Cftr modulators for the treatment of igg4-related diseases

Abstract

The present application relates to the new use of CFTR modulators as the treatment of IgG4-related diseases, belonging to the field of biopharmacy. Specifically, the present application finds that CFTR modulators can significantly reduce the concentration of IgG1 in serum and reduce the inflammatory characteristics of the kidney in IgG4-related disease model mice through non-clinical pharmacodynamic tests, and has good therapeutic effect on IgG4-related diseases, and has the new use as the treatment of IgG4-related diseases. The present application also relates to a pharmaceutical composition comprising a CFTR modulator drug and a combination for such use.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of biopharmaceuticals, and particularly relates to the use of CFTR modulators in the preparation of a medicament for treating IgG4-related diseases. BACKGROUND

[0002] IgG4-related disease (IgG4-RD) is a newly defined immune-mediated chronic inflammation with fibrosis disease in recent years, and the main histopathological manifestations are lymphocyte and plasma cell infiltration mainly with IgG4+ plasma cells, accompanied by storiform fibrosis, occlusive phlebitis and eosinophil infiltration. This disease can almost involve all parts of the body, and a small number of patients have only single organ involvement, while most patients have multiple organ lesions at the same time or in succession. The most common clinical manifestations of this disease are significantly elevated serum IgG4 levels and mass-like lesions. The fibrosis caused by mass-like lesions and persistent immune inflammatory response can cause compression and irreversible damage to the involved organs and their surrounding tissues, and even organ failure.

[0003] For IgG4-RD, the main treatment drugs at present are still glucocorticoids or combined with immunosuppressive agents, and there is no specific drug for treating this disease. The drugs in the current III phase clinical research are all biological products. Therefore, it is urgent to find chemical drugs with better efficacy and less side effects for the treatment of this disease.

[0004] Drug discovery for treating diseases is extremely dependent on the development of animal models of diseases. In recent years, the Lat-Y136F mouse model has been gradually used for the research and development of IgG4-related diseases. The Lat-Y136F knock-in mouse model is a mouse in which the tyrosine at position 136 is replaced with phenylalanine, resulting in the loss of its ability to bind to PLC-gamma 1. The mouse then develops a lymphocyte proliferation disorder and shows expansion of CD4+ T cells and high expression of various Th2 type cytokines. At the same time, B cells are activated, and serum IgG1 and IgE levels are elevated. Lymphocyte infiltration is observed in the inflammatory lesions of the salivary glands, pancreas and kidneys of Lat-Y136F knock-in mice, and Azan staining shows that all Lat-Y136F knock-in mice develop severe fibrosis in the salivary glands, pancreas and kidneys. These phenotypes are very similar to the pathological basis of human IgG4-RD. Therefore, researchers predict that the Lat-Y136F knock-in mouse is a mouse model that is more suitable for the study of human IgG4-RD. It is worth noting that in the IgG4-RD disease model mice, the plasma cells infiltrating the organs mainly express IgG1 (the homolog of human IgG4). SUMMARY

[0005] The present application provides a solution that is the use of CFTR modulators as a treatment for IgG4-related diseases.

[0006] In particular, it has been found that CFTR modulators are effective in reducing the concentration of IgG1 in the serum of mice and in reducing the inflammatory features of the kidney in a mouse model of IgG4-RD.

[0007] The technical solution adopted by the present application is as follows: using CFTR modulators for the treatment of IgG4-related diseases.

[0008] Non-limiting examples of CFTR modulators include Tezacaftor, Lumacaftor, Elexacaftor, Ivacaftor or derivatives, prodrugs, metabolites or pharmaceutically acceptable salts and pharmaceutical compositions thereof.

[0009] In chemistry, the general name Tezacaftor refers to compound I, Lumacaftor refers to compound II, Elexacaftor refers to compound III, and Ivacaftor refers to compound IV.

[0010]

[0011]

[0012] The present application relates to formula I, II, III, IV, or a pharmaceutically acceptable salt and / or solvate and / or hydrate thereof, and a pharmaceutical composition containing the above-mentioned compounds, for the treatment of IgG4-related diseases.

[0013] The solvate of the compound of formula I, II, III, IV and / or the solvate of the pharmaceutically acceptable salt thereof is preferably used for the treatment of IgG4-related diseases.

[0014] The hydrate of the compound of formula I, II, III, IV and / or the hydrate of the pharmaceutically acceptable salt thereof is preferably used for the treatment of IgG4-related diseases.

[0015] The present application also relates to a pharmaceutical composition comprising a compound of formula I, II, III, IV or a pharmaceutically acceptable salt and / or solvate and / or hydrate thereof.

[0016] The pharmaceutical composition also comprises a pharmaceutically acceptable carrier or excipient, and in particular, the pharmaceutical composition is a solid preparation, a liquid preparation, an oral preparation, an injection or a compound preparation.

[0017] According to the present application, the pharmaceutical composition can be administered in any of the following ways: oral administration, parenteral administration such as subcutaneous, intravenous, intramuscular injection. Among them, oral administration is preferred.

[0018] When orally administered, the compound of formula I or its pharmaceutically acceptable salt and / or solvate and / or hydrate thereof can be prepared into any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions or suspensions. Among them, the carriers commonly used in tablets include lactose, corn starch, microcrystalline cellulose, sodium crosslinked cellulose and sodium carboxymethyl cellulose, and lubricants such as magnesium stearate can also be added. The diluents commonly used in capsule preparations include lactose and dry corn starch. The suspension preparation is usually a mixture of active ingredients with suitable emulsifiers and suspending agents. If necessary, some sweeteners, fragrances or colorants can also be added to the above oral dosage forms.

[0019] When injected, the compound of formula I, II, III, IV or its pharmaceutically acceptable salt and / or solvate and / or hydrate thereof can be prepared into injection solutions or injection powders, wherein the carriers that can be used include but are not limited to injection water, bulking carrier materials, pH adjusters, antioxidants, supporting agents, etc.

[0020] The beneficial effects of the technical solutions of the present application are: through non-clinical pharmacological tests, it is found that the compound of formula I tizacatol can significantly reduce the concentration of IgG1 in the serum of IgG4-related disease model mice, and reduce the inflammatory characteristics of the kidney, has a good therapeutic effect on IgG4-related diseases, and has the potential for the treatment of IgG4-related diseases. In the present application, the drug treatment object is mammalian, including humans, canids, rodents, etc. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 : The concentration of IgG1 in the serum of rats in each group after 21 days of drug treatment

[0022] Figure 2 : The pathological characteristics of the kidney of the blank group rats after 21 days of drug treatment

[0023] Figure 3 : The pathological characteristics of the kidney of the model group rats after 21 days of drug treatment

[0024] Figure 4 : The pathological characteristics of the kidney of the treatment group rats after 21 days of drug treatment DETAILED DESCRIPTION

[0025] The present application will be further described in detail below in combination with examples, but is not limited thereto.

[0026] A: Pharmacological and pharmacodynamic evaluation

[0027] Example 1: Pharmacodynamics test of tizacatol in IgG4 related disease mouse model

[0028] Test design: 14 Lat-Y136F knock-in mice, 6-8 weeks old, female, were randomly divided into 2 groups, model group, tizacatol treatment group (hereinafter referred to as treatment group), and 3 C57BL / 6 mice with suitable body weight were selected as blank control group. The blank control group and the model group were given blank solvent (10% DMSO + 10% HS-15 + 80% normal saline) by gavage, and the treatment group was given tizacatol 40 mg / kg / d by gavage, once a day, for 21 days of continuous administration. After the last administration, the samples were taken.

[0029] Detection index: ① Serum IgG1 level, ② Kidney pathology.

[0030] The animal grouping and drug administration scheme are summarized as follows:

[0031]

[0032] Example 2: Evaluation of serum IgG1 level in tizacatol treatment of IgG4 related disease mouse model

[0033] In the test of Example 1, the serum IgG1 concentration of mice in the blank control group, model group and treatment group was measured after 21 days of administration, and the data of each group are shown in Table 1 and Figure 1 . The results show that the IgG1 level of the model group is significantly higher than that of the blank group, showing the feasibility of the mouse model. After treatment with tizacatol, the IgG1 level of the treatment group is significantly decreased compared with the model group, and has statistical difference.

[0034] Table 1 IgG1 level of mice in each group

[0035]

[0036] In the experiment, one way ANOVA was used for statistics, * indicates P<0.05 compared with the control group, and * indicates P<0.05 compared with the model group.

[0037] Example 3: Evaluation of kidney pathology in tizacatol treatment of IgG4 related disease mouse model

[0038] In the test of Example 1, after 21 days of administration, the kidneys were taken, fixed with formalin, paraffin-embedded and stained with H&E for pathological analysis. The results show that the blank group has few inflammatory features, the inflammation score of the model group is higher than that of the blank group, showing the feasibility of the mouse model. After treatment with tizacatol, the inflammation score of the treatment group is significantly decreased compared with the model group, and has statistical difference.

[0039] Table 2: Inflammatory level score of kidney in each group of mice

[0040]

[0041] In the experiment, one way ANOVA was used for statistics, * represents P<0.05, comparison between the model group and the control group, # P<0.05.

[0042] Example 4: Comprehensive therapeutic effect analysis of tizacatol in the treatment of IgG4-related disease model mice

[0043] According to the results and evaluation of the above multiple indicators, the Lat-Y136F mice have obvious IgG4-related disease phenotype characteristics, tizacatol can significantly reduce the concentration of IgG1 in the serum of IgG4-related disease model mice, and reduce the inflammatory characteristics of the kidney, and has good therapeutic effect on IgG4-related disease.

[0044] B: Pharmaceutical composition

[0045] Example 5: Preparation of a pharmaceutical composition containing tizacatol, oral tablet prescription:

[0046]

[0047] Preparation process:

[0048] (1) Weigh the prescription amount of tizacatol, microcrystalline cellulose, lactose, talc, cross-linked sodium carboxymethyl cellulose, and silicon dioxide in the hopper mixer and mix, the mixing speed is 15 rpm, and the mixing time is 5 min;

[0049] (2) Granulate the above mixed powder using a dry granulator, the granulation parameters are: pressure: 6 bar, vertical feeding speed: 10 rpm, horizontal feeding speed: 30 rpm, roller speed: 8 rpm, and whole granulation speed: 100 rpm;

[0050] (3) Mix the prepared granules with the prescription amount of sodium dodecyl sulfate and magnesium stearate in the hopper mixer, the mixing speed is 15 rpm, and the mixing time is 5 min.

[0051] (4) The above mixed powder is compressed into naked tablets according to the tablet weight of 200 mg and the hardness of 60-90 N;

[0052] (5) Coat the naked tablets with coating material, stop coating after the weight increases by 4%, and obtain the finished product.

[0053] Example 6: Preparation of a pharmaceutical composition containing tizacatol, injection prescription:

[0054]

[0055] Preparation process:

[0056] (1) The prescribed amount of edetate disodium, Tween 20, sodium chloride, and tizacatol are sequentially dissolved completely using about 90% of the prescribed amount of water for injection;

[0057] (2) The pH of the drug solution is adjusted to 6.0-8.0 using 1 mol / L sodium hydroxide;

[0058] (3) The water for injection is added to the constant volume;

[0059] (4) The above constant volume drug solution is filtered using a polyether sulfone 0.22 micron filter membrane;

[0060] (5) The filtered drug solution is filled into ampoules and fusion sealed;

[0061] (6) The finished product is obtained by sterilization at 121°C for 15 min.

Claims

1. Use of tizacator or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating IgG4-related nephropathy.

2. The use according to claim 1, wherein the medicament comprises tizzacator or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.

3. The use according to claim 1, wherein the medicament comprises tizzacator or a pharmaceutically acceptable salt thereof, one or more therapeutic agents and one or more pharmaceutically acceptable excipients.

4. The method according to claim 3, wherein the one or more therapeutic agents are selected from hormone drugs, traditional immunosuppressants, rituximab, inerizumab, obexelimab, and bortezomib.

5. The use according to claim 4, wherein the traditional immunosuppressant is selected from mycophenolate mofetil, azathioprine, cyclophosphamide, leflunomide, methotrexate, cyclosporine, tacrolimus, 6-mercaptopurine, thalidomide, and iguratimod.

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