Method for treating autoimmune diseases

Abstract

Disclosed is a method for treating autoimmune diseases, wherein a therapeutically effective amount of a proteasome inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered to a patient with autoimmune diseases. This method has a certain therapeutic effect on patients with autoimmune diseases, such as systemic lupus erythematosus, lupus nephritis (LN), and autoimmune hepatitis. The proteasome inhibitor or the pharmaceutically acceptable salt or pharmaceutical composition thereof has low toxicity, thereby showing excellent clinical application prospects.

Description

A method for treating autoimmune diseases Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a method for treating autoimmune diseases, more specifically to the use of proteasome inhibitors and their in vivo active ingredients for treating patients with autoimmune diseases, such as patients with systemic lupus erythematosus. Technical Background

[0002] The ubiquitin-proteasome pathway (UPP) is a major pathway for the degradation of intracellular proteins and participates in many physiologically important cellular processes, including signal transduction, immune responses, unfolded protein responses, and cell cycle progression. This pathway is significantly associated with neurodegenerative diseases and disorders, as well as autoimmune diseases such as amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus and lupus nephritis (SLE / LN), glomerulonephritis, autoimmune hepatitis (AIH), rheumatoid arthritis, inflammatory bowel disease (IBD), osteoarthritis, arteriosclerosis, myasthenia gravis, pulmonary fibrosis, and hematologic malignancies. Proteasome inhibitors have been used in cancer treatment. In 2003, the first proteasome inhibitor, bortezomib, was approved by the FDA for the treatment of relapsed myeloma.

[0003] Preclinical studies have shown that selective proteasome inhibition produces a broad anti-inflammatory response in animal models of various autoimmune diseases while avoiding immunosuppression. Kezar Life Sciences' selective proteasome inhibitor, Zetomipzomib, is intended for the treatment of a range of autoimmune diseases, including systemic lupus erythematosus, lupus nephritis (LN), and autoimmune hepatitis (AIH).

[0004] Many autoimmune diseases, including lupus nephritis and systemic lupus erythematosus (SLE), have a higher incidence in Asia than in other regions. It is estimated that there are 1 million SLE patients in China alone, and 40%–60% of SLE patients have kidney involvement, i.e., lupus nephritis. Lupus nephritis is the most common secondary immune glomerular disease, which can gradually lead to kidney failure as it progresses, and is one of the common causes of end-stage renal disease. Disease progression can lead to organ damage, increased medical costs, deterioration of quality of life, and increased mortality. Current treatment options for SLE are limited. Although many biologics have entered clinical trials and achieved good results (such as Belimumab, Rituximab, anifrolumab, and Baricitinib), most are unable to reduce organ damage in the early stages (26% of lupus nephritis patients develop end-stage renal disease) or control the progression and recurrence of skin lesions, and may even lead to worsening of skin lesions.

[0005] Therefore, developing a low-cost, highly effective proteasome inhibitor with few side effects for precise targeted treatment of autoimmune diseases such as systemic lupus erythematosus, lupus nephritis (LN), and autoimmune hepatitis (AIH), and studying its efficacy are key issues that we need to address at present. Summary of the Invention

[0006] This invention provides a method for treating an autoimmune disease, comprising administering a therapeutically effective amount of a proteasome inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a patient with an autoimmune disease.

[0007] This invention provides a method for treating autoimmune diseases, comprising administering a therapeutically effective amount of a proteasome inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a patient with an autoimmune disease; wherein the autoimmune disease is selected from: systemic lupus erythematosus, lupus nephritis, autoimmune hepatitis, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis.

[0008] Furthermore, the autoimmune diseases mentioned are selected from: systemic lupus erythematosus, lupus nephritis, and autoimmune hepatitis.

[0009] Furthermore, the proteasome inhibitor is a compound of formula (I):

[0010] Furthermore, the compound of formula (I) is administered orally;

[0011] Furthermore, the compound of formula (I) is administered intravenously.

[0012] The present invention also provides a method for treating an autoimmune disease, comprising administering a therapeutically effective amount of a proteasome inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a patient with an autoimmune disease.

[0013] Furthermore, the proteasome inhibitor is a compound of formula (II):

[0014] Furthermore, the compound of formula (II) is administered orally;

[0015] Furthermore, the compound of formula (II) is administered intravenously.

[0016] In some embodiments, the compounds provided by the present invention may be used in the preparation of medicaments for treating autoimmune diseases;

[0017] Furthermore, the autoimmune diseases mentioned are: systemic lupus erythematosus, lupus nephritis, autoimmune hepatitis, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis.

[0018] Furthermore, the autoimmune diseases mentioned are: systemic lupus erythematosus, lupus nephritis, and autoimmune hepatitis.

[0019] The method for treating autoimmune diseases provided by this invention involves administering a therapeutically effective amount of a proteasome inhibitor or its pharmaceutically acceptable salt or pharmaceutical composition to patients with autoimmune diseases. This method has a certain therapeutic effect on patients with autoimmune diseases such as systemic lupus erythematosus, manifested in varying degrees of weight reduction, improvement of skin lesion scores and lymph node scores, reduction of splenomegaly, reduction of lymph node hyperplasia, improvement of renal function trends, and reduction of proteinuria. Moreover, it has low toxicity and excellent clinical application prospects. Attached Figure Description

[0020] Figure 1 shows the effect of compound I and the positive control group prednisolone acetate tablets on the body weight (g) of SLE mice (mean, n=10);

[0021] Figure 2 shows the effect of compound I and the positive control group prednisolone acetate tablets on the skin lesion score (AUC0-8w) of SLE mice;

[0022] Figure 3 shows the effect of compound I and the positive control group prednisolone acetate tablets on the lymph node score (AUC0-8w) of SLE mice.

[0023] Figure 4 shows the effects of compound I and the positive control group prednisolone acetate tablets on organ coefficients in SLE mice (mean ± SD, n = 10).

[0024] Figure 5 shows the effect of compound I and the positive control group prednisolone acetate tablets on the lymph node coefficient of SLE mice (mean ± SD, n = 10).

[0025] Figure 6 shows the effects of compound I and the positive control group prednisolone acetate tablets on urinary protein in SLE mice (mean ± SD, n = 10).

[0026] Figure 7 shows the effect of compound I and the positive control group prednisolone acetate tablets on serum anti-dsDNA antibody (μg / mL) and serum inflammatory factors in SLE mice (mean±SD, n=10).

[0027] Figure 8 shows the effects of compound I and the positive control group prednisolone acetate tablets on serum inflammatory factors in SLE mice (mean ± SD, n = 10).

[0028] Figure 9 shows the effect of compound I and prednisolone acetate tablets on activated T cells (CD4+) in the spleen of SLE mice. + CD69 + )Influence.

[0029] Figure 10 shows the effect of compound I and prednisolone acetate tablets on CD19 cells in the spleen of SLE mice. + )Influence.

[0030] Figure 11 shows the effect of compound I and prednisolone acetate tablets on CD19 cells in the spleen of SLE mice. - CD138 + )Influence. Detailed Implementation

[0031] The present invention will be further described below with reference to specific embodiments, based on common technical knowledge and conventional methods in the art. The following embodiments are only some preferred embodiments of the present invention and should not be regarded as limitations on the present invention. For those skilled in the art, several improvements can be made without departing from the scope of the present invention, and these improvements should also be considered within the protection scope of the present invention.

[0032] Example 1: Selective inhibition of B lymphocyte proliferation by compound I and control compound

[0033] The Cell Counting-Lite 2.0 assay kit was used to detect the effect of compound I on the proliferation of human peripheral B lymphocytes and mouse fibroblasts, and to explore the inhibitory and selective effects of compound I on B lymphocyte proliferation.

[0034] As shown in Table 1 below, compound I inhibits the IC50 of human peripheral B lymphocytes. 50 The values ​​were 3.34 ± 0.78 nM, respectively; while the IC50 for fibroblasts was 3.34 ± 0.78 nM. 50The values ​​were 155.5 ± 3.73 nM, indicating that compound I can effectively inhibit the proliferation of B lymphocytes without affecting normal cells.

[0035] Table 1. Inhibition of cell proliferation by compound I in vitro (IC50) 50 Summary (n=3) a:Selectivity=IC 50(L929) / IC 50(IM-9)

[0036] Simultaneously, this study also examined the B lymphocyte inhibitory activity of the proteasome inhibitor zetomipzomib. As shown in Table 2 below, compared to zetomipzomib, compound I exhibited a stronger inhibitory effect on B lymphocyte proliferation, indicating that compound I has a stronger function in clearing B lymphocytes. This also suggests that compound I and zetomipzomib have different mechanisms of action.

[0037] Table 2: Inhibition IC50 of Zetomipzomib on cell proliferation in vitro 50 Summary (n=3)

[0038] Example 2: Pharmacodynamic study of compound I in MRL / MpJ-Faslpr / J systemic lupus erythematosus model mice

[0039] This study used female MRL / MpJ-Faslpr / J systemic lupus erythematosus (SLE) model mice, which are spontaneously mutant Faslpr mice exhibiting systemic autoimmunity, giant lymphadenopathy associated with abnormal T-cell proliferation, and immune complex glomerulonephritis. Their pathological manifestations represent the clinicopathological features of SLE, and therefore were used to evaluate the therapeutic effect of compound I on SLE, providing a basis for clinical research. The active form of compound I in vivo is compound II.

[0040] Eight-week-old female model mice were purchased for this experiment and randomly divided into five groups at 10 weeks of age based on serum anti-dsDNA antibody levels. Specific grouping and administration information are detailed in Table 3. The measured indicators included body weight, skin lesion score, lymph node score, spleen, kidney, lymph node (submandibular, axillary, and inguinal lymph nodes) weight and organ coefficient, serum renal function, urine protein, anti-dsDNA antibody, serum inflammatory factors, T and B cell subsets, and hematologic pathology of the kidneys and facial skin.

[0041] Table 3 Grouping and Dosing Information Note: 1. The normal control group used MRL / MpJ mice, which are non-mutant faslpr mice. They also showed autoimmune diseases, but the onset time was later than that of the MRL / MpJ-Faslpr / J model mice.

[0042] Effects on weight

[0043] The results are shown in Table 4 and Figure 1. After 16 weeks, the body weight of the SLE model mice increased significantly, showing a significant difference compared with the normal control group (P<0.05). Compared with the model control mice, the high-dose group of compound I (0.8 mg / kg) treated for 5-8 weeks had a certain reduction in body weight (P<0.05-0.01), while the low- and medium-dose groups of compound I (0.2 and 0.4 mg / kg) had no significant effect on body weight. The positive control group treated with prednisolone acetate tablets for 6-8 weeks also had a certain reduction in body weight (P<0.05-0.01).

[0044] Table 4. Effects on body weight (g) of SLE mice (mean ± SD, n = 10) Note 1. Compared with the normal control group: # P<0.05; 2. Compared with the model control group: * P<0.05, ** P<0.01.

[0045] Impact on skin lesion score

[0046] As shown in Tables 5 and 6 and Figure 2, the mice in the model control group began to show skin lesions 3 weeks after treatment, including hair loss on both sides of the nose and lichenification of the skin. The skin lesions became more severe over time. Compared with the normal control group, there was a significant difference in skin lesion scores from 5 to 8 weeks after treatment (P<0.001).

[0047] Table 5. Effects on skin lesion scores (points) in SLE mice (mean ± SD, n = 10) Note 1. Compared with the normal control group: ### P<0.001; 2. Compared with the model control group: * P<0.05, ** P<0.01, *** P<0.001.

[0048] Table 6. Effects of AUC0-8w on skin lesion scores (points) in SLE mice (mean ± SD, n = 10) Note 1. Compared with the normal control group: ### P<0.001; 2. Compared with the model control group: ** P<0.01, *** P<0.001.

[0049] Effect on lymph node score

[0050] In the model control group, lymph node enlargement could be palpated 3-8 weeks after treatment. The lymph node score increased with the extension of treatment time, and the difference was statistically significant compared with the normal control group (P<0.01-0.001).

[0051] Compound I was administered at low, medium, and high doses (0.2, 0.4, and 0.8 mg / kg) for 5–8 weeks. The lymph node scores in each group decreased in a dose-dependent manner (P<0.05–0.001). Compared with the model control group, it reduced the AUC of lymph node scores. 0-8w The levels decreased by 39.4% (P<0.001), 40.0% (P<0.001), and 47.6% (P<0.001), respectively. In the positive control group, prednisolone acetate tablets reduced the lymph node score AUC. 0-8w The decrease was 52.4% (P<0.001). The results are shown in Tables 7 and 8 and Figure 3.

[0052] Table 7. Effects on lymph node scores (points) in SLE mice (mean ± SD, n = 10) Note 1. Compared with the normal control group: ### P<0.001; 2. Compared with the model control group: * P<0.05, ** P<0.01, *** P<0.001.

[0053] Table 8. Effects of AUC0-8w on lymph node scores (points) in SLE mice (mean ± SD, n = 10)

[0054] Impact on organ coefficient

[0055] SLE, due to abnormal activation of the body's immune system, leads to inflammatory responses and damage to major tissues and organs; therefore, the state of the spleen can reflect the severity of the disease. As shown in Table 9 and Figure 4, compared with the normal control group, the spleen weight and spleen coefficient of the model control group mice were significantly increased, indicating significant splenomegaly. Treatment with low, medium, and high doses of compound I (0.2, 0.4, and 0.8 mg / kg) for 8 weeks dose-dependently inhibited splenomegaly, significantly reducing spleen weight and spleen coefficient. Compared with the model control group, spleen weight decreased by 20.7% (P<0.05), 26.0% (P<0.01), and 52.4% (P<0.001), respectively; spleen coefficient decreased by 22.7% (P<0.01), 25.0% (P<0.01), and 46.1% (P<0.001), respectively. The positive control group also showed a significant inhibitory effect on splenomegaly, reducing spleen weight and spleen coefficient by 78.2% (P<0.001) and 74.4% (P<0.001), respectively.

[0056] Table 9. Effects of spleen weight and spleen coefficient on SLE mice (mean ± SD, n = 10) Note 1. Compared with the normal control group: ### P<0.001; 2. Compared with the model control group: * P<0.05, ** P<0.01, *** P<0.001.

[0057] As shown in Table 10 and Figure 4, compared with the normal control group, the kidney weight and kidney coefficient of the model control group mice were significantly increased, indicating obvious renal enlargement. Treatment with low, medium, and high doses of compound I (0.2, 0.4, and 0.8 mg / kg) for 8 weeks showed a decreasing trend in kidney weight, but no significant effect on the kidney coefficient. The positive control group, prednisolone acetate tablets, significantly reduced kidney weight by 27.8% (P<0.01) and showed a certain decreasing trend in the kidney coefficient.

[0058] Table 10 Effect of SLE on kidney coefficient in mice (mean ± SD, n = 10) Note 1. Compared with the normal control group: ### P<0.001; 2. Compared with the model control group: ** P<0.01.

[0059] In studies on the effects on major organs, lymph nodes, as peripheral immune organs, indirectly reflect the disease status of SLE. The results are shown in Table 11 and Figure 5. Compared with the normal control group, the submandibular lymph nodes, axillary lymph nodes, and inguinal lymph nodes of the model control group mice were significantly enlarged, and the weight of lymph nodes in each location, the total weight of lymph nodes, and the total lymph node coefficient were all significantly increased (P<0.05-0.001). Compound I, at low, medium, and high doses (0.2, 0.4, and 0.8 mg / kg), administered for 8 weeks, dose-dependently inhibited lymph node enlargement at various sites, significantly reducing lymph node weight, total lymph node weight, and total lymph node coefficient at all sites (P<0.05–0.001). Compared with the model control group, it reduced total lymph node weight by 27.5% (P<0.05), 37.8% (P<0.001), and 63.9% (P<0.001), respectively, and reduced total lymph node coefficient by 29.1% (P<0.01), 36.2% (P<0.001), and 59.8% (P<0.001), respectively. In the positive control group, prednisolone acetate tablets significantly reduced the weight of lymph nodes, total lymph node weight, and total lymph node coefficient at all sites, decreasing the total lymph node weight by 72.9% (P<0.001) and the total lymph node coefficient by 68.4% (P<0.001), respectively.

[0060] Table 11 Effects of these effects on lymph node weight and coefficient in SLE mice (mean ± SD, n = 10) Note 1. Compared with the normal control group: # P<0.05, ### P<0.001; 2. Compared with the model control group: * P<0.05, ** P<0.01, ***P<0.001.

[0061] Effects on kidney function

[0062] Lupus nephritis is the most common and severe target organ damage in SLE, with the main clinical manifestations of kidney damage being hematuria and / or proteinuria. As shown in Tables 12 and 13, in the model control group, Cr and BUN levels increased at 4 and 8 weeks of treatment, with statistically significant differences compared to the normal control group (P < 0.05–0.01). In the low, medium, and high dose groups of compound I (0.2, 0.4, and 0.8 mg / kg), Cr and BUN levels showed a decreasing trend at 4 and 8 weeks of treatment. The positive control group, prednisolone acetate tablets, also showed a certain decreasing trend in Cr.

[0063] Table 12 Effects of Cr (μmol / L) on renal function in SLE mice (mean±SD, n=10) Note 1. Compared with the normal control group: # P<0.05, ## 1. P<0.01; 2. Compared with the model control group: P>0.05.

[0064] Table 13 Effects of BUN (mmol / L) on renal function in SLE mice (mean±SD, n=10) Note 1. Compared with the normal control group: # 1. P<0.05; 2. Compared with the model control group: P>0.05.

[0065] Effects on urinary protein

[0066] Compared with the normal control group, the model control group showed a slight increase in urinary protein at 4 weeks of treatment and a significant increase at 8 weeks (P<0.01). Compared with the model control group, treatment with low, medium, and high doses of compound I (0.2, 0.4, and 0.8 mg / kg) for 8 weeks reduced urinary protein in model mice by 15.7% (P>0.05), 21.2% (P<0.05), and 37.6% (P<0.001), respectively. The positive control group, prednisolone acetate tablets, also significantly reduced urinary protein by 27.5% (P<0.01). Results are shown in Table 14 and Figure 6.

[0067] Table 14 Effects on urinary protein in SLE mice (mean ± SD, n = 10) Note 1. Compared with the normal control group: ## P<0.01; 2. Compared with the model control group: * P<0.05, ** P<0.01, *** P<0.001.

[0068] Effects on serum anti-dsDNA antibodies

[0069] SLE is caused by impaired immune regulation, which prevents the body from maintaining normal autoimmune tolerance, leading to the production of large amounts of autoantibodies against self-antigens, such as antinuclear antibodies (ANA) and anti-dsDNA antibodies. These autoantibodies can form immune complexes with self-antigens, which then deposit in tissues such as the kidneys, causing tissue damage. Moreover, anti-dsDNA antibodies are highly specific for the diagnosis of SLE and are an important indicator for testing lupus mouse models.

[0070] As shown in Table 15 and Figure 7, treatment with high-dose compound I (0.8 mg / kg) for 8 weeks reduced anti-ds-DNA antibodies in the serum of model mice (P<0.001); treatment with prednisolone acetate tablets for 8 weeks in the positive control group also reduced anti-ds-DNA antibodies (P<0.05).

[0071] Table 15 Effects of serum anti-dsDNA antibody (μg / mL) on SLE mice (mean±SD, n=10) Note 1. Compared with the normal control group: ### P<0.001; 2. Compared with the model control group: * P<0.05, *** P<0.001.

[0072] As shown in Table 16 and Figure 8, compared with the normal control group, the serum levels of inflammatory factors TNF-α, IL-6, and IFN-γ were significantly increased in the model control group after 8 weeks of treatment (P<0.001). Compared with the model control group, low, medium, and high doses of compound I (0.2, 0.4, and 0.8 mg / kg) resulted in a dose-dependent decrease in serum levels of inflammatory factors TNF-α, IL-6, and IFN-γ (P<0.05–0.001). Prednisolone acetate tablets in the positive control group also significantly reduced the levels of inflammatory factors TNF-α, IL-6, and IFN-γ (P<0.001).

[0073] Table 16 Effects on serum inflammatory factors in SLE mice (mean ± SD, n = 10) Note 1. Compared with the normal control group: ###P<0.001; 2. Compared with the model control group: * P<0.05, ** P<0.01, *** P<0.001.

[0074] Effects on T and B cell subsets

[0075] As shown in Tables 17 and Figures 9, 10, and 11, compared with the normal control group, the number of activated T cells in the spleen of mice in the model control group increased (P<0.001), and B cells transformed into effector B cells, i.e., plasma cells, resulting in a decrease in the proportion of B cells (P<0.001) and an increase in the proportion of plasma cells (P<0.001). Treatment with medium and high doses of compound I (0.4 and 0.8 mg / kg) for 8 weeks showed a certain decreasing trend in activated T cells and plasma cells; low, medium, and high doses of compound I (0.2, 0.4, and 0.8 mg / kg) reduced the total proportion of B cells and plasma cells to varying degrees, decreasing by 1.8% (P>0.05), 5.15% (P>0.05), and 15.04% (P<0.05) respectively compared with the model control group, and by 19.17% (P<0.01) in the positive control group (prednisolone acetate tablets).

[0076] Table 17 Effects on spleen T and B cell subsets in SLE mice (mean ± SD, n = 10) Note 1. Compared with the normal control group: ### P<0.001; 2. Compared with the model control group: * P<0.05, ** P<0.01.

[0077] Effects on histopathology

[0078] Kidney pathological findings: In the normal control group, the overall structure of the kidney tissue was basically normal, with glomeruli and renal tubules visible, and no obvious inflammatory cell infiltration was observed. All scores were grade 0. In the model control group, the overall structure of the kidney tissue was slightly abnormal. In some animals, localized glomerular mesangial proliferation and a small amount of tubular atrophy were observed, and glomerular crescent formation was seen in some cases. A small to a large number of inflammatory cells were observed in the tissue. The number of animals with scores of 0, 1, 2, 3, and 4 were 0, 5, 3, 0, and 2, respectively. In the low, medium, and high dose groups of the test drug compound I, the overall structure of the tissue was slightly abnormal, with localized mild glomerular mesangial proliferation and a small to a large number of inflammatory cells observed. Compared with the model control group, the score grade showed a decreasing trend. Prednisolone acetate tablets in the positive control group improved the score grade. The results are shown in Table 18.

[0079] Table 18 Effects on renal pathology in SLE mice (mean ± SD, n = 10)

[0080] Skin pathology findings: In the normal control group, the overall structure of facial skin tissue was basically normal. Keratinized squamous epithelium was visible in the epidermis, and hair follicles and sebaceous glands were visible in the dermis. No obvious inflammatory cell infiltration was observed. The skin pathology score was 0.1±0.32. In the model control group, the overall structure of skin tissue was abnormal. Mildly thickened keratinized layer and squamous epithelium were visible in the epidermis, with moderate dermal atrophy, reduced hair follicles and sebaceous glands, and some areas showing telangiectasia and congestion. Epidermal hyperplasia was observed, and a small amount of inflammatory cell infiltration was observed. The skin pathology score was 8.5±3.98. In the low, medium, and high dose groups of Compound I, the overall tissue structure was abnormal. Focal thickened keratinized layer and slightly thickened squamous epithelium were visible in the epidermis, and focal dermal atrophy and reduced hair follicles and sebaceous glands were observed. Fibrous tissue hyperplasia was observed, and homogeneous, deeply stained pink unstructured material was visible in some hair follicles. Telangiectasia and congestion were observed, and a small amount of inflammatory cell infiltration was observed. Compared with the model control group, the dermatopathology score was reduced. The scores of the low, medium, and high dose groups of compound I (0.2, 0.4, and 0.8 mg / kg) were 6.70±2.54 (P>0.05), 3.30±1.49 (P<0.001), and 1.50±1.78 (P<0.001), respectively. The positive control, prednisolone acetate tablets, reduced the score, with a dermatopathology score of 1.90±1.73 (P<0.001). The results are shown in Table 19.

[0081] Table 19 Effects on skin pathology in SLE mice (mean ± SD, n = 10) Note 1. Compared with the normal control group: ### P<0.001; 2. Compared with the model control group: *** P<0.001.

[0082] In summary, in the MRL / MpJ-Faslpr / J systemic lupus erythematosus (SLE) mouse model, low, medium, and high doses of compound I (0.2, 0.4, and 0.8 mg / kg) administered twice weekly showed a certain therapeutic effect on SLE, manifested in varying degrees of weight reduction, improvement in skin lesion scores and lymph node scores, reduction in splenomegaly, reduction in lymph node hyperplasia, improvement in renal function, and reduction in proteinuria. After 8 weeks of treatment, compound I significantly reduced skin pathological damage and showed a certain trend of improvement in renal pathological damage. The therapeutic effect of compound I is related to reducing the production of antinuclear antibodies, reducing inflammatory factor damage, and reducing activated T cells and effector B cells (i.e., plasma cell transformation), thereby reducing lymphocyte proliferation.

Claims

1. A method of treating an autoimmune disease, comprising administering a therapeutically effective amount of a proteasome inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a patient with an autoimmune disease.

2. The method according to claim 1, wherein the autoimmune disease is selected from: systemic lupus erythematosus, lupus nephritis, autoimmune hepatitis, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis.

3. The method according to claim 1, wherein the autoimmune disease is selected from: systemic lupus erythematosus, lupus nephritis, and autoimmune hepatitis.

4. The method according to claim 1, wherein the proteasome inhibitor is characterized by a compound of formula (I):

5. The method according to claim 1, wherein the proteasome inhibitor is characterized by a compound of formula (II):

6. The method according to claim 4 or 5, wherein the compound of formula (I) or formula (II) is administered orally.

7. The method according to claim 4 or 5, wherein the compound of formula (I) or the compound of formula (II) is administered intravenously.

8. Use of a compound of formula (I) or formula (II) in the preparation of a medicament for the treatment of autoimmune diseases.

9. The use according to claim 8, wherein the autoimmune disease is selected from: systemic lupus erythematosus, lupus nephritis, autoimmune hepatitis, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis.

10. The use according to claim 8, wherein the autoimmune disease is selected from: systemic lupus erythematosus, lupus nephritis, and autoimmune hepatitis.

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