reduces vascular resistance and right heart load, and overcomes the limitation of existing vasodilator drugs that cannot reverse vascular structural remodeling, providing a new strategy for disease treatment.

[0015] 2. The present invention adopts highly selective small molecule antagonists and targeted delivery systems to significantly improve the drug enrichment efficiency in the lungs, while avoiding interference with the same family receptors and reducing the risk of off-target. Combined with subcutaneous sustained-release implants and nebulized inhalation dosage forms, it can achieve precise regulation of steady-state blood drug concentrations, reduce systemic adverse reactions, and improve patient compliance.

[0016] 3. This invention targets patients with pulmonary arterial hypertension who carry BMPR2 gene mutations or specific imaging features. It uses Chemerin concentration thresholds to screen for treatment responders, achieves precise typing, and combines existing drugs such as endothelin receptor antagonists to form a multi-pathway synergistic intervention, enhance efficacy and delay disease progression, and provide personalized solutions for patients at different stages of the disease. DETAILED DESCRIPTION

[0017] A Chemerin inhibitor is used in the preparation of a drug for treating pulmonary hypertension. The Chemerin inhibitor improves pulmonary vascular remodeling, reduces pulmonary vascular resistance and alleviates right ventricular hypertrophy by inhibiting the activity of Chemerin protein or its receptor CMKLR1.

[0018] Preferably, the Chemerin inhibitor is any one of the following: A monoclonal neutralizing antibody or antigen-binding fragment thereof that specifically binds to Chemerin; Highly selective small molecule antagonists targeting CMKLR1; Peptide inhibitors that inhibit the reorganization of the Chemerin-CMKLR1 signaling pathway.

[0019] Preferably, the small molecule antagonist has a selectivity of at least 10 times higher than that of the same family receptors such as CCR2 and CXCR4 when inhibiting CMKLR1, and the IC50 value is less than 100 nM.

[0020] A pharmaceutical composition for treating pulmonary hypertension comprises a Chemerin inhibitor and a pharmaceutically acceptable carrier. The composition is administered in the form of an intravenous injection, a subcutaneous sustained-release implant, or an aerosol inhalation preparation.

[0021] Preferably, the particle size of the aerosol inhalation preparation is 1-3 μm, and polyethylene glycol-modified liposomes are used as delivery vehicles to enhance lung targeting.

[0022] Preferably, the drug is used for individuals carrying BMPR2 gene mutations or with imaging features of precapillary pulmonary hypertension, and the dosing regimen is a low dose once a week to maintain a steady-state blood drug concentration of 10-100 nM.

[0023] Preferably, the subcutaneous sustained-release implant uses a PLGA carrier, the sustained-release period conforms to the zero-order kinetic characteristics, and the in vitro release is maintained for ≥14 days.

[0024] A combined drug kit for treating pulmonary arterial hypertension, comprising: Chemerin inhibitors; at least one drug selected from an endothelin receptor antagonist, a phosphodiesterase type 5 inhibitor, a prostacyclin analogue, or a soluble guanylate cyclase agonist; Package insert describing the combination regimen.

[0025] A detection kit for pulmonary hypertension risk assessment, comprising: Antibodies or probes for detecting Chemerin protein; A reference substance with a concentration threshold of 20 ng / mL and instructions for determining the results.

[0026] In order to further illustrate the technical effects of the present invention, the following experiments were performed to verify: Experiment 1: Effects of Chemerin Inhibitors on Pulmonary Vascular Resistance in a Mouse Model of Pulmonary Hypertension 1. Experimental Materials and Methods Experimental animals: Thirty healthy male C57BL / 6J mice weighing 20-25 g were randomly divided into three groups, with 10 mice in each group: control group, model group, and Chemerin inhibitor treatment group. The control group mice were fed a normal diet and breathed normoxic air; The pulmonary hypertension model was established in the model group mice by chronic hypoxia exposure (10% O2) combined with intraperitoneal injection of monoclonal antibody (10 mg / kg); While the model was being established, mice in the Chemerin inhibitor treatment group were given intravenous injections of a monoclonal neutralizing antibody that specifically binds to Chemerin (at a dose of 5 mg / kg, once a week).

[0027] Experimental period: The experiment lasted for 4 weeks.

[0028] Index detection: At the end of the experiment, the mean pulmonary artery pressure (mPAP) of mice in each group was measured by right heart catheterization technology, and the pulmonary vascular resistance (PVR) was calculated.

[0029] 2. Experimental results

[0030] 3. Conclusion: Compared with the control group, the mean pulmonary artery pressure and pulmonary vascular resistance of the mice in the model group were significantly increased (P<0.01); compared with the model group, the mean pulmonary artery pressure and pulmonary vascular resistance of the mice in the Chemerin inhibitor treatment group were significantly decreased (P<0.01), indicating that Chemerin inhibitor can effectively improve pulmonary vascular resistance in the mouse model of pulmonary hypertension.

[0031] Experiment 2: Evaluation of the effect of combined medication on improving pulmonary vascular remodeling in patients with pulmonary hypertension 1. Experimental Materials and Methods Study participants: Sixty patients with clinically confirmed pulmonary arterial hypertension were randomly divided into two groups, 30 in each. The combination group received a chemerin inhibitor (a highly selective small molecule antagonist targeting CMKLR1, administered orally at a dose of 2 mg once daily) combined with an endothelin receptor antagonist (bosentan at a dose of 125 mg twice daily); the monotherapy control group received only the endothelin receptor antagonist (bosentan at a dose of 125 mg twice daily).

[0032] Experimental period: Both groups of patients were treated for 12 weeks.

[0033] Index detection: Before and after treatment, high-resolution chest CT scan and right cardiac catheterization were used to evaluate the patient's pulmonary vascular remodeling, including the pulmonary arteriolar wall thickness / outer diameter ratio (WT / OD) and pulmonary vascular resistance index (PVRI).

[0034] 2. Experimental results

[0035] 3. Conclusion: The results showed that after treatment, the pulmonary arteriolar wall thickness / outer diameter ratio and pulmonary vascular resistance index in the combination group were significantly lower than those in the single-drug control group (P<0.05), indicating that the combination of Chemerin inhibitors and endothelin receptor antagonists can more effectively improve pulmonary vascular remodeling in patients with pulmonary hypertension and enhance the therapeutic effect.

[0036] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the invention can be embodied in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as illustrative and non-restrictive, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations that come within the meaning and range of equivalents of the claims be embraced therein.

[0037] In addition, it should be understood that although this specification is described in terms of implementation methods, not every implementation method contains only one independent technical solution. This narrative method of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment can also be appropriately combined to form other implementation methods that can be understood by those skilled in the art.

Claims

1. Use of an adipose factor Chemerin inhibitor in the preparation of a drug for treating pulmonary arterial hypertension, characterized in that: The Chemerin inhibitor improves pulmonary vascular remodeling, reduces pulmonary vascular resistance and alleviates right ventricular hypertrophy by inhibiting the activity of Chemerin protein or its receptor CMKLR1.

2. The use according to claim 1, characterized in that The Chemerin inhibitor is any one of the following: A monoclonal neutralizing antibody or antigen-binding fragment thereof that specifically binds to Chemerin; Highly selective small molecule antagonists targeting CMKLR1; Peptide inhibitors that inhibit the reorganization of the Chemerin-CMKLR1 signaling pathway.

3. The use according to claim 2, characterized in that When inhibiting CMKLR1, the small molecule antagonist has a selectivity at least 10 times higher than that of the same family receptors such as CCR2 and CXCR4, and the IC50 value is lower than 100 nM.

4. A pharmaceutical composition for treating pulmonary arterial hypertension, comprising the Chemerin inhibitor according to claim 1 or 2 and a pharmaceutically acceptable carrier, characterized in that: The composition is administered in the form of intravenous injection, subcutaneous sustained-release implant or aerosol inhalation preparation.

5. The pharmaceutical composition according to claim 4, characterized in that The particle size of the aerosol inhalation preparation is 1-3 μm, and polyethylene glycol-modified liposomes are used as delivery carriers to enhance lung targeting.

6. The pharmaceutical composition according to claim 4, characterized in that The drug is used for individuals carrying BMPR2 gene mutations or with imaging features of precapillary pulmonary hypertension. The dosing regimen is a low dose once a week to maintain a steady-state blood drug concentration of 10-100 nM.

7. The pharmaceutical composition according to claim 4, characterized in that The subcutaneous sustained-release implant adopts a PLGA carrier, the sustained-release period conforms to the zero-order kinetic characteristics, and the in vitro release is maintained for ≥14 days.

8. A combined drug kit for treating pulmonary hypertension, characterized in that: Include: Chemerin inhibitors; at least one drug selected from an endothelin receptor antagonist, a phosphodiesterase type 5 inhibitor, a prostacyclin analogue, or a soluble guanylate cyclase agonist; Package insert describing the combination regimen.

9. A detection kit for pulmonary hypertension risk assessment, characterized in that: Include: Antibodies or probes for detecting Chemerin protein; A reference substance with a concentration threshold of 20 ng / mL and instructions for determining the results.

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