Immunoproteasome inhibitors and immunosuppressants in the treatment of autoimmune disorders
阅读说明：本技术 自身免疫性病症的治疗中的免疫蛋白酶体抑制剂和免疫抑制剂 (Immunoproteasome inhibitors and immunosuppressants in the treatment of autoimmune disorders ) 是由 T.穆查米尔 于 2018-08-23 设计创作，主要内容包括：本文提供了治疗自身免疫性疾病的方法,其包括向患有所述自身免疫性疾病的受试者施用免疫蛋白酶体抑制剂和免疫抑制剂。(Provided herein are methods of treating an autoimmune disease comprising administering to a subject having the autoimmune disease an immunoproteasome inhibitor and an immunosuppressant.)
1. A method of treating a subject having an autoimmune disease comprising administering to the subject (a) an immunoproteasome inhibitor and (b) an immunosuppressant in amounts sufficient to treat the autoimmune disease.
2. The method of claim 1, wherein the immunoproteasome inhibitor has the structure of formula (I):
wherein
K is CH (OH) or O;
e is N or CH;
R1is CH3、CH2OH、CH(OH)CH3Or CH2CN；
R2Is composed of
R3Is composed of
Or a pharmaceutically acceptable salt thereof.
3. The method of claim 2, wherein the immunoproteasome inhibitor hasOr a pharmaceutically acceptable salt thereof.
4. The method of any one of claims 1-3, wherein the immunoproteasome inhibitor is administered in an amount of 1-300mg per day.
5. The method of claim 4, wherein the immunoproteasome inhibitor is administered in an amount of 40-120mg per day.
6. The method of any one of claims 1-5, wherein the immunoproteasome inhibitor is administered orally, subcutaneously, topically, or intravenously.
7. The method of claim 6, wherein the immunoproteasome inhibitor is administered subcutaneously.
8. The method of any one of claims 1-7, wherein the immunoproteasome inhibitor is administered from every 7 days to every 15 days.
9. The method of claim 8, wherein the immunoproteasome inhibitor is administered once every 7 days.
10. The method of any one of claims 1-9, wherein the immunosuppressive agent comprises a corticosteroid, an anti-miotic agent, a cytokine antagonist, a B cell depleting agent, a non-steroidal anti-inflammatory agent, or an antimalarial agent.
11. The method of any one of claims 1-10, wherein the immunosuppressive agent comprises one or more of: aspirin (aspirin), prednisone (prednisone), methylprednisolone (methylprednisone), sulfasalazine (sulfasalazine), leflunomide (leflunomide), hydroxychloroquine (hydroxychloroquine), belimumab (belimumab), mycophenolate mofetil, mycophenolic acid, azathioprine, rituximab (rituximab), ocrelizumab (ocrelizumab), etanercept (entanercept), adalimumab (adalimumab), tollizumab (tocilizab), tofacitinib (tofacitinib), barlacitinib (baracitinib), cyclosporine (cyclosporine), cyclophosphamide, and tacrolimus (tacrolimus).
12. The method of claim 11, wherein the immunosuppressive agent comprises mycophenolate, mycophenolic acid, or a pharmaceutically acceptable salt thereof.
13. The method of claim 12, wherein the mycophenolate ester or pharmaceutically acceptable salt thereof is administered in an amount of 0.5-3g per day by weight of mycophenolate ester.
14. The method of claim 12, wherein the mycophenolic acid or pharmaceutically acceptable salt thereof is administered in an amount of 700mg to 1500mg per day by weight of mycophenolic acid.
15. The method of any one of claims 12-14, wherein the immunosuppression is administered once daily or twice daily.
16. The method of claim 11, wherein the immunosuppressive agent is hydroxychloroquine, azathioprine, or cyclophosphamide, or a pharmaceutically acceptable salt thereof.
17. The method of claim 16, wherein said hydroxychloroquine or pharmaceutically acceptable salt thereof is administered in an amount of from 150 to 325mg per day, based on the weight of hydroxychloroquine.
18. The method of claim 16, wherein the azathioprine or pharmaceutically acceptable salt thereof is administered in an amount of 1 to 4mg/kg per day, based on the weight of azathioprine.
19. The method of claim 16, wherein the cyclophosphamide or pharmaceutically acceptable salt thereof is 500 to 1000mg/m every two to four weeks by weight of cyclophosphamide2The amount of (c) is administered.
20. The method of any one of claims 1-19, wherein the immunosuppressive agent is administered orally, subcutaneously, topically, or intravenously.
21. The method of any one of claims 1-20, wherein the immunoproteasome inhibitor and the immunosuppressant are administered simultaneously.
22. The method of claim 21, wherein the immunoproteasome inhibitor and the immunosuppressant are co-formulated.
23. The method of any one of claims 1-20, wherein the immunoproteasome inhibitor and the immunosuppressant are administered sequentially.
24. The method of claim 23, wherein the immunoproteasome inhibitor is administered prior to the immunosuppressant.
25. The method of claim 23, wherein the immunoproteasome inhibitor is administered after the immunosuppressant.
26. The method of any one of claims 1-25, wherein the autoimmune disease is lupus nephritis or Systemic Lupus Erythematosus (SLE).
27. The method of claim 26, wherein the autoimmune disease is SLE.
28. The method of claim 26, wherein the autoimmune disease is lupus nephritis.
29. The method of any one of claims 1-25, wherein the autoimmune disease is systemic vasculitis or idiopathic inflammatory myopathy.
30. The method of any one of claims 1-29, wherein the subject is a human.
31. The method of any one of claims 1-30, wherein the therapeutic effect of administering the immunoproteasome inhibitor and the immunosuppressant is greater than the therapeutic effect of administering the immunoproteasome inhibitor or the immunosuppressant alone.
32. The method of any one of claims 1-31, wherein the therapeutic effect is exhibited by a decrease in proteinuria or urinary protein/creatinine ratio as compared to: (a) a subject not administered with the immunoproteasome inhibitor and the immunosuppressant or (b) the same subject prior to administration of the immunoproteasome inhibitor and the immunosuppressant.
33. The method of claim 31 or 32, wherein the subject exhibits at least a 50% reduction in the urine protein/creatinine ratio as compared to the urine protein/creatinine ratio of the subject prior to administration of the immunoproteasome inhibitor and the immunosuppressant.
34. The method of any one of claims 31-33, wherein the subject exhibits a urine protein/creatinine ratio of 0.5 or less following administration of the immunoproteasome inhibitor and the immunosuppressant.
Background
In eukaryotes, protein degradation is primarily mediated through the ubiquitin-proteasome pathway, where proteins targeted for destruction are linked to the 76 amino acid polypeptide ubiquitin. Once targeted, the ubiquitinated protein then serves as a substrate for the 26S proteasome, a multicatalytic protease that cleaves proteins into short peptides through the action of its three major proteolytic activities. Although having a general function in intracellular protein turnover, proteasome-mediated degradation also plays a key role in many processes, such as Major Histocompatibility Complex (MHC) class I antigen presentation, apoptosis, cell growth regulation, NF- κ B activation, antigen processing, and transduction of pro-inflammatory signals.
The 20S proteasome is a700 kDa cylindrical-shaped multicatalytic protease complex comprising 28 subunits organized into four loops. In yeast and other eukaryotes, 7 different α subunits form the outer loop and 7 different β subunits make up the inner loop. The alpha subunit serves as a binding site for the 19S (PA700) and 11S (PA28) regulatory complexes, as well as a physical barrier to the internal proteolytic compartment formed by the two beta subunit loops. Thus, in vivo, the proteasome is thought to exist as a 26S particle ("26S proteasome"). In vivo experiments have shown that inhibition of the 20S form of the proteasome can be readily correlated with inhibition of the 26S proteasome. Cleavage of the amino-terminal pro sequence of the active site β subunit during particle formation exposes an amino-terminal threonine residue that acts as a catalytic nucleophile. The subunits responsible for catalytic activity in proteasomes thus have amino-terminal nucleophilic residues, and these subunits belong to the family of N-terminal nucleophile (Ntn) hydrolases (where the nucleophilic N-terminal residues are, for example, Cys, Ser, Thr and other nucleophilic moieties). This family includes, for example, Penicillin G Acylase (PGA), Penicillin V Acylase (PVA), glutamine PRPP amidotransferase (GAT), and bacterial glycosylasparaginase. By using different peptide substrates, three main proteolytic activities have been defined for the eukaryotic 20S proteasome: chymotrypsin-like activity (CT-L), which cleaves after large hydrophobic residues; trypsin-like activity (T-L), which cleaves after a basic residue; and peptidyl glutamyl peptide hydrolyzing activity (PGPH) or caspase-like (C-L), the PGPH or C-L being cleaved after an acidic residue. In mammals, most cells and tissues express the "constitutive proteasome," where the 3 active sites are β 5, β 1, and β 2, which encode CT-L, C-L and T-L activities, respectively. Higher order vertebrates also have three interferon-gamma inducible β subunits (LMP7, LMP2, and MECL1) that replace their constitutive proteasome counterparts, β 5, β 1, and β 2, respectively, thereby altering the catalytic activity of the proteasome. The major proteasome proteolytic activities appear to be contributed by different catalytic sites, as inhibitors, point mutations in the β subunit and exchange of the γ interferon-inducible β subunit alter these activities to various degrees.
Disclosure of Invention
Provided herein are methods of treating a subject having an autoimmune disease, comprising administering to the subject (a) an immunoproteasome inhibitor and (b) an immunosuppressant in amounts sufficient to treat the autoimmune disease. In each case, the subject is a human. In some cases, the autoimmune disease is lupus nephritis or Systemic Lupus Erythematosus (SLE). In some cases, the autoimmune disease is systemic vasculitis or idiopathic inflammatory myopathy.
In each case, the immunoproteasome inhibitor and the immunosuppressant are administered simultaneously, and in some cases, can be co-formulated. In some cases, the immunoproteasome inhibitor and the immunosuppressant are administered sequentially (e.g., the immunoproteasome inhibitor is administered before or after the immunosuppressant).
In each case, the therapeutic efficacy of administration of the immunoproteasome inhibitor and the immunosuppressant is greater than the therapeutic efficacy of administration of the immunoproteasome inhibitor or the immunosuppressant alone. In each case, the therapeutic effect is exhibited by a decrease in proteinuria or urinary protein/creatinine ratio compared to: (a) a subject not administered with the immunoproteasome inhibitor and the immunosuppressant or (b) the same subject prior to administration of the immunoproteasome inhibitor and the immunosuppressant. In each case, the subject exhibits at least a 50% reduction in the urine protein/creatinine ratio as compared to the urine protein/creatinine ratio of the subject prior to the immunoproteasome inhibitor and the immunosuppressant. In each case, the subject exhibits a urine protein/creatinine ratio of 0.5 or less following administration of the immunoproteasome inhibitor and the immunosuppressant.
In some cases, the immunoproteasome inhibitor has the structure of formula (I):
In each instance, the immunosuppressive agent comprises a corticosteroid, an anti-miotic agent, a cytokine antagonist, a B cell depleting agent, a nonsteroidal anti-inflammatory agent, or an antimalarial agent. In some cases, the immunosuppressive agent comprises one or more of: aspirin (aspirin), prednisone (prednisone), methylprednisolone (methylprednisone), sulfasalazine (sulfasalazine), leflunomide (leflunomide), hydroxychloroquine (hydroxychloroquine), belimumab (belimumab), mycophenolate mofetil, mycophenolic acid, azathioprine, rituximab (rituximab), ocrelizumab (ocrelizumab), etanercept (entanercept), adalimumab (adalimumab), tollizumab (tocilizab), tofacitinib (tofacitinib), barlacitinib (baracitinib), cyclosporine (cyclosporine), cyclophosphamide, and tacrolimus (tacrolimus). In some cases, the immunosuppressive agent is administered orally, subcutaneously, topically, or intravenously.
In some cases, the immunosuppressive agent comprises mycophenolate, mycophenolic acid, or a pharmaceutically acceptable salt thereof. In such cases, the mycophenolate ester or pharmaceutically acceptable salt thereof may be administered in an amount of 0.5 to 3g per day by weight of the mycophenolate ester, or the mycophenolic acid or pharmaceutically acceptable salt thereof may be administered in an amount of 700mg to 1500mg per day by weight of the mycophenolic acid. In such cases, mycophenolate mofetil, mycophenolic acid, or a pharmaceutically acceptable salt thereof may be administered once daily or twice daily.
In some cases, the immunosuppressive agent is hydroxychloroquine, azathioprine, or cyclophosphamide, or a pharmaceutically acceptable salt thereof. In some cases, the hydroxychloroquine or pharmaceutically acceptable salt thereof is administered in an amount of from 150 to 325mg per day, based on the weight of hydroxychloroquine. In some cases, the azathioprine or pharmaceutically acceptable salt thereof is administered in an amount of 1 to 4mg/kg per day, based on the weight of azathioprine. In some cases, the cyclophosphamide or pharmaceutically acceptable salt thereof is administered in an amount of 500 to 1000mg/m2 every two weeks to every four weeks by weight of the cyclophosphamide.
Drawings
Figure 1 shows the total proteinuria score of mice given vehicle (circles), 5mg/kg KZR-616 subcutaneously once a week (squares), 30mg/kg Mycophenolate Mofetil (MMF) orally once a day (upper triangles), or 5mg/kg KZR-616 subcutaneously once a week and 30mg/kg MMF orally once a day (lower triangles) over 25-35 weeks. The upper right panel shows the prevention of severe proteinuria by these therapies, and the lower left panel shows the survival rate of mice at 24 to 36 weeks of administration of these therapies.
Detailed Description
Provided herein are methods of treating a subject having an autoimmune disease, the method comprising administering a combination therapy of an immunoproteasome inhibitor and an immunosuppressant in an amount sufficient to treat the autoimmune disease. The immunoproteasome inhibitor and/or immunosuppressant may be present as a pharmaceutically acceptable salt thereof. The term "pharmaceutically acceptable salt" refers to the relatively non-toxic inorganic or organic acid addition salts of the compounds provided herein. These salts can be prepared in situ during the final isolation and purification of the compounds provided herein, or by separately reacting the free base form of the compound with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, metasilicate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, dodecylsulfonate, and amino acid salts and the like. (see, e.g., Berge et al, (1977) "Pharmaceutical Salts", journal of Pharmaceutical sciences (J.pharm.Sci.) 66:1-19.)
The immunoproteasome inhibitor and immunosuppressant can be administered simultaneously or separately. In some cases of simultaneous administration, the two agents are co-formulated. In the case of separate administration, the immunosuppressant is administered prior to the immunoproteasome inhibitor. In other cases, administered alone, the immunosuppressant is administered after the immunoproteasome inhibitor.
The methods disclosed herein can result in a decrease in proteinuria or urinary protein/creatinine ratio as compared to: (a) a subject not administered with the immunoproteasome inhibitor and the immunosuppressant or (b) the same subject prior to administration of the immunoproteasome inhibitor and the immunosuppressant. Measurement of proteinuria or the urinary protein/creatinine ratio may be performed by any means known in the art. In some cases, the subject exhibits at least a 50% reduction in the urine protein/creatinine ratio as compared to the urine protein/creatinine ratio of the subject prior to administration of the immunoproteasome inhibitor and the immunosuppressant. In some cases, the subject exhibits a reduction in urine protein/creatinine ratio of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, or at least 85% compared to the urine protein/creatinine ratio of the subject prior to administration of the immunoproteasome inhibitor and the immunosuppressant. In some cases, the subject exhibits a urine protein/creatinine ratio of 0.5 or less following administration of the immunoproteasome inhibitor and the immunosuppressant. In some cases, the ratio is 0.4 or less, 0.35 or less, 0.3 or less, 0.25 or less, 0.2 or less, 0.15 or less, or 0.1 or less.
Autoimmune diseases
The methods provided herein are useful for treating autoimmune diseases. As used herein, an "autoimmune disease" is a disease or disorder that arises from and is directed against an individual's own tissue. Examples of autoimmune diseases include, but are not limited to, inflammatory reactions, such as inflammatory skin diseases including psoriasis and dermatitis (e.g., atopic dermatitis); systemic scleroderma and sclerosis; reactions associated with inflammatory bowel diseases (such as crohn's disease and ulcerative colitis); respiratory distress syndrome (including Adult Respiratory Distress Syndrome (ARDS)); dermatitis; meningitis; encephalitis; uveitis; colitis; glomerulonephritis; allergic conditions such as eczema and asthma and other conditions involving T cell infiltration and chronic inflammatory reactions; atherosclerosis; insufficient leukocyte adhesion; rheumatoid arthritis; systemic Lupus Erythematosus (SLE); diabetes (e.g., type I diabetes or insulin dependent diabetes); multiple sclerosis; raynaud's syndrome; autoimmune thyroiditis; allergic encephalomyelitis; sjogren's syndrome; juvenile onset diabetes mellitus; and immune responses associated with acute and delayed-type hypersensitivity reactions mediated by cytokines and T lymphocytes commonly found in tuberculosis, sarcoidosis, polymyositis, granulomatosis, and vasculitis; pernicious anemia (addison's disease); diseases involving leukocyte extravasation; central Nervous System (CNS) inflammatory disorders; multiple organ injury syndrome; hemolytic anemia (including but not limited to cryoglobulinemia or coom's positive anemia); myasthenia gravis; antigen-antibody complex mediated diseases; resistance to glomerular basement membrane disease; antiphospholipid syndrome; allergic neuritis; graves' disease; lambert-eaton myasthenia syndrome; bullous pemphigus bullous; pemphigus; autoimmune polyendocrine adenopathy; raitch's disease; stiff person syndrome; beset's disease; giant cell arteritis; immune complex nephritis; IgA nephropathy; IgM polyneuropathy; immune Thrombocytopenic Purpura (ITP) or autoimmune thrombocytopenia. In particular cases, the autoimmune disease is systemic lupus erythematosus or lupus nephritis. In some cases, the autoimmune disease is systemic vasculitis or idiopathic inflammatory myopathy.
Systemic Lupus Erythematosus (SLE) is a complex, multi-organ autoimmune disease characterized by the development of a wide variety of autoantibodies other than red blood cells, platelets, serum proteins and phospholipids, particularly directed to components of the nucleus, specifically directed to DNA, RNA and histones.
SLE infects young adults, occurs more frequently in women than in men (9:1 ratio), and is more common in the african american, african caribbean, hispanic and asian populations (about 200 per 100,000) than caucasian (about 40 per 100,000). It is estimated that there are approximately 250,000 patients with SLE in the united states (Feldman, 2013; Helmick et al, 2008).
Clinical manifestations range from relatively mild rashes and arthritis to glomerulonephritis, antibody-mediated hemolytic anemia and thrombocytopenia, vasculitis, heart disease, and central nervous system disorders including epilepsy, psychiatric disorders, and cerebrovascular accidents (Wallace,2015) (Tsokos, 2011). Accurate diagnosis of SLE can be difficult because clinical manifestations vary widely between patients, and individual signs and symptoms of SLE can have multiple etiologies. Classification criteria have been established by the American College of Rheumatism (ACR) (Hochberg, 1997; Tsokos, 2011).
SLE is thought to be the result of dysfunction of various components of the immune system, including defective clearance of apoptotic cell components, disruption of T cell tolerance induction, and production of antibodies Against Nuclear Antigens (ANA) such as anti-double stranded DNA (anti-dsDNA) (Kaul et al, 2016). These ANA complexes with antigen for the production of antigen-antibody (Ag-Ab) complexes deposit in various tissues and elicit inflammatory responses through complement activation (e.g., arthritis and glomerulonephritis) or type II hypersensitivity responses in which antibodies directly target host cells and activate immune effector mechanisms that cause phagocytosis (e.g., hemolytic anemia or immune thrombocytopenia). These inflammatory reactions result in excessive complement activation, secretion of inflammatory cytokines, and activation of macrophages and neutrophils.
SLE cannot be cured. The goal of treatment is to control inflammation using various anti-inflammatory and immunosuppressive agents, including glucocorticoids, aspirin, other non-steroidal anti-inflammatory agents (NSAIDs), and anti-malarial drugs (Hahn, 2011). Among 3 approved therapies for SLE, NSAIDs were approved in 1948; hydroxychloroquine and corticosteroids were approved in 1955; and belimumab was approved in 2011 as a monoclonal antibody targeting B cell activating factor (BAFF) (Lamore, Parmar, Patel and Hilas, 2012).
Lupus Nephritis (LN) is one of the most serious complications of SLE. LN characterized by the presence of proteinuria >1 g/day and active urinary sediments (hematuria, purulent, casts) developed about 50% of patients within 10 years of the initial diagnosis of SLE (Bertsias et al, 2012); one in the Draft EMA guide (EMA Draft guide), 2015, 2 months. LN is associated with a considerable incidence of morbidity including increased risk of end-stage renal disease and increased risk of mortality requiring dialysis or kidney transplantation. The prevalence of LN is about 74,000 in the united states and varies by race, occurring in about 20% of caucasians and up to 60% of black, hispanic and asian ethnicity with SLE (Feldman et al, 2013; Fernandez et al, 2007; Seligman, Lum, Olson, Li and Criswell, 2002).
LN is produced when Ag-Ab complexes (mainly DNA-anti-DNA) are deposited in the glomerular mesangium and glomerular basement membrane and activate serum complement. The resulting inflammatory response results in damage to the glomerular epithelium and loss of function. It is usually accompanied by mesangial proliferation and subsequent glomerulosclerosis. Histopathologically, LN can take many forms, ranging from normal glomerular architecture and Ag-Ab complexes identified by immunofluorescence to proliferative glomerulonephritis or extensive sclerosis of the glomerulus associated with end-stage renal disease. The proliferative and membranous forms of glomerulonephritis are most often associated with proteinuria, which usually reaches renal levels. LN was classified according to the 2003 International Society of Renal and Renal pathologies (International Society of Renal Pathology/New Pathology Society, ISN/RPS) (Weining et al, 2004).
About 50% of patients respond to these treatment regimens with an improvement in proteinuria, but only about 25% achieve a Complete Renal Response (CRR) after 1 year of treatment, which is generally defined as normalization of proteinuria and stabilization or improvement of serum creatinine (Rovin et al, 2012; wofsy, Hillson and Diamond,2012 acquisition of CRR results in a significant reduction in the risk of end stage renal disease (Chen, Korbet, Katz, Schwartz and Lewis, 2008.) thus, about 75% of patients with LN respond poorly to induction therapy, these patients may subsequently be treated with various alternative immunosuppressive or experimental agents, including rituximab, cyclosporine, tacrolimus or other agents, treatment in combination with long-term corticosteroids (Dall' Era,2017) these patients are still at risk of developing end-stage renal disease in addition to complications arising from continued treatment with immunosuppressive agents.
Immunoproteasome inhibitors
Proteasomes have been considered as targets for drug development in chronic inflammatory conditions and autoimmune disorders (Elliott, Zollner and Boehncke, 2003). Bortezomib blocks cytokine release from immune effector cells and has been shown to have anti-inflammatory activity in several animal models of autoimmune disorders including Rheumatoid Arthritis (RA) (palombellar et al, 1998) and SLE (Neubert et al, 2008). Recently, bortezomib was shown to have clinical activity in patients with refractory SLE and LN who failed standard immunosuppressive therapy (Alexander et al, 2015; de Groot et al 2015; Zhang et al 2017). However, systemic toxicity associated with dual targeted proteasome inhibition, such as anemia and thrombocytopenia, limits chronic administration (Bross et al, 2004). Further, bortezomib is associated with dose-limiting side effects of peripheral neuropathy that may be caused by off-target inhibition of the serine protease HtrA2 in neurons (Arastu-Kapur et al, 2011). Peripheral neuropathy was not induced by the peptide ketone epoxide proteasome inhibitor carfilzomib (Arastu-Kapur et al, 2011; Dimopoulos et al, 2016).
The discovery of the selective immunoproteasome inhibitor ONX0914 demonstrated that the immunomodulatory and anti-inflammatory effects of the dual targeting proteasome inhibitor are due to inhibition of immunoproteasome activity in immune effector cells and inflamed tissues (Ichikawa et al, 2012; Muchamuel et al, 2009). ONX0914 is a tripeptide keto epoxide analog of carfilzomib and selectively inhibits immunoproteasome in vitro and after administration to mice. ONX0914 exposure inhibits cytokine production in immune effector cells, decreases the number and activity of inflammatory T cell subsets (such as Th1 and Th17), increases the number of regulatory T cells (Tregs), and blocks autoantibody formation (Ichikawa et al, 2012; Kalim, Basler, Kirk and Groettrup, 2012); (Muchamuel et al, 2009). In a mouse model of RA, ONX0914 was found to prevent joint-specific inflammation, reduce cytokine production and improve joint injury at one-tenth the Maximum Tolerated Dose (MTD) (Muchamuel et al, 2009). Treatment of mice with ONX0914 did not reduce the number of splenic lymphocytes or impair viral clearance in various infection models (Muchamuel et al, 2009; Mundt, Engelhardt, Kirk, Groettrup and Basler, 2016). In addition, ONX0914 was shown to have therapeutic activity in a mouse model of multiple sclerosis and SLE where it exhibited comparable activity but better tolerance than bortezomib (Basler et al, 2014; Ichikawa et al, 2012).
Immunoproteasome inhibitors contemplated in the disclosed methods include, for example, WO 07/149512 (e.g., ONX0914), WO 96/13266 (e.g., bortezomib)) And those immunoproteasome inhibitors described in WO 14/152134, the disclosures of each of which are incorporated by reference in their entirety. Some specific immunoproteasome inhibitors contemplated include those immunoproteasome inhibitors having the structure of formula (I):
wherein
K is CH (OH) or O;
e is N or CH;
R1is CH3、CH2OH、CH(OH)CH3Or CH2CN；
R2Is composed of
R3Is composed of
Or a pharmaceutically acceptable salt thereof. In more particular embodiments, the compound of formula (I) may have the stereochemistry of formula (Γ):
in each case, the immunoproteasome inhibitor can be a compound having the structure shown below:
or a pharmaceutically acceptable salt thereof.
Specifically imagine having a structureOr a pharmaceutically acceptable salt thereof. This compound may alternatively be referred to generally as KZR-616.
KZR-616 induces efficient and selective inhibition of immunoproteasome in human cells in vivo and in blood and tissues when administered to rats and monkeys. KZR-616 does not inhibit any nonproteasome targets in a wide diverse panel comprising biochemical assays of 110 receptors/ligands as well as enzymatic assays.
In vitro, KZR-616 exhibits potent and selective inhibition of LMP7 subunit of immunoproteasome (relative to β 5), and can target multiple subunits of immunoproteasome at therapeutically relevant concentrations. Inhibition of immunoproteasome subunits by KZR-616 occurs by an irreversible mechanism, similar to carfilzomib and ONX0914 (Bennett and Kirk, 2008; Huber, 2012). In vitro, KZR-616 blocks cytokine production across multiple immune cell types, reduces the activity of inflammatory T helper cell subsets, increases the number of regulatory T cells, and blocks and interrupts plasma cell formation and autoantibody production.
KZR-616 can be administered once a week (e.g., every seven days) to once a half month (e.g., every 15 days), e.g., once every 7 days, once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, once every 14 days, or once every 15 days. The dose of KZR-616 may be 1-300 mg/day. If the frequency of dosing is less than once a day (e.g., once every 7 days), the total dose administered to the subject will be multiplied by the dose, e.g., 7-2100mg administered once every 7 days. In some cases, the dose of KZR-616 is 40-120 mg/day (and may also be given less frequently than daily dosing). Thus, the daily dose of KZR-616 does not represent the amount administered daily, but may be combined with other daily doses to be administered to a subject in less frequent doses.
The immunoproteasome inhibitor may be administered orally, subcutaneously, topically or intravenously. In some particular cases, the immunoproteasome inhibitor is administered subcutaneously.
Immunosuppressant
The combination therapy methods disclosed herein comprise the use of an immunosuppressive agent. As used herein, "immunosuppressive agent" refers to a substance that acts to suppress or mask the immune system of a subject treated herein. Thus, agents that inhibit cytokine production, down-regulate or inhibit autoantigen expression, or mask MHC antigens are contemplated. Examples of such agents include corticosteroids, anti-miotics, cytokine antagonists, B-cell depleting agents, non-steroidal anti-inflammatory agents, and antimalarial agents.
Contemplated immunosuppressive agents include 5-amino-6-aryl-5-substituted pyrimidines (see U.S. patent No. 4,665,077); non-steroidal anti-inflammatory drugs (NSAIDs); ganciclovir (ganciclovir), tacrolimus, glucocorticoids such as cortisol or aldosterone, anti-inflammatory agents such as cyclooxygenase inhibitors, 5-lipoxygenase inhibitors or leukotriene receptor antagonists; purine antagonists, such as azathioprine or Mycophenolate Mofetil (MMF); alkylating agents, such as cyclophosphamide; bromocriptine; danazol; dapsone; glutaraldehyde (masking MHC antigens as described in U.S. patent No. 4,120,649); anti-idiotypic antibodies for MHC antigens and MHC fragments; cyclosporin a; steroids, such as corticosteroids or glucocorticoids or glucocorticoid analogues, e.g. prednisone, methylprednisolone and dexamethasone; dihydrofolate reductase inhibitors, such as methotrexate (oral or subcutaneous); hydroxychloroquine; sulfasalazine; leflunomide; a cytokine or cytokine receptor antagonist comprising an anti-interferon-alpha, -beta, or-gamma antibody, an anti-tumor necrosis factor-alpha antibody (infliximab or adalimumab), an anti-TNF-alpha immune eosin (etanercept), an anti-tumor necrosis factor-beta antibody, an anti-interleukin 2 antibody, and an anti-IL-2 receptor antibody; anti-LFA-1 antibodies, comprising anti-CD 11a and anti-CD 18 antibodies; anti-L3T 4 antibody; heterologous anti-lymphocyte globulin; pan-T antibodies, preferably anti-CD 3 or anti-CD 4/CD4a antibodies: a soluble peptide containing the LFA-3 binding domain (WO 90/08187 published on 26.7.1990); a streptokinase; TGF-beta; a streptococcal enzyme; RNA or DNA from a host; FK 506: RS-61443; deoxyinsulin seminal plasma; rapamycin; t cell receptors (Cohen et al, U.S. Pat. No. 5,114,721); t cell receptor fragments (Offner et al, Science (Science) 251:430-432 (1991); WO 90/11294; Ianeway, Nature (Nature) 341:482 (1989); and WO 91/01133); and T cell receptor antibodies (EP 340,109), such as T10B 9.
In some cases, the immunosuppressive agent is one or more of: aspirin, prednisone, methylprednisolone, sulfasalazine, leflunomide, hydroxychloroquine, belimumab, mycophenolate mofetil, mycophenolic acid, azathioprine, rituximab, ocleilizumab, etanercept, adalimumab, tositumomab, tofacitinib, basicinib, cyclosporine, cyclophosphamide, and tacrolimus.
In some cases, the immunosuppressive agent comprises mycophenolate, mycophenolic acid, or a pharmaceutically acceptable salt thereof. Mycophenolate mofetil, mycophenolic acid, or a pharmaceutically acceptable salt thereof may be administered in an amount of 500mg to 3g or 700mg to 1500mg per day, by weight of mycophenolate mofetil or mycophenolic acid. In some cases, the immunosuppressive agent is administered once or twice daily.
In some cases, the immunosuppressive agent comprises hydroxychloroquine, azathioprine, or cyclophosphamide, or a pharmaceutically acceptable salt thereof.The hydroxychloroquine or pharmaceutically acceptable salt thereof may be administered in an amount of from 150 to 325mg per day, based on the weight of hydroxychloroquine. The azathioprine or pharmaceutically acceptable salt thereof may be administered in an amount of 1 to 4mg/kg per day, based on the weight of azathioprine. The cyclophosphamide or pharmaceutically acceptable salt thereof may be present in an amount of 500 to 1000mg/m per two to four weeks based on the weight of the cyclophosphamide2The amount of (c) is administered.
The immunosuppressive agent may be administered orally, subcutaneously, topically or intravenously.
Examples of the invention
NZB/W F1 mice were purchased from Jackson Laboratories (Jackson Laboratories). All mice were housed in an animal facility of Kezar Life Sciences (Kezar Life Sciences). All experimental protocols were reviewed and approved by the Kezar Animal Resources Committee (KezarCommittee on Animal Resources). NZB/WF1 mice (24 weeks old, with persistent proteinuria ≧ 1+ proteinuria) with established nephritis were treated with vehicle alone, a combination of 2.5mg/kg KZR-616SCQW, 30mg/kg QDx7 PO MMF, or 2.5mg/kg KZR-616SC QW KZR-616 and 30mg/kg QDx7 PO MMF. Proteinuria was monitored weekly using urine dipstick (Uristix from Bayer) and observed for survival.
To investigate immunoproteasome inhibition in combination with standard of care treatment MMF, NZB/w mice were administered vehicle alone, 2.5mg/kg KZR-616SC QW, 30mg/kg QDx7 PO MMF, or a combination of KZR-616 and MMF. Treatment with 2.5mg/kg KZR-616 or 30mg/kg MMF significantly reduced proteinuria levels and improved survival compared to untreated mice. The combination of KZR-616 and MMF showed significantly stronger disease inhibition (as measured by proteinuria) and prolonged survival compared to vehicle alone or KZR-616 and MMF treatment.
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