WO2022122668A1 - Combined inhibition of amino acid transporters for inhibiting human plasmacytoid dendritic cell activity during autoimmunity - Google Patents
Combined inhibition of amino acid transporters for inhibiting human plasmacytoid dendritic cell activity during autoimmunity Download PDFInfo
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- WO2022122668A1 WO2022122668A1 PCT/EP2021/084428 EP2021084428W WO2022122668A1 WO 2022122668 A1 WO2022122668 A1 WO 2022122668A1 EP 2021084428 W EP2021084428 W EP 2021084428W WO 2022122668 A1 WO2022122668 A1 WO 2022122668A1
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- inhibitor
- targeting
- acid
- autoimmune disease
- disease
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Definitions
- the present invention relates to the treatment of autoimmune diseases through inhibition of human plasmacytoid dendritic cell activity.
- the treatment is based on a combination of one inhibitor of antiporter system x c ⁇ , and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2, particularly a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, ot an inhibitor targeting STAT5.
- the present invention also provided pharmaceutical compositions comprising said combination.
- Plasmacytoid dendritic cells reside in blood and lymphoid organs, but during inflammation enter tissues where they serve as a major source of type I interferons (IFN) (Barrat et al. J. Exp. Med. 2019, 216(9), 1974-1985). They play roles in both protective immune responses and disease related immune responses to viral infections, and are implicated in inflammatory and autoimmune diseases like systemic lupus erythematosus, SLE.
- IFN interferons
- SLE is a life-threatening chronic autoimmune disease that can affect kidneys, skin, brain and other tissues.
- IFNa interferon-alpha
- IL-6 interleukin 6
- TLR7 toll-like receptor 7
- IFNa and IL-6 both, in turn, support auto-reactive B cells and plasmablast expansion, subsequently driving the differentiation and accumulation of auto-antibody producing plasma cells.
- B cell depleting antibodies such as anti-CD20, e.g.
- B cell depletion or inhibition of B cell maturation has proven useful in cases of severe disease and occasionally in patients who do not respond to global immune suppression with steroids or nonsteroidal anti-inflammatory drugs: the current “standard of care”.
- B cell depleting therapies offer a more directed treatment with fewer side effects than the traditional standard of care options, patients still experience serious adverse events.
- An alternative treatment option on the horizon relates to direct targeting of pDCs.
- TLR7 or TLR9 The primary mechanism of activation of pDC is through ligation of endosomal TLR7 or TLR9 by their nucleic acid agonists. Physiologically, access of nucleic acid ligands to these TLRs is promoted by the uptake of nucleic acid-containing immune complexes. Downstream of TLRs, type I IFN are induced through an MyD88-lnterferon regulatory factor 7 (IRF7)-dependent pathway, but further signaling through MYD88-dependent NFK-B activation leads to the additional production of TNF-a.
- IRF7 MyD88-lnterferon regulatory factor 7
- activated pDC can produce chemokines, which in turn can contribute to the development of SLE.
- pDC express high levels of interleukin 3 receptor a (IL- 3Ra) compared to other leukocytes.
- IL-3 along with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-5, is a member of the common [3 chain cytokine family.
- GM-CSF granulocyte-macrophage colony-stimulating factor
- IL-5 is a member of the common [3 chain cytokine family.
- mAb Monoclonal antibodies directed against IL-3Ra were recently shown to diminish responses by human pDC to TLR7/9 stimulation and to selectively deplete these cells from peripheral blood mononuclear cells (PBMC). Likewise, in a mouse model of SLE, MRL/lpr, administration of anti-IL-3 mAb ameliorated disease symptoms associated with kidney damage. However, the nature of the effect of IL-3 on pDC has remained unclear.
- JAK inhibitors impacts the cardiovascular system of patients with rheumatoid arthritis and particularly the modification of heart performance, progression of atherosclerosis, lipid profile disturbance, and risk of thromboembolic complications (Kotyla et al. Int. J. Mol. Sci. 2020, 21(19), 7390).
- the JAK inhibitor methotrexate inhibits 5-aminoimidazole-4-carboxamide ribonucleotide transformylase. Its main mechanism of action is related to the increase in extracellular adenosine, which leads to the effects of A2 A receptor in M1 macrophages that dampens TNFc and IL12 production and increases IL1 Ra and TNFRp75 (Gremese et al. J.
- JAK inhibitors in the therapy of rheumatoid arthritis provide an efficacy and safety profile comparable or superior to those of biologic agents, while being easier and cheaper to manufacture (Angelini et al. Biomolecules 2020, 10(7), 1002).
- AANS azo amino-naphthylene sulfonic acid
- the European patent application EP 2 599 771 A1 relates to naphthalene derivatives which may regulate ATPase activity of Valosin-containing protein (VCP) that is involved in neurodegenerative diseases such as Machado-Joseph disease (MJD) and Huntington's chorea.
- VCP Valosin-containing protein
- the present invention relates to a combination of at least one inhibitor of antiporter system x c — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2 for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells.
- the inventors have found that IL-3-induced Janus kinase 2-dependent expression of System L amino acid transporter SLC7A5:SLC3A2 was required for mammalian target of rapamycin complex 1 (mTORCI ) nutrient sensor activation in response to toll-like receptor agonists, and the expression of the SLC7A11 subunit of xc — , the cystine/glutamate antiporter. Loss of function of these amino acid transporters synergistically blocks cytokine production by plasmacytoid dendritic cells (pDCs), which is relevant in autoimmune disease development.
- pDCs plasmacytoid dendritic cells
- the term "compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2” refers to a compound that inhibits or blocks the expression of SLC7A5:SLC3A2 or to a compound that inhibits or blocks the activity of SLC7A5:SLC3A2.
- inhibitors of the JAK2-STAT5 pathway belong to the compounds that inhibit expression or activity of System L amino acid transporter SLC7A5:SLC3A2, such as a JAK2 inhibitor, an inhibitor targeting STAT5.
- the term "compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2" refers also to compounds that suppress the stimulation of the JAK2-STAT5 pathway by IL3 or GM-CSF.
- inhibitors targeting IL-3 receptor alpha, inhibitors targeting IL-3 receptor beta, inhibitors targeting GM-CSF, and inhibitors targeting GM-CSF receptor alpha are also compounds that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2.
- the present invention relates to a combination of at least one inhibitor of antiporter system x c — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2 for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells, wherein the at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2 is selected from a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, or an inhibitor targeting STAT5.
- the present invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
- the present invention relates to a combination for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells, wherein the combination consists of: at least one inhibitor of antiporter system x c — a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor.
- the present invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
- a preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2; wherein at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2- ⁇ 4-
- a preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine-2-
- a preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells, wherein the combination consists of: at least one inhibitor of antiporter system x c — , a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor; wherein at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2- ⁇ 4-
- a more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2- ⁇ 4
- a preferred embodiment of the invention is directed to combination of at least one inhibitor of antiporter system x c — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2 for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells, wherein at least one inhibitor of the antiporter system x c — is sulfasalazine.
- a further preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein at least one inhibitor of the antiporter system x c — is sulfasalazine.
- a more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein at least one inhibitor of the antiporter system x c — is sulfasalazine.
- a more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at SLC
- An even more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the JAK2 inhibitor is baricitinib; or wherein the at SLC7A5:SLC3A2 inhibitor is JPH203 (KYT-0353), or wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN- CD123A; or wherein the inhibitor
- a more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of at least one inhibitor of antiporter system x c — , a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,
- a more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraio
- a further preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one a JAK2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the at least one JAK2 inhibitor is baricitinib, or delgocitinib.
- Another embodiment of the invention provides a combination of at least one inhibitor of antiporter system x c — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2 for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells; wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE- induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted
- Another preferred embodiment of the invention provides a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis
- Another embodiment of the invention provides a combination of at least one inhibitor of antiporter system x c — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2 for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells; wherein the autoimmune disease is systemic lupus erythematosus.
- a further embodiment of the invention provides a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is systemic lupus erythematosus.
- a preferred embodiment of the invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system x c — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent.
- a preferred embodiment of the invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent.
- a further preferred embodiment of the invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system x c — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2- 4 ⁇ 4-[(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2- ⁇ 4-[(pyridine-2-yl)sulfamoyl]pheny
- a further preferred embodiment of the invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2- 4 ⁇ 4-[(pyridine-2-yl)sulfamoyl]phenyl
- the present invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system x c — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine.
- the present invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine.
- the present invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the SLC7A5:SLC3A2 inhibitor is selected from the group comprising
- the present invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the JAK2 inhibitor is baricitinib; or wherein the at SLC7A5:SLC3A2 inhibitor is JPH203 (KYT-0353), or wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN- CD123A; or wherein the inhibitor targeting IL-3 receptor beta is IGN523 antibody, or wherein
- the present invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one JAK2 inhibitor is baricitinib.
- the present invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one JAK2 inhibitor is delgocitinib.
- the present invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
- the present invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system x c — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; viti
- the present invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
- the present invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; i
- the present invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
- Plasmacytoid dendritic cells is a unique cell population that produces large amounts of type I interferon upon recognition of nucleic acids placing them at the crossroad of both innate and adaptive immunity. Their ability to produce interferon makes them central to anti-viral responses. They are also responsive to circulating autoantibodies bound to nuclear antigens and in that scenario the release of interferons initiates self-directed immune responses. There are now a growing number of autoimmune disorders where unabated activation of pDC is suspected to be pathogenic (Panda et al., Curr Opin Immunol 2017, 44: 20 - 25).
- IL-3 primed for cytokine and chemokine production by activated pDC in response to CpG-A, CpG-B and CpG-C (all TLR9 ligands) and TLR7 ligands: resiquimod (R848) and imiquimod (R837) stimulation ( Figures 1A - 1 C).
- IL-3 played a critical role in priming pDC to allow mTORCI activation upon CpG-A, CpG-B, CpG-C, R8484, R837 stimulation ( Figures 2A, 2B), which mediated production of IFNa and TNF ( Figures 2C, 2D). It was further observed that stimulation with CpG-A, CpG-B, CpG-C, R8484, and R837 also induced the expression of a range of proinflam matory and homeostatic chemokines (Figure 2E).
- results also showed that mTORCI facilitates increased anabolic activity (Figure 3B - 3G) linked to type I IFN and TNF production (Figure 4C), and the coexpression of the SLC7A11 (Figure 12A, 12C) together with ENPP2 and MYO1 E.
- SLC7A11 is a catalytic subunit of xc — , which when bound to SLC3A2 forms the cystine/glutamate antiporter; ENPP2 encodes for autotaxin; and MYO1 E encodes for a non-muscle myosin.
- ENPP2 and MYO1E encodes for a non-muscle myosin.
- IL-3 induces JAK2-dependent expression of the SLC7A5 and SLC3A2 (Figure 5B, 5C) components of the System L amino acid (System LAA) transporter, activity of which is required for activation of mTORCI (mammalian target of rapamycin complex 1 ) in response to TLR agonists ( Figure 6A).
- System LAA System L amino acid
- GM-CSF supported pDC survival, induced a population of cells with high rates of kynurenine uptake and mTORCI activity (Figure 8A) and these cells were IFNa producers in response to CpG-A ( Figure 8B). Moreover, all of these parameters were inhibited by JAK2 inhibitor AZD ( Figures 8A and 8B).
- a valuable advantage of the present invention is that it can simultaneously target a set of cytokines, i.e. IFNa and TNF, whereas most prior art therapies are only directed to one of them, mostly IFNa, for example by using IFNa blocking antibodies.
- the combination therapy described herein targets two independent pathways, IL-3/GM-CSF/JAK2/STAT5/SLC7A5:SLC3A2, and system x c — on the other side, each critical for full pDC activation, in a single multi-hit approach.
- Targeting each pathway independently is shown to have significant inhibitory effects on cytokine production by activated pDCs, and targeting both pathways together results in synergistic inhibitory effects on cytokine production. This offers the possibility of a scaled step-up or step-down approach for therapy.
- both drugs could be administered initially to minimize organ damage, and then the treatment could be tapered by the removal of one of the drugs.
- the present invention is directed to a combination for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2.
- the present invention is directed to a combination for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2 selected from: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5.
- SLC7A5:SLC3A2 selected from: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5.
- the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
- the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one a JAK2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
- the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
- the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor targeting IL-3 receptor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
- the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor targeting GM-CSF, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
- the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor targeting GM-CSF receptor alpha, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
- the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor targeting STAT-5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
- hydroxychloroquine in the treatment of autoimmune diseases mediated by plasmacytoid dendritic cells.
- Hydroxychloroquine although approved for medical use, suffers from dangerous side effects.
- hydroxychloroquine should not be prescribed to individuals with known hypersensitivity to 4-aminoquinoline compounds as well as other contraindications. Therefore, alternative therapies without the use of hydroxychloroquine are desired.
- the present invention is also directed to a combination for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2, wherein the combination does not comprise hydroxychloroquine.
- the present invention is directed to a combination for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2 selected from: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the combination does not comprise hydroxychloroquine.
- SLC7A5:SLC3A2 selected from: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting ST
- pDCs have a unique role in linking innate and adaptive immunity. They have a lymphoid shape and a plasma cell morphology with an extensive endoplasmic reticulum, multiple mitochondria, and a small Golgi apparatus. pDCs have poor antigen presentation ability, in particular for exogenous antigens, but can acquire antigen-presenting cell function following activation with the expression of co-stimulatory molecules that can instruct T cells toward specific functional subsets. Once activated by TLRs, the expression of costimulatory molecules is induced in all pDCs, which confers T cell priming properties to these cells.
- pDCs can be activated through different cell surface receptors and cytosolic nucleic acid sensors, the sensing of nucleic acids through TLR7 and TLR9 seems to be the dominant mode of activation of these cells with respect to IFN production. Signaling through these two TLRs leads to the rapid and massive production of all type I and type III IFNs, which triggers the induction of IFN-stimulated genes (ISGs), many of them with antiviral properties. Because of these properties, it is postulated that the key function of pDCs is to act as antiviral cells. The activation of pDCs and the production of IFN-I can be important to the antiviral response and can promote tissue repair. However, the chronic or long-term persistent activation of these cells, which can be seen in autoimmunity and persistent viral infections, can lead or contribute to impaired immunity and disease progression, as discussed below.
- the term "in combination” refers to the use of more than one therapeutic agent (e.g., one inhibitor selected from a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, an inhibitor targeting STAT5, and a system x c — inhibitor).
- a therapeutic agent e.g., one inhibitor selected from a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, an inhibitor targeting STAT5, and a system x c — inhibitor.
- the use of the term “in combination” does not restrict the order in which said therapeutic agents are administered to a subject with a disease or disorder, e.g., an autoimmune disease.
- antagonist refers to a compound or combination of compounds that can reduce, minimize, suppress, block, or eliminate expression or function of a target molecule.
- “Inhibitors” or “inhibitor compounds” contemplated by the present disclosure can take any of a variety of forms including natural compounds, chemical small molecule compounds or biological compounds.
- Exemplary compounds include a nucleic acid (e.g., an aptamer), a polypeptide, a peptide, a small molecule, an antibody, a monoclonal antibody, a polyclonal antibody, a chimeric antibody, an humanized antibody, an antigen binding fragment of an antibody, an antibody-drug conjugate, a fusion protein, multispecific antibodies, bispecific antibodies.
- in vitro or “ex vivo” refers to an artificial environment and to processes or reactions that occur within an artificial environment, for example, but not limited to, test tubes and cell cultures.
- in vivo refers to a natural environment (e.g., an animal or a cell) and to processes or reactions that occur within a natural environment.
- Immunoglobulin or “antibody” is used broadly to refer to both antibody molecules and a variety of antibody-derived molecules and includes any member of a group of glycoproteins occurring in higher mammals that are major components of the immune system.
- antibody is used in the broadest sense and specifically covers monoclonal antibodies, antibody compositions with polyepitopic specificity, bispecific antibodies, diabodies, and single-chain molecules, as well as antibody fragments (e.g., Fab, F(ab')2, and Fv), so long as they exhibit the desired biological activity.
- An immunoglobulin molecule includes antigen binding domains, which each include the light chains and the end-terminal portion of the heavy chain, and the Fc region, which is necessary for a variety of functions, such as complement fixation.
- antigen binding domains which each include the light chains and the end-terminal portion of the heavy chain
- Fc region which is necessary for a variety of functions, such as complement fixation.
- the alpha, delta, epsilon, gamma, and mu chains correspond to IgA, IgD, IgE, IgG and IgM, respectively.
- immunoglobulin or “antibody” includes all subclasses of alpha, delta, epsilon, gamma, and mu and also refers to any natural (e.g., IgA and IgM) or synthetic multimers of the four-chain immunoglobulin structure. Antibodies non-covalently, specifically, and reversibly bind an antigen.
- monoclonal antibody refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that can be present in minor amounts.
- monoclonal antibodies may be produced by a single clone of antibody-producing cells.
- monoclonal antibodies are monospecific (e.g., specific for a single epitope of a single antigen).
- the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
- chimerized refers to an immunoglobulin, wherein the heavy and light chain variable regions are not of human origin and wherein the constant regions of the heavy and light chains are of human origin.
- “Humanized” refers to an immunoglobulin such as an antibody, wherein the amino acids directly involved in antigen binding, the complementarity determining regions (CDR), of the heavy and light chains are not of human origin, while the rest of the immunoglobulin molecule, the framework regions of the variable heavy and light chains and the constant regions of the heavy and light chains, are of human origin.
- CDR complementarity determining regions
- Fully human refers to an immunoglobulin, such as an antibody, where the whole molecule is of human origin or consists of an amino acid sequence identical to a human form of the antibody.
- an “inhibitor of system x c —” refers to a compound or combination of compounds that can reduce, minimize, suppress, block, or eliminate expression or function of system x c ⁇ .
- SLC7A11 (AB026891 , NM_014331 ) together with SLC3A2 form a heterodimer constituting the cystine/glutamate transporter system x c — , which provides in many cell types cystine for the synthesis of glutathione. It is Na + independent and electroneutral and obeys an obligatory exchange mode, exchanging extracellular anionic cystine (pH dependence) for glutamate with a stoichiometry of 1 :1 .
- System x c — inhibitors for use in the present method include small molecule inhibitors such as, but not limited to, sulfasalazine (SAS), erastin and erastin analogs, azo-linked amino-naphthyl-sulfonate analogs (AANS) of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4-[(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1-yl]- benzoate, 2-Hydroxy-5-[(E)-2- ⁇ 4-[(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1-yl]benzamide, 4-[(E)-2-(2-Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid,
- SAS sulfasalazine
- erastin analogs are preferably piperazine erastin (PE) and carbonyl erastin analogs (Larraufie et al., Bioorg Med Chem Lett. 2015; 25(21 ): 4787- 4792), such as: ketone erastin (KE), a-fluoro ketone erastin (FKE), trifluoroketone erastin (TFKE), morpholine ketone erastin (MKE), N-methylpiperazine ketone erastin (MPKE), N-allylpiperazine ketone erastin (APKE), N-p- methoxybenzylpiperazine ketone erastin (PMB-PKE), aldehyde erastin (AE), imidazole ketone erastin (IKE), piperazine ketone erastin (PKE).
- PE piperazine erastin
- FKE a-fluoro ketone erastin
- Piperazine erastin has a piperazine moiety on the meta position of the aniline ring of erastin, whereas carbonyl erastin analogs have reactive carbonyl moieties in the meta position of the aniline-derived moiety of erastin.
- AANS azo amino-naphthylene sulfonic acid
- a preferred embodiment of the invention is a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2- 4 ⁇ 4-[(pyridine-2
- a more preferred embodiment of the invention is a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine.
- the second component of the combination according to the present invention is at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5.
- a "JAK2 inhibitor,” as used herein, includes any compound that disrupts JAK2 activity or production and or the JAK2/STAT signaling pathway.
- JAK2 inhibitors include, but are not limited to, baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480.
- the heterodimer “SLC7A5:SLC3A2” constitutes the system LAA (L-amino acids) transporter.
- the SLC7 family is divided into two sub-groups, the cationic amino acid transporters (the CAT family, SLC7A1-4) and the glycoprotein-associated amino acid transporters (the gpaAT family, SLC7A5-11 ), also called light chains or catalytic chains of the heterodimeric amino acid transporters (HAT).
- the CAT transporters subfamily members have 14 putative transmembrane (TM) segments and are glycosylated, whereas the gpaAT transporters have two TM segments less, are not glycosylated, and need to associate with a glycoprotein of the SLC3 family, heavy chains 4F2hc (CD98, SLC3A2) or rBAT (related to bO,+AT-type amino acid transporter, where bO,+AT is the basic and neutral amino acid transporter) for surface expression.
- TM transmembrane
- gpaAT transporters have two TM segments less, are not glycosylated, and need to associate with a glycoprotein of the SLC3 family, heavy chains 4F2hc (CD98, SLC3A2) or rBAT (related to bO,+AT-type amino acid transporter, where bO,+AT is the basic and neutral amino acid transporter) for surface expression.
- SLC7A5 also named LAT1 , L-type amino acid transporter-1 , NM_003486
- LAT1 L-type amino acid transporter-1
- SLC3A2 SLC3A2
- this HAT protein also transports 2-(-)-endoamino-bicycloheptane-2- carboxylic acid (BCH) and its function is not Na + sensitive. Its uptake selectivity range is relatively broad and the apparent affinity for the uptake of branched and aromatic amino acids is quite high (micromolar range).
- SLC7A5:SLC3A2 is an obligatory exchanger that does not mediate any measurable amino acid efflux in the absence of extracellular amino acids, i.e. no facilitated diffusion.
- Predominant substrates of SLC7A5:SLC3A2 are large neutral l-amino acids, T3, T4, L-DOPA, BCH.
- SLC7A5:SLC3A2 inhibitors for use in the present method include small molecule inhibitors such as, but not limited to,
- JPH203 (KYT-0353), a tyrosine derivative; triiodothyronine (T3) analogs: 3,3',5-triiodothyronine (L-T3), 3’,5’,3- triodothyronine (r L-T3), 3-iodo-L-tyrosine; 3,5-diiodo-L-tyrosine, SKN102- 105; tetraiodothyronine (L-T4), which is a thyroxine (T4) analog;
- L-DOPA also known as levodopa and L-3,4-dihydroxyphenylalanine
- KHK2898 a fully human anti CD98 (SLC3A2) monoclonal antibody
- IGN523 a human anti CD98 (SLC3A2) monoclonal antibody
- JPH203 (KYT-0353), is a tyrosine derivative and a known selective L-type amino acid transporter 1 inhibitor.
- JPH203 is the abbreviation for (S)-2-Amino-3-(4-((5- amino-2-phenylbenzo[d]oxazol-7-yl)methoxy)-3,5-dichlorophenyl)propanoic acid.
- 1.2.3-dithiazole derivatives are compounds which have 1 ,2,3-dithiazoles, primary aromatic or heteroaromatic amines or alcohols that are reacted with 4,5-dichloro-
- 1,2,3-dithiazole derivatives are compound 5, 10, 11 , 12, 16, 17, 19 described by Napolitano et al, (Biochemical Pharmacology, 2017, 143: 39- 52), shown in Table 3 below.
- 1.2.4-dithiazine derivatives are compounds synthetized by reaction of the appropriate (Z)-N-(4-chloro-5H-1 ,2, 3-dithiazol-5-ylidene)-1 H-pyrazol-5-amine III with diethylamine followed by treatment with concentrated H2SO4.
- Example for 1 ,2,4-dithiazine derivatives is compound 59, described by Napolitano et al, (Biochemical Pharmacology, 2017, 143: 39-52), shown in Table 3 below.
- phenylalanine derivatives are 3-([1 , 10-biphenyl]-3-yl)-2- aminopropanoic acid, and compounds 28, 36, 42 (reported below, Singh et al, Int J Mol Sci, 2019);
- Nitrogen mustard derivatives of phenylalanine comprise p-N-di-(2 chloroethyl)aminophenylalanine, melphalan ((2S)-2-amino-3- ⁇ 4-[bis(2 chloroethyl)amino]phenyl ⁇ propanoic acid), o-Sarcolysin, m-Sarcolysin
- IL-3 receptor is comprised of a ligand specific alpha subunit (IL3RA or IL3R- alpha) and a signal transducing beta subunit (IL3RB, or IL3R-beta) shared by the receptors for interleukin 3 (IL-3), colony stimulating factor 2 (CSF2/GM-CSF), and interleukin 5 (IL5).
- IL3RA or IL3R- alpha a ligand specific alpha subunit
- IL3RB signal transducing beta subunit
- IL5 interleukin 5
- IL-3R-alpha is a type I transmembrane protein with a deduced molecular weight of about 41 kDa containing an extracellular domain involved in IL-3 binding, a transmembrane domain and a short cytoplasmic tail of about 50 amino acids.
- an “inhibitor targeting IL-3 receptor alpha” is preferably an inhibitor able to interact with IL-3 receptor alpha chain and blocking its binding with the ligand IL-3.
- An “inhibitor targeting IL-3 receptor beta” is also preferably an inhibitor able to interact with IL-3 receptor beta chain causing blocking signal transduction upon binding of IL-3 to the receptor and the biological activities of IL-3.
- an “inhibitor targeting IL-3 receptor alpha” as used in present invention is selected from the group comprising: CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, SGN-CD123A.
- An “inhibitor targeting IL-3 receptor beta” as used in present invention is preferably CSL311 antibody.
- GM-CSF Granulocyte macrophage-colony stimulating factor
- GM-CSF glycoprotein growth factors that control the production, differentiation, and function of granulocytes and monocytes-macrophages.
- GM-CSF was originally discovered as a protein with the capacity to generate both granulocyte and macrophage colonies from precursor cells in mouse bone marrow, and was accordingly named. Subsequent studies have demonstrated a role of GM-CSF in potentiating the function of mature macrophages and granulocytes, suggesting a role for GM-CSF in inflammatory responses.
- GM-CSF has other functions arising from its ability to affect the properties of more mature myeloid cells such as granulocytes, macrophages and eosinophils.
- the functions of GM- CSF are mediated by binding to CD116, the granulocyte-macrophage colony stimulating factor receptor, also known as colony stimulating factor 2 receptor alpha (GM-CSFRa, GM-CSF receptor alpha) that binds GM-CSF with low affinity.
- the beta subunit, called CD131 which is also shared with the IL-3 and IL-5 receptors, has no detectable binding activity for GM-CSF by itself but is necessary for high affinity binding when in association with the alpha subunit and plays a fundamental role in signal transduction.
- an “inhibitor targeting GM-CSF” is a compound, more preferably an antibody, that can antagonize the activity of GM-CSF.
- An “inhibitor targeting GM-CSF” as used in present invention is selected from otilimab (MOR103/GSK3196165), namilumab (MT203), lenzilumab (KB003), plonmarlimab (TJ003234 or TJM2), and gimsilumab.
- an "inhibitor targeting GM-CSF receptor alpha” is a compound, more preferably an antibody or blocking antibody, that can neutralise the biological activity of GM- CSF receptor alpha by binding to GM-CSF receptor alpha or by inhibiting binding of GM-CSF to GM-CSF receptor alpha.
- An "inhibitor targeting GM-CSF receptor alpha" as used in present invention is mrajimumab.
- STAT5 protein activation is tightly regulated by cytokines (IL-3, IL- 2, IL-5, IL-7, GM-CSF, erythropoietin, thrombopoietin and prolactin) and growth factors. Binding of these extracellular ligands to the target receptor induces activation of receptor-associated JAK kinase, which induces STAT5 phosphorylation. Phosphorylated STAT5 monomers form homo- or hetero-STAT5- STATX dimers due to the interaction between phosphorylated tyrosine and SH2.
- cytokines IL-3, IL- 2, IL-5, IL-7, GM-CSF, erythropoietin, thrombopoietin and prolactin
- Activated STAT5 dimers migrate to the nucleus where they bind to STAT5 DNA response elements and Induces transcription of specific genes involved in controlled cell growth and division, cell proliferation, programmed cell death, or apoptosis, cell specialization, or differentiation and inflammation.
- an “inhibitor targeting STAT5" is a compound that neutralizes biological activity of STAT5.
- an “inhibitor targeting STAT5" is a monovalent small molecule that degrades STAT5.
- an “inhibitor targeting STAT5" is selected from the group comprising:
- an "inhibitor targeting STAT5" is JPX1188, JPX0802, JPX1185, compound 17f , compound AC-4-130, CAS 285986-31 -4, BP-1-075, BP-1-107, BP- 1 -108, SF-1 -087, SF-1 -088, IQDMA, or CAS 2062-78-4.
- a preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at
- a more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor JAK2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the at least one JAK2 inhibitor is baricitinib.
- a still more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor JAK2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the at least one JAK2 inhibitor is delgocitinib.
- the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3-dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2- carboxylic acid; (S)- 2-Amino-3-(3-((2,4-dicyano-3-(4-(2-amino
- the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor targeting IL-3 receptor alpha or at least one inhibitor targeting IL-3 receptor beta wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN- CD123A; wherein the inhibitor targeting IL-3 receptor beta is CSL311 antibody.
- the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor targeting GM-CSF, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab.
- the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor targeting GM-CSF receptor alpha, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the inhibitor targeting GM-CSF receptor alpha is methosimumab.
- the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor targeting STAT-5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the inhibitor targeting STAT5 is JPX1188, JPX0802, JPX1185, compound 17f, compound AC-4-130, CAS 285986-31-4, BP-1-075, BP-1-107, BP-1-108, SF-1-087, SF-1 -088, IQDMA, or CAS 2062-78-4.
- a further more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)-2-
- a further more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)-2-
- a still more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine
- a further preferred embodiment of the invention is a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitini
- a still more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)-2- ⁇ 4-
- a still more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)-2- ⁇ 4-
- a more preferred embodiment of the invention is a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine, and wherein the at least one JAK2 inhibitor is baricitinib.
- a further more preferred embodiment of the invention is a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine, and wherein the at least one JAK2 inhibitor is delgocitinib.
- autoimmune diseases is a disease or disorder arising from and directed against an individual's own tissues or a cosegregate or manifestation thereof or resulting condition therefrom. This class of disorders is highly varied, both between and within different kinds of autoimmune diseases, which complicates diagnosis and effective treatment. The causes of autoimmune diseases are also poorly understood, which results in courses of treatment that focus primarily on the symptoms.
- An "autoimmune disease mediated by plasmacytoid dendritic cells” refers to an autoimmune disease characterized by a chronic activation of plasmacytoid dendritic cells releasing high amounts of type I interferon (IFN-I).
- an "autoimmune disease mediated by plasmacytoid dendritic cells” is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug- induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott-Aldrich syndrome; ataxia
- SLE Systemic Lupus Erythematosus
- SLE Systemic Lupus Erythematosus
- a characteristic feature of SLE is the presence of antinuclear autoantibodies that form immune complexes with cellular debris and cause end-organ damage.
- Current treatment regimens are limited to non-specific immune suppression and management of inflammatory symptoms.
- lupus is an autoimmune disease or disorder that in general involves antibodies that attack connective tissue.
- the principal form of lupus is a systemic one, systemic lupus erythematosus (SLE); including cutaneous SLE and subacutecutaneous SLE, as well as other types of lupus including nephritis, extrarenal, cerebritis, pediatric, non-renal, discoid, and alopecia.
- systemic lupus erythematosus refers to a chronic autoimmune disease that can result in skin lesions, joint pain and swelling, kidney disease (lupus nephritis), fluid around the heart and/or lungs, inflammation of the heart, and various other systemic conditions.
- the term “lupus nephritis” refers to inflammation of the kidneys that occurs in patients with SLE. Lupus nephritis may include, for example, glomerulonephritis and/or interstitial nephritis, and can lead to hypertension, proteinuria, and kidney failure.
- Lupus nephritis classes include class I (minimal mesangial lupus nephritis), class II (mesangial proliferative lupus nephritis), class 111 (focal lupus nephritis), class IV (diffuse segmental (IV-S) or diffuse global (IV-G) lupus nephritis), class V (membranous lupus nephritis), and class VI (advanced sclerosing lupus nephritis).
- the term "lupus nephritis" encompasses all of the classes.
- condition induced by SLE includes, for example serositis, malar rash (rash over the cheeks and bridge of the nose), discoid rash (scaly, disk-shaped sores on the face, neck and chest), sensitivity to light, alopecia, Raynaud's syndrome (sensitivity to cold), sores or ulcers (on the tongue, in the mouth or nose), abdominal pain, including peritonitis and bowel infarction, lupus hepatitis, hemolytic anemia, low lymphocytic count, low platelet count, leukopenia (low white blood cells count), the presence of antinuclear bodies in the blood, skin lesions, central nervous system (CNS) effects including loss of memory, seizures, strokes and psychosis, CNS lupus, lung symptom s/effects including inflammation (pleuritis), chronic pneumonitis, chronic diffuse interstitial lung disease and scarring of the lungs, alternations in pulmonary vessel structure and
- an embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug- induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyo
- a further embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein at least one inhibitor of the antiporter system x c — is selected from the group comprising erastin, imidazole ketone erastin, erastin analogs, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate (L-[3
- a preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous s
- a more preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group compris
- a still more preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, wherein the at least one JAK2 inhibitor is baricitinib, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid
- a still more preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, wherein the at least one JAK2 inhibitor is delgocitinib, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumato
- a further embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2- 4 ⁇ 4-[(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1
- An embodiment of the invention is a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD14
- a preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, wherein at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2- 4 ⁇ 4-[(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)- 2- ⁇ 4-[(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1 -yl]benza-mide, 4-[(E)-2-(2-
- a more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, wherein at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2- 4 ⁇ 4-[(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)- 2- ⁇ 4-[(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1 -yl]benza-mide, 4-[(E)-2-(
- a more preferred embodiment of the invention is a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine and wherein the at least one JAK2 inhibitor is baricitinib, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus;
- a still more preferred embodiment of the invention is a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine and wherein the at least one JAK2 inhibitor is delgocitinib, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen plan
- a more preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug- induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis
- a still more preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2- ⁇ 4-
- An embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia are
- a preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3-di
- an embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is systemic lupus erythematosus.
- a further embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein at least one inhibitor of the antiporter system x c — is selected from the group comprising erastin, imidazole ketone erastin, erastin analogs, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate (L-[3
- a preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is systemic lupus erythematosus.
- a more preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group compris
- a still more preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, wherein the at least one JAK2 inhibitor is baricitinib, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is systemic lupus erythematosus.
- a still more preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, wherein the at least one JAK2 inhibitor is delgocitinib, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is systemic lupus erythematosus.
- a further embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2- 4 ⁇ 4-[(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1
- An embodiment of the invention is a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD14
- a preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, wherein at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2- 4 ⁇ 4-[(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)- 2- ⁇ 4-[(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1 -yl]benza-mide, 4-[(E)-2-(2-
- a more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, wherein at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2- 4 ⁇ 4-[(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)- 2- ⁇ 4-[(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1 -yl]benza-mide, 4-[(E)-2-(
- a more preferred embodiment of the invention is a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine and wherein the at least one JAK2 inhibitor is baricitinib, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
- a still more preferred embodiment of the invention is a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine and wherein the at least one JAK2 inhibitor is delgocitinib, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
- a more preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is systemic lupus erythematosus.
- a still more preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)-2- ⁇ 4-
- An embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is systemic lupus erythematosus.
- a preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3-di
- compositions comprising one or more of the disclosed inhibitors in association with a pharmaceutically acceptable carrier.
- the present invention relates to a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent.
- a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or d
- the present invention relates to a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine-2-yl)sulfamoyl]pheny
- the present invention relates to a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine.
- An embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected
- a particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one JAK2 inhibitor is baricitinib.
- a particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one JAK2 inhibitor is delgocitinib.
- a more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine-2-yl)sulfamoyl]pheny
- Another more preferred embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine, and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tof
- a further embodiment of the present invention is a a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, , azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)-2- ⁇ 4-
- Another still more preferred embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine, and wherein the at least one JAK2 inhibitor is baricitinib.
- a further embodiment of the present invention is a a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, , azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)-2- ⁇ 4-
- Another still more preferred embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine, and wherein the at least one JAK2 inhibitor is delgocitinib.
- a more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
- a still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome;
- a further more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
- Another embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, , azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine-2-yl)sulfamoyl]pheny
- Another preferred embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, , azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine-2-yl)sulfamoyl]phen
- Another more preferred embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, , azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine-2-yl)sulfamoyl]
- a particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
- a more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus
- a still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
- a further more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2
- a still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2
- Another still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2
- a further more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; and wherein the at least one JAK2 inhibitor is delgocitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
- a still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; and wherein the at least one JAK2 inhibitor is delgocitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus;
- Another still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; and wherein the at least one JAK2 inhibitor is delgocitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
- a further more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; and wherein the at least one JAK2 inhibitor is baricitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
- a still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; and wherein the at least one JAK2 inhibitor is baricitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; viti
- Another still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; and wherein the at least one JAK2 inhibitor is baricitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
- a more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine, and wherein the at least one JAK2 inhibitor is baricitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
- a more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine, and wherein the at least one JAK2 inhibitor is delgocitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
- a further particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine, and wherein the at least one JAK2 inhibitor is baricitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; p
- a further more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine, and wherein the at least one JAK2 inhibitor is delgocitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis
- a particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine, and wherein the at least one JAK2 inhibitor is baricitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
- a more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine, and wherein the at least one JAK2 inhibitor is delgocitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
- the present invention relates to a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent.
- the present invention relates to a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2- ⁇ 4-
- the present invention relates to a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, and wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine.
- An embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,
- a more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2- ⁇ 4-
- Another more preferred embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine, and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-
- a more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
- a still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen s
- a further more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
- Another embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, , azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2- ⁇ 4-
- Another preferred embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, , azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2- ⁇ 4-
- Another more preferred embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4- [(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2- ⁇ 4-
- a particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
- a more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomy
- a still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
- a further more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine;
- a still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine;
- Another still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system x c — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine;
- “Pharmaceutical composition” refers to a preparation in a form that allows the biological activity of the active ingredient(s) to be effective, and which contain no additional components which are toxic to the subjects to which the formulation is administered.
- the terms “pharmaceutically acceptable”, “physiologically tolerable” and grammatical variations thereof, are used interchangeably and represent that the materials are capable of administration to or upon a mammal without the production of undesirable physiological effects such as nausea, dizziness, gastric upset and the like.
- “Pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical composition, other than an active ingredient, which is nontoxic to the subject to whom it is administered.
- a pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.
- the pharmaceutical composition is designed to facilitate the administering of the inventive polypeptides comprising the single domain antibodies in an effective manner.
- “Pharmaceutically acceptable vehicle” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to the subject to whom it is administered.
- a pharmaceutically acceptable vehicle includes, but is not limited to, a buffer, stabilizer, or preservative.
- Suitable vehicles or excipients include, without limitation, lactose, dextrose, sucrose, glucose, powdered sugar, sorbitol, mannitol, xylitol, starches, acacia gum, xanthan gum, guar gum, tara gum, mesquite gum, fenugreek gum, locust bean gum, ghatti gum, tragacanth gum, inositol, molasses, maltodextrin, extract of Irish moss, panwar gum, mucilage of isapol husks, Veegum, larch arabogalactan, calcium silicate, calcium phosphate, dicalcium phosphate, calcium sulfate, kaolin, sodium chloride, polyethylene glycol, alginates, gelatine, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, saline, syrup, methylcellulose, ethylcellulose, hydroxypropyl
- the pharmaceutical composition can be formulated into powders, granules, tablets, capsules, suspensions, emulsions, syrups, oral dosage form, external preparation, suppository or in the form of sterile injectable solutions, such as aerosolized in a usual manner, respectively.
- a diluent or excipient such as generally used fillers, extenders, binders, wetting agents, disintegrating agents, surface active agents.
- the solid preparation for oral administration may be a tablet, pill, powder, granule, or capsule.
- the solid preparation may further comprise an excipient. Excipients may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatine.
- the solid preparation may further comprise a lubricant, such as magnesium stearate, or talc.
- liquid preparations for oral administration may be best suspensions, solutions, emulsions, or syrups.
- the liquid formulation may comprise water, or liquid paraffin.
- the liquid formulation may, for excipients, for example, include wetting agents, sweeteners, aromatics or preservatives.
- compositions containing the polypeptides of the invention are preferably dissolved in distilled water and the pH preferably adjusted to about 6 to 8.
- compositions of the invention for parenteral administration also include sterile aqueous and non-aqueous solvents, suspensions and emulsions.
- useful non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oil, fish oil, and injectable organic esters.
- the principal active ingredient is mixed with a pharmaceutically acceptable carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to for a solid preformulation composition containing a homogeneous mixture for a compound of the present invention, or a pharmaceutically acceptable salt thereof.
- a pharmaceutically acceptable carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water
- a pharmaceutically acceptable carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate,
- This solid pre-form ulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
- Typical unit dosage forms contain from 1 to 100 mg, for example, 1 , 2, 5, 0, 25, 5 or 00 mg, of the active ingredient.
- the tablets or pills can be coated o otherwise compounded to provide a dosage affording the advantage of prolonged action.
- the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
- the two components can be separated by an enteric layer which, serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
- enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, acetyl alcohol and cellulose acetate.
- Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium caboxymethylcellulose, luethylcellulose, polyvinylpyrrolidone or gelatin.
- Also described herein is a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system x c — , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
- a method for the treatment of an autoimmune disease comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system x c — , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4 ⁇ 4-[(pyridine-2-yl)sulfamoyl]phenyl ⁇ diazen-1
- Also described herein is a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system x c — , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine.
- a method for the treatment of an autoimmune disease comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system x c — , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203
- Also described herein is a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system x c — , and a therapeutically effective amount of at least one JAK2 inhibitor, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one JAK2 inhibitor is baricitinib.
- Also described herein is a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system x c — , and a therapeutically effective amount of at least one JAK2 inhibitor, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one JAK2 inhibitor is delgocitinib.
- Also described herein is a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system x c — , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions ; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata;
- Also described herein is a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system x c ⁇ , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
- Also described herein is a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system x c — , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM- CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
- a method for the treatment of an autoimmune disease comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system x c — , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM- CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one inhibitor of the antiporter system x c — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazin
- Also described herein is a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system x c — , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM- CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one inhibitor of the antiporter system x c — is sulfasalazine.
- a method for the treatment of an autoimmune disease comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system x c — , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM- CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitin
- Also described herein is a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system x c — , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM- CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE- induced conditions ; systemic sclerosis; cutaneous scleroderma
- Also described herein is a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system x c ⁇ , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM- CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
- administering refers to bringing a subject, tissue, organ or cells in contact with a therapeutically effective amount of a combination consisting of at least one inhibitor of antiporter system x c — , and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, or of a pharmaceutical composition comprising said combination, as described in this disclosure.
- the present invention encompasses administering a therapeutically effective amount of a combination consisting of at least one inhibitor of antiporter system x c — , and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, or of a pharmaceutical composition comprising said combination, as described in this disclosure to a patient or subject.
- Treatment refers to clinical intervention in an attempt to alter the natural course of a disease or disorder in the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desired results of treatment can include, but are not limited to, preventing occurrence or recurrence of the disorder, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disorder, slowing or stopping the progression or worsening of a disease, disorder, or condition and/or the remission of the disease, disorder or condition, decreasing the rate of progression, amelioration or palliation of a disease state, and remission or improved prognosis.
- treatment can include administration of a therapeutically effective amount of at least one inhibitor of antiporter system x c — , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5,or a pharmaceutical composition comprising said combination, to a subject to delay development or slow progression of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
- a therapeutically effective amount of at least one inhibitor of antiporter system x c — a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF
- Constant administration includes administration of the active agents (e.g., monoclonal antibodies, small molecules, biomolecules), in conjunction or combination, together, or before or after each other.
- the multiple agent(s) may be administered by the same or by different routes, simultaneously or sequentially, as long as they are given in a manner sufficient to allow all agents to achieve effective concentrations at the site of action.
- a person of ordinary skill in the art would have no difficulty determining the appropriate timing, sequence, and dosages of administration for particular drugs and compositions of the present invention.
- an agent or a pharmaceutical formulation
- the therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the seventy of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
- the specific "effective amount” will vary depending on the particular agent chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, and the physical delivery system in which it is carried.
- the specific "effective amount” will also vary with such factors as the particular condition being treated, the physical condition of the patient, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed.
- the optimum effective amounts can be readily determined by one of ordinary skill in the art using routine experimentation.
- the term “subject” and “patient” are used interchangeably herein and refer to both human and nonhuman animals.
- the term “nonhuman animals” of the disclosure includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dog, cat, horse, cow, chickens, amphibians, reptiles, and the like.
- the subject is a human patient that is at for, or suffering from, an autoimmune disease.
- FIG. 1 shows IL-3 priming of activated pDC for cytokine production.
- Figure 2 shows IL-3 priming of activated pDC for mTORCI activation.
- Isolated pDC maintained in IL-3 were probed for pS6 (S235/236) expression, where indicated cells were treated with rapamicin (RAP) inhibitor for indicated time [r? 5 in 4 experiments];
- Isolated pDCs maintained ⁇ - IL-3 and indicated inhibitors o/n, then stimulated ⁇ CpG-A (for 5h) and probed for
- C) IFNa (r? 4 in 2 experiments) and
- D) TNF production (n 7 in 4 experiments);
- E isolated pDC maintained ⁇ IL-3 o/n were stimulated ⁇ indicated TLR9 or TLR7 agonists for 5 h and
- FIG. 3 shows that pDC activation is coupled to mTORCI activity and changes in metabolism.
- FIG. 4 shows that pDC activation is coupled to mTORCI activity and changes in metabolism.
- FIG. 5 shows that IL-3 induces the expression of functional System LAA transporters that license mTORCI activation.
- E ex vivo isolated pDC from healthy donor were probed for kynurenine uptake (
- Figure 6 shows IL-3 induces the expression of functional System LAA transporters that license mTORCI activation.
- Figure 7 shows that inhibition of JAK2 prevents mTORCI activation and cytokine production.
- Figure 8 shows that inhibition of JAK2 prevents mTORCI activation and cytokine production.
- A Representative plots from individual donors (/?) are shown. Bar graphs are shown in (B) mean ⁇ SD. Dots represent individual donors.
- Figure 9 shows changes in activated vs untreated pDC.
- a - D isolated pDC maintained in IL-3 o/n, then stimulated ⁇ CpG-A for 5h (in vitro pDC) were subjected to scRNA-seq analysis presented as: (A) LIMAP plot colored by clusters and separated by condition (numbers in red indicate cells that were sequenced); (B) bar graph of changes in cell frequencies across clusters after CpG-A stimulation; (C) LIMAP plot coloured by clusters and violin plot of IFNA2, IFNB1 , and IFNL1 ; (D) LIMAP plot coloured by clusters and violin plot of TNF expression across clusters; (E) LIMAP plot coloured by clusters and violin plot of SLC7A11 , ENPP2, and MYO1 E expression across clusters; (F) dot plot with the relative expression and percent expression of genes (x axis) across clusters in pDC (y axis).
- Figure 10 shows in (A, B, C, H, I) re-analysed scRNA-seq data of pDC (SLE pDC) and other immune cells from kidney biopsies of lupus nephritis patients (in vivo SLE pDC) presented as UMAP plot colored by clusters and violin plots of (B, C) IL3RA, CSF2RA, CSF2RB, SLC7A5, SLC3A2 and (H) SLC7A11, ENPP2, and MY01E expression across clusters; (D, E) comparative analysis of differentially expressed genes from in vitro pDC and in vivo SLE pDC (C22) presented as (D) UpSet plot with the intersection of differentially expressed genes between pDC and SLE pDC; (E) dot plot with the relative expression and percent expression of genes (x axis) across clusters in pDC (y axis); (F) isolated pDC maintained in IL-3 o/n, then
- Figure 21 shows diagram illustrating the two-step model of pDC activation that leads to expression of SLC7A5:SLC3A2 and SLC7A11 and cytokine production.
- PBMC from buffy coats from healthy blood donors were isolated by density gradient centrifugation using SepMate tubes and Lymphoprep (both STEMCELL Technologies).
- pDC were negatively selected from PBMC using the plasmacytoid dendritic cell isolation kit II (Miltenyi Biotec).
- Buffy coats were kindly provided by the Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg (donor consent, anonymized). Skin samples of lupus patients were obtained through the biobank of the SFB829 (Z4 project) with informed consent from all the subjects and ethical approval obtained from the Ethics Committee at the University of Cologne (votes 12-163 and 19-1146).
- Isolated pDC were maintained in RPMI (Roswell Park Memorial Institute 1640 Medium, Gibco) supplemented with 10% FBS (HyClone), 4 mM L-Glutamine (Invitrogen), 100 U/ml Penicillin/Streptomycin (Invitrogen), 55 pM [3-Mercapto- ethanol (Sigma) and, where indicated, 50 ng/ml IL-3 (Peprotech) or 50 ng/ml GM- CSF (Peprotech).
- cells were cultured in RPMI without L-leucine and L-glutamine (MP Biomedicals) supplemented 2 mM L-glutamine (Invitrogen), or RPMI without methionine (Gibco), or RPMI without L-cystine, L-glutamine and L-methionine (MP Biomedicals) supplemented with 2 mM L-glutamine (Invitrogen) and 0.1 mM L-methionine (Sigma) or HPLM (Gibco).
- Amino acid free and HPLM media were supplemented with 10% dialyzed FBS (HyClone), 100 U/ml Penicillin/Streptomycin (Invitrogen), 55 pM [3-mercapto- ethanol (Sigma) and 50 ng/ml IL-3 (Peprotech).
- Cells were stimulated with 5 pM CpG-A (ODN2216) or 5 pM CpG-B (ODN2006) or 5 pM CpG-C (ODN2395) or 0.5 pg/ml R848 (resiquimod) or 5 pg/ml R837 (imiquimod) (all fromlnvivoGen) for times indicated.
- cells were treated with GolgiPlug (BD Bioscience) for the last 4 h of the culture. For overnight (o/n) incubations, cells were plated at 0.5 - 1x10 6 /ml. Where indicated, cells were treated with the following inhibitors for indicated times: 20 nM rapamycin, RAP (Calbiochem), 250 nM torinl , TOR (Tocris), 10pM heptelidic acid, HPA (Adipogen), 1 pM oligomycin (Sigma), 1 pM AZD1480, AZD (Selleckchem), 25 nM-1 pM baricitinib, BAR (LY3009104, Selleckchem), 200 ng/ml tofacitinib (CP690550, Tocris), 5 pM erastin, ERA (Sigma), 100 pM or 200 pM sulfasalazine, SAZ (Tocris) 5 or 10
- IL-3Ra CD123
- HLA-DR HLA-DR
- CD303 BDCA2, BioLegend, clone 201A
- CD116 BD Bioscience, clone hGMCSFR-M1
- CD4 Biolegend, clone A161A1
- Whole PBMC-staining was performed in 0.5% BSA in PBS for 30 min at 4° C, dead cells were excluded with the LIVE/DEAD Fixable Near-IR Dead Cell Stain Kit (Thermo scientific).
- Isolated pDC staining was performed in 0.5% BSA in PBS for 10 min at RT, dead cells were excluded with the LIVE/DEAD Fixable Near-IR or Aqua Dead Cell Stain Kits (Thermo scientific). Unspecific binding was blocked with FcR blocking reagent (Miltenyi).
- FcR blocking reagent Molethyi
- the following fluorochrome-conjugated Abs were used for intracellular staining: IFNa (Miltenyi, LT27:295), TNF (BioLegend, clone Mab11 ), pS6(S235/236; CST, clone D57.2.2e), pSTAT5 (Y694; CST, clone C71 E5).
- Kynurenine uptake was performed using pDC stained with antibody against IL-3Ra (Miltenyi) and LIVE/DEAD Fixable Near-IR Dead Cell Stain Kit (Thermo scientific), as described previous. Briefly, stained cells were incubated in HBSS (Gibco) with 200 pM kynurenine (Sigma) for 4 min at 37°C. Cells were then fixed and additional intracellular staining was performed as described above. Where indicated, at the time of kynurenine uptake, cells were treated with 10 mM BCH (Tocris). The 405 nm laser and 450/50 BP filter were used for kynurenine fluorescence detection.
- Detection of intracellular mRNAs was performed using PrimeFlow RNA Assays according to manufacturer’s protocol (Thermo scientific). Isolated pDC were stained using LIVE/DEAD Fixable Aqua Dead Cell Stain Kit (Thermo scientific) and fixed with fixation buffer I. Where indicated, intracellular staining with IFNa and/or TNF was performed in perm/wash buffer at previously determined concentrations. Then, cells were fixed with fixation buffer II.
- target-specific probes IFNA2A (type 6), TNF (type 1 ), SLC7A5 (type 6), SLC3A2 (type 4), SLC7A11 (type 1 ), ENPP2 (type 4), MY01E (type 6), CCL3 (type 1 ), CCL17 (type 6), CXCL8 (type 1 ), CXCL9 (type 1 ), CXCL10 (type 1 ) were hybridized to the target RNA transcript and signal was amplified. All buffers and times of incubation were provided by the manufacturer.
- Isolated pDC were plated at 1x10 6 /ml and incubated in RPMI (Gibco) supplemented with 10% FBS (HyClone), 2 mM L-glutamine (Invitrogen), 100 ll/rnl Penicillin/Streptomycin (Invitrogen), 55 pM [3-mercaptoethanol (Sigma) containing 50 ng/ml IL-3 (Perprotech) and 5 pM CpG-A (InvivoGen) for 24 hours. Where indicated cells were treated with either AZD or BAR (both at 1 pM, Selleckchem).
- Type I IFN IFNa, IFNp, IFNA
- TNF TNF
- CXCL8 CXCL10 secretion was measured from supernatants using the LEGENDplex human Anti-Virus responses panel (Biolegend, #7410390) according to the manufacturer protocol.
- Extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were measured using mitochondrial stress test in a 96 well Extracellular Flux Analyzer (Seahorse Bioscience).
- Cells were plated at 0.15x10 6 per well on poly-D-lysine coated wells and preincubated at 37°C for a minimum of 45 min in the absence of CO2 in un-buffered RPMI (Gibco) with 25 mM glucose (Invitrogen), 1 mM pyruvate (Invitrogen) and 2 mM L-glutamine (Invitrogen). Media was supplemented with 10% FBS (HyClone) and 50 ng/ml IL-3. (Peprotech).
- OCR and ECAR were measured under basal conditions following the addition of CpG-A. Results were collected with Wave software version 2.4 (Agilent). In Figure 3C, ECAR was measured in real time first in the absence of glucose and then following the addition of 10 mM glucose (Sigma). In this case data is presented as baseline- corrected.
- Glucose and lactate were measured in cell culture supernatants using the Cedex Bio Analyzer (Roche) and data presented as mmol/L.
- metabolite analysis 0.6x10 6 pDC were washed in ice-cold PBS (Gibco) and metabolites were extracted using 30 pl extraction buffer (50:30:20, methanol:acetonitrile:water, Sigma) cooled on dry ice for 30 min beforehand. Samples were centrifuged at 2000 g for 3 min to remove protein debris and supernatants were stored at -80°C until acquisition.
- LC-MS was carried out using an Agilent 1290 Infinity II LIHPLC in-line with a Bruker Impact II QTOF operating in negative ion mode. Scan range was from 30 to 1050 Da. Mass calibration was performed at the beginning of each run. LC separation was on a Phenomenex Luna propylamine column (50 x 2 mm, 3 urn particles) using a solvent gradient of 100% buffer B (5mM ammonium carbonate in 90% acetonitrile) to 90% buffer A (10 mM NH 4 in water). Flow rate was from 1000 to 750 pl/min. The Autosampler temperature was 5°C and injection volume was 2 pL. Metabolites were quantified using AssayR (Wills et al., Anal Chem 2017, 89, 9616 - 9619), and identified by matching accurate mass and retention time to standards.
- Single cell RNA sequencing was performed using a 10X Genomics Chromium Controller. Single cells were processed with GemCode Single Cell Platform using GemCode Gel Beads, Chip and Library Kits (v2) following the manufacturer’s protocol. An estimated 1400 cells were sequenced ( ⁇ 700 from each condition), with a mean of 64338 reads per cell and a mean of 2200 genes detected per cell. Libraries were sequenced on HiSeq 3000 (Illumina). Samples were demultiplexed and aligned using Cell Ranger 2.2 (10X genomics) to genome build GRCh38 to obtain a raw read count matrix of barcodes corresponding to cells and features corresponding to detected genes.
- STAT5 binding sites were identified by retrieving raw sequencing data from Gene Expression Omnibus (accession GSE43119), which was produced from human T cells (Schmidl et al., Blood 2014, 123, e68-78). The analysis performed was limited specifically to conventional T cells (samples SRR639410 and SRR639408). Retrieved data were processed using the default settings of the snakePipe methodology developed by the Bioinformatics core at the Max-Planck-lnstitute for Immunobiology and Epigenetics which is described at https://snakepipes.readthedocs.io/en/latest/index.html. Samples were mapped to GRCh38 and binding sites were identified using "Model-based Analysis of ChlP- Seq" MACS2 (Zhang et al., Genome Biol, 2008, 9, R137) with the input control used as background.
- Immunostaining for SLC7A11 and IL3-Ra was performed on paraffin sections (6 mm). First, they were deparaffinized by xylol and ethanol incubations and washed in Tris-buffered saline (TBS). Heat-induced epitope retrieval was performed using Tris-EDTA buffer (10mM Tris, 1 mM EDTA, pH 9) for 20 min in a heated (95°C) water bath.
- RNP complexes were prepared by annealing (5 min, 98°C) equimolar amounts of crRNA and tracrRNA (180 pmol each per donor, IDT), followed by incubation with 60 pmol Alt-R S.p. Cas9 Nuclease V3 (IDT). Two separate crRNAs per target were used and mixed. RNPs were delivered into purified human pDC by electroporation in P4 Primary Cell buffer (Lonza) in the presence of 2 pM enhancer (IDT) using the CM-137 program (4D-Nucleofector, Lonza).
- Example 1 primes pDC for cytokine production and mTORCI activation in response to CpG-A pDC produce type I IFN in response to stimulation through endosomal/lysosomal TLR7 or TLR9.
- cytokine production was measured over time by isolated pDC from healthy donors and cultured in medium containing IL-3, with or without the TLR9 agonist CpG-A (class A CpG-A oligonucleotides, ODN2216). Maximal IFNa secretion occurred between 10 h and 12 h post activation, during which time approx. 50% of the cells made this cytokine (Figure 1A).
- IL-3 acts as a growth factor to enhance anabolic pathways. Since anabolism is controlled centrally by mTORCI , and mTORCI has been shown to be important for pDC activation, regulation of mTORCI activity by IL-3 was evaluated by measuring phosphorylation of Ser235/236 of ribosomal protein S6 (pS6 (S235/236)), which provides a measure of activation of p70S6K, a direct mTORCI target.
- pS6 S235/236
- pS6 was found in ⁇ 20% of pDC maintained without IL-3, and this was not increased by stimulation with CpG-A ( Figure 2A).
- rapamycin a selective mTORCI inhibitor
- IL-3 plays a critical role in priming pDC to allow mTORCI activation upon TLR stimulation. Since pDC were unable to make cytokines in response to CpG-A and other TLR agonists in the absence of IL-3, it was reasoned that this could reflect the role of IL-3 in mTORCI priming. Consistent with this, RAP-mediated inhibition of S6 (S235/236) phosphorylation was sufficient to partially inhibit production of IFNa ( Figure 2C) but also TNF ( Figure 2D) by CpG-A-stimulated pDC.
- RAP rapamycin
- mTORCI controls protein synthesis through 4E-BP translation initiation factor
- CpG-A resulted in a significant increase in translation that was prevented by treatment with RAP ( Figure 3A).
- RAP was almost as effective as a selective mTORCI /2 inhibitor that blocks rapamycin-resistant functions of mTORCI , torin 1 (TOR) and the translation inhibitor cyclohexamide (CXH) (Figure 3A).
- mTORCI is recognized to promote anabolic metabolism linked to increased glycolysis.
- activated pDC consumed more glucose than resting cells ( Figure 3B).
- the extracellular acidification rate (ECAR) was increased in activated vs. unstimulated pDC ( Figures 3C, 3D).
- Increased ECAR was linked to increased release of lactate (Figure 3E), was glucosedependent ( Figure 3C), and began to occur within minutes after the addition of CpG-A ( Figure 3D). Elevated ECAR persisted for at least 10 h, in line with the time course of cytokine production and mTORCI activity.
- IL-3 induces the expression of functional System L amino acid transporters that permit mTORCI activation in response to CpG-A mTORCI activation is dependent on the presence of sufficient environmental levels of amino acids, amongst which leucine and methionine are of particular importance.
- System LAA transporters comprising a heterodimer of the solute carriers SLC7A5 and SLC3A2 (CD98).
- Other System LAA transporters are composed of SLC7A6, SLC7A7 or SLC7A8 paired with SLC3A2.
- Single cell RNA sequencing revealed that the majority of pDC maintained in IL-3 primarily express SLC7A5, regardless of CpG-A stimulation (Figure 5A). SLC7A6 expression was limited in these cells ( Figure 5A) and SLC7A7 and SLC7A8 transcripts were not detected.
- Analysis by PrimeFlow RNA revealed that SLC7A5 and SLC3A2 were coexpressed in the majority of pDC cultured in IL-3 and stimulated with CpG-A ( Figure 5B). This was a result of the signal delivered by IL-3, since approx. 97% of pDC cultured in IL-3 but not stimulated with CpG-A were also positive for SLC7A5 and SLC3A2 transcripts. In contrast, significantly fewer cells maintained without IL- 3 expressed these solute carriers and stimulation with CpG-A did not rescue their expression (Figure 5B).
- Example 4 IL-3 stimulation of SLC7A5:SLC3A2 and cytokine production is mediated by JAK2 and STAT5
- CSF2RB common [3 chain (encoded by CSF2RB)
- Example 5 GM-CSF stimulates activity of SLC7A5:SLC3A2 and cytokine production.
- the common [3 subunit of the IL-3R is also the signaling component of the GM- CSF and IL-5 receptors.
- Human pDC express GM-CSFRa as well as IL-3Ra but do not express IL-5Ra, which is consistent with previous reports that pDC can respond to GM-CSF as well as to IL-3. It was found that, like IL-3, GM-CSF supported pDC survival, induced a population of cells with high rates of kynurenine uptake and mTORCI activity (Figure 8A) and that these cells were IFNa producers in response to CpG-A ( Figure 8B). Moreover, all of these parameters were inhibited by AZD ( Figures 8A, 8B).
- TLR stimulation induces selective expression of SLC7A11, ENPP2 and MYO1 E in type I IFN producing pDC
- activated pDC from the analysis were compared with recently reported scRNA-seq data from immune cells isolated from lupus nephritis kidney biopsies (Arazi et al. Nat Immunol 20, 902-914). The published data were reanalyzed and focusing specifically on the transcriptomes of pDC at the site of pathology (SLE pDC, C22, Figures 10A, 10B, 10C).
- RNA- flow analysis confirmed that SLC7A11, ENPP2 and MYO1E were expressed when pDC were stimulated with CpG-A and also with other TLR agonists (Figure 10J). The majority of cells expressing these genes co-expressed IFNA2 when stimulated with CpG-A ( Figure 10L).
- SLC7A11 As expression of SLC7A11, ENPP2 and MY01E seemed to mark type I IFN and TNF producing pDC, it was evaluated if SLC7A11 is detectable in pDC in other pathological sites in which pDC infiltration is implicated in disease. To this aim, sections from diseased skin from patients with cutaneous lupus were stained with antibodies against SLC7A11 and the IL-3Ra, a known marker of pDC in tissue sections.
- the microscopic analysis revealed a marked increase in SLC7A11- positive cells in the skin of cutaneous lupus patients compared to skin from healthy donors (HD, Figure 11 A) and the majority of these were IL-3Ra positive, although other cells, presently unidentified, also expressed SLC7A11 ( Figure 11 B). Further analysis included testing pDC isolated from PBMC collected from SLE patients with varying degrees of disease activity (Systemic Lupus Erythematosus Disease Activity Index, SLEDAI, from 0 to 8), but results showed no evidence for SLC7A11 expression in these circulating cells (Figure 11 C). Further, no evidence of ENPP2 or MY01E expression in ex vivo pDC from HD was observed ( Figure 11 D).
- SLC7A11, ENPP2 and MY01E were not expressed by circulating pDC and therefore its expression was unlikely to be induced by signaling downstream of the common [3 chain of the IL-3 or GM-CSF receptors. This was confirmed by the finding that IL-3 alone was incapable of inducing expression of SLC7A11 ( Figures 12A, 12B, 12C). Rather, this gene was expressed in response to stimulation with CpG-A ( Figures 12A - 12C).
- SLC7A11 encodes the specific subunit of the cystine/glutamate exchanger x c — , which when chaperoned by SLC3A2 allows cells to take up cystine in exchange for glutamate.
- Expression of SLC7A11 was coupled to expression of SLC3A2 ( Figure 12A), indicating that activated pDC can express functional x c — transporter. While IL-3 alone was incapable of inducing SLC7A11 expression, it was critical for priming cells to express SLC7A11 in response to CpG-A, since JAK2 inhibition prevented this from happening ( Figures 12A, C).
- Example 8 Inhibition of x c ⁇ potently blocks cytokine production by activated pDC
- the antiporter x c — is a target of the small molecule inhibitors erastin (ERA) and sulfasalazine (SAZ). It was reasoned that inhibition of x c — , which comprises SLC7A11, might prevent the production of cytokines by pDC.
- HPLM human plasma like medium
- JAK2 inhibitors (AZD or BAR), SLC7A11/x c — inhibitors (ERA and SAZ), the ENPP2 inhibitor ZIR ( Figures 131, 13K and 16E), and combinations of BAR and SAZ ( Figures 13J, 13L and 16F), were able to block pDC activation in HPLM.
- Results are shown in Figure 17A-17C.
- the data indicate a synergistic effect of STAT5 inhibitors with sulfasalazine in inhibition of cytokine production. Combinations of each inhibitor plus SAZ had synergistic effects compared to single suboptimal doses of either STAT5 inhibitors or SAZ alone, at inhibiting IFNa and TNF production by TLR9- activated pDC.
- crosslinking Ab was added at ratio 1 :5 as previously shown. Results are shown in Figure 19. Values are shown as normalized to CpG-A. Dots represent individual donors (n).
- the data indicate a weak synergistic effect of a combination of an inhibitor targeting IL-3 receptor beta with sulfasalazine in inhibition of cytokine production.
- IGN523 A monoclonal Ab specific for SLC3A2 (CD98), IGN523 was tested. A single dose of IGN523 significantly abrogated production of IFNa and TNF by TLR9-activated activated pDC. IGN523 was maximally efficient at blocking cytokine production at the lowest tested Ab concentration (200 ng/ml). Combining IGN523 with SAZ revealed a slight additive effect, compared to single doses of IGN523, at inhibiting IFNa and TNF by TLR9-activated pDC.
- MTX methotrexate
- Example 13 Combination of an inhibitor targeting GM-CSF receptor alpha and Sulfasalazine
- Isolated pDC maintained in IL-3 and treated with mdressimumab o/n were then stimulated with CpG-A for 5 h and probed for IFNa and TNF production with mdressimumab and SAZ.
- the data indicate a synergistic effect of a combination of an inhibitor targeting GM-CSF receptor alpha with sulfasalazine in inhibition of cytokine production.
- Combination of mdressimumab plus SAZ had a synergistic effect compared to single suboptimal doses of either mdressimumab or SAZ, at inhibiting IFNa and TNF by TLR9-activated pDC.
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Abstract
The present invention relates to the treatment of autoimmune diseases through inhibition of human plasmacytoid dendritic cell activity. The treatment is based on a combination of one inhibitor of antiporter system xc—, and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5. The present invention also provided pharmaceutical compositions comprising said combination.
Description
Combined inhibition of amino acid transporters for inhibiting human plasmacytoid dendritic cell activity during autoimmunity
Specification
The present invention relates to the treatment of autoimmune diseases through inhibition of human plasmacytoid dendritic cell activity. The treatment is based on a combination of one inhibitor of antiporter system xc~, and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2, particularly a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, ot an inhibitor targeting STAT5. The present invention also provided pharmaceutical compositions comprising said combination.
Background of the invention
Plasmacytoid dendritic cells (pDC) reside in blood and lymphoid organs, but during inflammation enter tissues where they serve as a major source of type I interferons (IFN) (Barrat et al. J. Exp. Med. 2019, 216(9), 1974-1985). They play roles in both protective immune responses and disease related immune responses to viral infections, and are implicated in inflammatory and autoimmune diseases like systemic lupus erythematosus, SLE.
SLE is a life-threatening chronic autoimmune disease that can affect kidneys, skin, brain and other tissues.
Although SLE varies patient to patient, one of the clinical hallmarks is the presence of autoantibodies and immune complexes, which contain host-derived nucleic acids, in the circulation. These immune complexes stimulate type I interferon-alpha (IFNa) and interleukin 6 (IL-6) production from plasmacytoid dendritic cells (pDC) via toll-like receptor 7 (TLR7) and TLR9. IFNa and IL-6 both, in turn, support auto-reactive B cells and plasmablast expansion, subsequently driving the differentiation and accumulation of auto-antibody producing plasma cells. In the last decade, B cell depleting antibodies such as anti-CD20, e.g. Rituximab, Ocrelizumab, Ofatumumab, and drugs that inhibit B cell activating factors, e.g. Belimumab, BLyS inhibition; Atacicept, BLyS/APRIL inhibition, have been introduced as new therapies for SLE patients. B cell depletion or inhibition of B cell maturation has proven useful in cases of severe disease and occasionally in patients who do not respond to global immune suppression with steroids or nonsteroidal anti-inflammatory drugs: the current “standard of care”. Although B cell depleting therapies offer a more directed treatment with fewer side effects than the
traditional standard of care options, patients still experience serious adverse events. The main concern is an elevated risk of severe infection, such as upper respiratory tract and urinary tract infections, as well as influenza, in addition to patients experiencing headaches and joint pain. Moreover, current B-cell targeting strategies fail to target plasma cells and do not reduce circulating levels of autoantibodies and immune complexes. Thus, there remains a desperate need for new SLE-specific treatment options.
An alternative treatment option on the horizon relates to direct targeting of pDCs.
The primary mechanism of activation of pDC is through ligation of endosomal TLR7 or TLR9 by their nucleic acid agonists. Physiologically, access of nucleic acid ligands to these TLRs is promoted by the uptake of nucleic acid-containing immune complexes. Downstream of TLRs, type I IFN are induced through an MyD88-lnterferon regulatory factor 7 (IRF7)-dependent pathway, but further signaling through MYD88-dependent NFK-B activation leads to the additional production of TNF-a.
In addition, activated pDC can produce chemokines, which in turn can contribute to the development of SLE. pDC express high levels of interleukin 3 receptor a (IL- 3Ra) compared to other leukocytes. IL-3, along with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-5, is a member of the common [3 chain cytokine family. Binding of these cytokines to their respective cytokine-specific a subunits results in dimerization with common [3 chain which initiates signaling through Janus kinase 2 (JAK2), which in turn phosphorylates Signal transducer and activator of transcription 5 (STAT5), causing translocation of STAT5 to the nucleus and initiation of transcription. A correlation between elevated levels of IL-3 and SLE incidents has been noted, and there is a link between an IL-3-stimulated gene signature and the type I Interferon-stimulated gene signature in SLE patients. Monoclonal antibodies (mAb) directed against IL-3Ra were recently shown to diminish responses by human pDC to TLR7/9 stimulation and to selectively deplete these cells from peripheral blood mononuclear cells (PBMC). Likewise, in a mouse model of SLE, MRL/lpr, administration of anti-IL-3 mAb ameliorated disease symptoms associated with kidney damage. However, the nature of the effect of IL-3 on pDC has remained unclear.
The treatment of the common disease rheumatoid arthritis with 1 ) methotrexate alone, 2) a combination of sulfasalazine and hydroxychloroquine, and 3) a combination of methotrexate, sulfasalazine and hydroxychloroquine is investigated
by O'Dell et al. (New England Journal of Medicine 1996, 334(20), 1287-1291 ). In a double-blind, controlled, randomized study it was demonstrated that the combination therapy with methotrexate, hydroxychloroquine, and sulfasalazine is beneficial compared with methotrexate alone. An enhanced efficacy occurred with no increase in toxicity. Capell et al. (Annals of the Rheumatic Diseases 2007, 66(2), 235-241 ) have evaluated the double-blind placebo-controlled MASCOT study. The study showed that a combination of disease-modifying antirheumatic drugs methotrexate and sulfasalazine is more effective than monotherapy in patients with rheumatoid arthritis with a suboptimal response to sulfasalazine. Schipper et al. (Rheumatology 2009, 48(7), 828-833) have compared the results of randomized controlled trials on the combination of methotrexate and sulfasalazine in naive patients and in patients with an insufficient response to sulfasalazine. It turned out that methotrexate in combination with sulfasalazine is more effective in rheumatoid arthritis patients who failed sulfasalazine than in patients naive to both drugs.
The activity of JAK inhibitors impacts the cardiovascular system of patients with rheumatoid arthritis and particularly the modification of heart performance, progression of atherosclerosis, lipid profile disturbance, and risk of thromboembolic complications (Kotyla et al. Int. J. Mol. Sci. 2020, 21(19), 7390). The JAK inhibitor methotrexate inhibits 5-aminoimidazole-4-carboxamide ribonucleotide transformylase. Its main mechanism of action is related to the increase in extracellular adenosine, which leads to the effects of A2A receptor in M1 macrophages that dampens TNFc and IL12 production and increases IL1 Ra and TNFRp75 (Gremese et al. J. Leukoc. Biol. 2009, 106(5), 1063-1068). By acting on A2B receptor on M2 macrophages it enhances IL10 synthesis and inhibits NF-kB signaling. Methotrexate has also been shown to exert JAK inhibition of JAK2 and JAK1 when tested in Drosophila melanogaster as a model of kinase activity and in human cell lines (nodular sclerosis Hodgkin’s lymphoma and acute myeloid leukemia cell lines). JAK inhibitors in the therapy of rheumatoid arthritis (RA) provide an efficacy and safety profile comparable or superior to those of biologic agents, while being easier and cheaper to manufacture (Angelini et al. Biomolecules 2020, 10(7), 1002).
Certain azo amino-naphthylene sulfonic acid (AANS) analogs of sulfasalazine are potent inhibitor of system xc — (Nehser et al. Neurochem. Res. 2019, 45(6), 1375- 1386; Patel et al. Drug Develop. Res. 2019, 80(6), 758-777; and Krupa et al. Bioorg. Med. Chem. Lett. 2011 , 21 (20), 6184-6187).
The European patent application EP 2 599 771 A1 relates to naphthalene derivatives which may regulate ATPase activity of Valosin-containing protein (VCP) that is involved in neurodegenerative diseases such as Machado-Joseph disease (MJD) and Huntington's chorea.
It is the objective of the present invention to provide combinations and/or pharmaceutical compositions targeting activation of plasmacytoid dendritic cells and that can be used especially for the treatment of autoimmune diseases.
The objective of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the figures, and the examples of the present application.
Brief description of the invention
The present invention relates to a combination of at least one inhibitor of antiporter system xc — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2 for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells.
The inventors have found that IL-3-induced Janus kinase 2-dependent expression of System L amino acid transporter SLC7A5:SLC3A2 was required for mammalian target of rapamycin complex 1 (mTORCI ) nutrient sensor activation in response to toll-like receptor agonists, and the expression of the SLC7A11 subunit of xc — , the cystine/glutamate antiporter. Loss of function of these amino acid transporters synergistically blocks cytokine production by plasmacytoid dendritic cells (pDCs), which is relevant in autoimmune disease development.
Thus, the term "compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2" refers to a compound that inhibits or blocks the expression of SLC7A5:SLC3A2 or to a compound that inhibits or blocks the activity of SLC7A5:SLC3A2. As the JAK2-STAT5 pathway induces the expression of SLC7A5:SLC3A2, inhibitors of the JAK2-STAT5 pathway belong to the compounds that inhibit expression or activity of System L amino acid transporter SLC7A5:SLC3A2, such as a JAK2 inhibitor, an inhibitor targeting STAT5. Moreover, the term "compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2" refers also to compounds that suppress the stimulation of the JAK2-STAT5 pathway by IL3 or GM-CSF. Thus, inhibitors targeting IL-3 receptor alpha, inhibitors targeting IL-3 receptor beta,
inhibitors targeting GM-CSF, and inhibitors targeting GM-CSF receptor alpha are also compounds that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2.
Particularly, the present invention relates to a combination of at least one inhibitor of antiporter system xc — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2 for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells, wherein the at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2 is selected from a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, or an inhibitor targeting STAT5.
In other words the present invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
More in particular, the present invention relates to a combination for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells, wherein the combination consists of: at least one inhibitor of antiporter system xc — a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor.
Reworded, the present invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of:
a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
A preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2; wherein at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]benzamide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, [3-N-methylamino-L- alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l- cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, S-3- carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4 - carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-naphthyl-4-bis-TFM- HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br-homoibotenate, S-2-naphthyl- ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4-hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone-dinitrophenol, sorafenib.
A preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells;
and wherein at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]benzamide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, [3-N-methylamino-L- alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l- cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, S-3- carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4 - carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-naphthyl-4-bis-TFM- HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br-homoibotenate, S-2-naphthyl- ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4-hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone-dinitrophenol, sorafenib.
A preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells, wherein the combination consists of: at least one inhibitor of antiporter system xc — , a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor; wherein at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]benzamide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, [3-N-methylamino-L- alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l- cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, S-3- carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4 - carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-naphthyl-4-bis-TFM- HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br-homoibotenate, S-2-naphthyl- ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4-hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone-dinitrophenol, sorafenib.
A more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]benzamide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, [3-N-methylamino-L- alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l- cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, S-3- carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4 - carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-naphthyl-4-bis-TFM- HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br-homoibotenate, S-2-naphthyl- ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4-hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone-dinitrophenol, sorafenib.
A preferred embodiment of the invention is directed to combination of at least one inhibitor of antiporter system xc — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2 for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells, wherein at least one inhibitor of the antiporter system xc — is sulfasalazine.
A further preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta,
an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein at least one inhibitor of the antiporter system xc — is sulfasalazine.
A more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein at least one inhibitor of the antiporter system xc — is sulfasalazine.
A more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3- dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2-carboxylic acid; (S)- 2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2- oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids-
phenylalanine, hydroxamic acids-leucine, hydroxamic acids-isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid (|3-(4- chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4- dihydroxyphenylalanine; KHK2898 antibody, IGN523 antibody; or wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN- CD123A; or wherein the inhibitor targeting IL-3 receptor beta is CSL311 antibody, or wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab; or wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab; or wherein the inhibitor targeting STAT5 is JPX1188, JPX0802, JPX1185, compound 17f, compound AC-4-130, CAS 285986-31-4, BP-1-075, BP-1-107, BP-1-108, SF-1-087, SF-1 -088, IQDMA, or CAS 2062-78-4.
An even more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the JAK2 inhibitor is baricitinib; or wherein the at SLC7A5:SLC3A2 inhibitor is JPH203 (KYT-0353), or wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN- CD123A; or wherein the inhibitor targeting IL-3 receptor beta is IGN523 antibody, or wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab; or wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab; or
wherein the inhibitor targeting STAT5 is AC-4-130, IQDMA, or CAS 2062-78-4 (pimozide).
A more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of at least one inhibitor of antiporter system xc — , a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3- dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2-carboxylic acid; (S)- 2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2- oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids-isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid (|3-(4- chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4- dihydroxyphenylalanine; KHK2898 antibody, IGN523 antibody.
A more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3- dithiazole derivatives, 1 , 2, 4-dithiazine derivatives; phenylalanine; phenylalanine
derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2-carboxylic acid; (S)- 2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2- oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids-isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid (|3-(4- chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4- dihydroxyphenylalanine; KHK2898 antibody, IGN523 antibody.
A further preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one a JAK2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the at least one JAK2 inhibitor is baricitinib, or delgocitinib.
Another embodiment of the invention provides a combination of at least one inhibitor of antiporter system xc — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2 for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells; wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE- induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott-Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune- mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
Another preferred embodiment of the invention provides a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott-Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
Another embodiment of the invention provides a combination of at least one inhibitor of antiporter system xc — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2 for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells; wherein the autoimmune disease is systemic lupus erythematosus.
A further embodiment of the invention provides a combination for use in the treatment of an autoimmune disease, wherein the combination consists of:
at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is systemic lupus erythematosus.
A preferred embodiment of the invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system xc — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent.
A preferred embodiment of the invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent.
A further preferred embodiment of the invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system xc — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2- 4{4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2- {4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]benza-mide, 4-[(E)-2-(2- Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic
acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L- alanosine, [3-N-methylamino-L-alanine, L-serine-O-sulphate, L-a- aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4- carboxyphenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, S-3-carboxy,3- hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]- phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-naphthyl-4-bis-TFM-HMICA, 5-4- TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br-homoibotenate, S-2-naphthyl-ethyl- ACPA, bis-trifluoromethyl-phenyl-isoxazole-4-hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone-dinitrophenol, sorafenib.
A further preferred embodiment of the invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2- 4{4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2- {4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]benza-mide, 4-[(E)-2-(2- Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L- alanosine, [3-N-methylamino-L-alanine, L-serine-O-sulphate, L-a- aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4- carboxyphenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, S-3-carboxy,3- hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]- phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-naphthyl-4-bis-TFM-HMICA, 5-4- TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br-homoibotenate, S-2-naphthyl-ethyl- ACPA, bis-trifluoromethyl-phenyl-isoxazole-4-hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone-dinitrophenol, sorafenib.
In another aspect, the present invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system xc — and at least one
compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine.
In another aspect, the present invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine.
In a particular aspect, the present invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3- dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2-carboxylic acid; (S)- 2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2- oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids-isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid (|3-(4- chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4- dihydroxyphenylalanine; KHK2898 antibody, IGN523 antibody; or
wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN- CD123A,; or wherein the inhibitor targeting IL-3 receptor beta is CSL311 antibody, or wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab; or wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab; or wherein the inhibitor targeting STAT5 is JPX1188, JPX0802, JPX1185, compound 17f, compound AC-4-130, CAS 285986-31-4, BP-1-075, BP-1-107, BP-1-108, SF-1-087, SF-1 -088, IQDMA, or CAS 2062-78-4.
In a further particular aspect, the present invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the JAK2 inhibitor is baricitinib; or wherein the at SLC7A5:SLC3A2 inhibitor is JPH203 (KYT-0353), or wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN- CD123A; or wherein the inhibitor targeting IL-3 receptor beta is IGN523 antibody, or wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab; or wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab; or wherein the inhibitor targeting STAT5 is AC-4-130, IQDMA, or CAS 2062-78-4 (pimozide).
In a preferred aspect, the present invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one JAK2 inhibitor is baricitinib.
In a preferred aspect, the present invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system xc — and at least
one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one JAK2 inhibitor is delgocitinib.
In a further preferred aspect, the present invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
In a more preferred aspect, the present invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system xc — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott-Aldrich syndrome; ataxiatelangiectasia; immune mediated cancers; multiple sclerosis (MS); immune- mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
In a still more preferred aspect, the present invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system xc — and at least
one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
In a more preferred aspect, the present invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott- Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
In a still more preferred aspect, the present invention provides a pharmaceutical composition containing at least one inhibitor of antiporter system xc — and at least
one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
Description of the invention
Plasmacytoid dendritic cells (pDC) is a unique cell population that produces large amounts of type I interferon upon recognition of nucleic acids placing them at the crossroad of both innate and adaptive immunity. Their ability to produce interferon makes them central to anti-viral responses. They are also responsive to circulating autoantibodies bound to nuclear antigens and in that scenario the release of interferons initiates self-directed immune responses. There are now a growing number of autoimmune disorders where unabated activation of pDC is suspected to be pathogenic (Panda et al., Curr Opin Immunol 2017, 44: 20 - 25).
The inventors have here found that IL-3 primed for cytokine and chemokine production by activated pDC in response to CpG-A, CpG-B and CpG-C (all TLR9 ligands) and TLR7 ligands: resiquimod (R848) and imiquimod (R837) stimulation (Figures 1A - 1 C).
Moreover, IL-3 played a critical role in priming pDC to allow mTORCI activation upon CpG-A, CpG-B, CpG-C, R8484, R837 stimulation (Figures 2A, 2B), which mediated production of IFNa and TNF (Figures 2C, 2D). It was further observed that stimulation with CpG-A, CpG-B, CpG-C, R8484, and R837 also induced the expression of a range of proinflam matory and homeostatic chemokines (Figure 2E).
Results also showed that mTORCI facilitates increased anabolic activity (Figure 3B - 3G) linked to type I IFN and TNF production (Figure 4C), and the coexpression of the SLC7A11 (Figure 12A, 12C) together with ENPP2 and MYO1 E. SLC7A11 is a catalytic subunit of xc — , which when bound to SLC3A2 forms the cystine/glutamate antiporter; ENPP2 encodes for autotaxin; and MYO1 E encodes for a non-muscle myosin. The data suggest that expression of ENPP2 and
MYO1E is dependent on SLC7A11. Thereafter, it was found that IL-3 induces JAK2-dependent expression of the SLC7A5 and SLC3A2 (Figure 5B, 5C) components of the System L amino acid (System LAA) transporter, activity of which is required for activation of mTORCI (mammalian target of rapamycin complex 1 ) in response to TLR agonists (Figure 6A).
The expression of SLC7A5 and SLC3A2 of system LAA transporter were necessary for the establishment of maximal mTORCI activity (Figures 6A - 6B) and cytokine production (Figures 6C - 6D) in response to the TLR9 agonist, CpG- A.
This pathway was only active in the type I IFN- and TNF-producing subset of TLR9-stimulated pDC (Figure 6A and 7G) and this population of cells was transcriptionally similar to pDC at the site of nephritic disease in SLE patients (Figures 10A - 10C -10E).
Importantly, the inventors found that IL-3, but not CpG-A, was able to induce phosphorylation of STAT5 (Y694) (Figure 7A).
As expected, AZD and BAR inhibited both IL-3-induced STAT5 (Y694) phosphorylation (Figure 7A), and IL-3 induced expression of SLC7A5.SLC3A2 and activity (Figure 7B, 7C) in TLR9-activated pDC. JAK2 and JAK2/1 inhibitors (AZD, BAR respectively) caused a decrease in IFNa and TNF production (Figure 7E) linked to reductions in SLC7A5:SLC3A2 expression (Figure 7B), and mTORCI activity (Figure 7D) in TLR9-activated pDC. Finally, only pDC with both high rates of kynurenine uptake and high mTORCI activity (S6 phosphorylation, Figure 7F) made IFNa (Figure 7G), and that cytokine production was lost following JAK2 inhibition (Figure 7G), arguing that the subset of activated cells that may play a pathological role during disease can be inhibited in this fashion.
Like IL-3, GM-CSF supported pDC survival, induced a population of cells with high rates of kynurenine uptake and mTORCI activity (Figure 8A) and these cells were IFNa producers in response to CpG-A (Figure 8B). Moreover, all of these parameters were inhibited by JAK2 inhibitor AZD (Figures 8A and 8B).
Taken together, these data reveal the emergence of a subpopulation of pDC capable of making IFNa and TNF in response to CpG-A. These cells express functional System LAA transporters (SLC7A5:SLC3A2) and are able to activate mTORCI upon exposure to CpG-A (TLR9 stimulation, also valid for CpG-B, CpG- C, R8484, R837). These processes are dependent on priming by IL-3 or GM-CSF
through the JAK2-STAT5 pathway downstream of the common [3 subunit of the IL- 3 and GM-CSF receptors.
These data highlight that inhibition of IL-3 signaling, GM-CSF signaling, JAK2, STAT5, SLC7A5:SLC3A2 activities is a therapeutic option in conditions where pDC activation is implicated in disease.
SLC7A11 expression, a subunit of the glutamine cystine transporter xc — , was shared between in v/fro-activated pDC (Figures 10D - 10G) and pDC at sites of SLE-associated pathology (Figures 10H, 101 11 A, 11 B), but not by pDC in the bloodstream (Figure 11C).
IL-3 depletion and JAK2 inhibitors prevented expression of SLC7A11 in response to TLR9 ligand CpG-A (Figure 12A, 12 B, 12C), suggesting that this is due to their ability to effectively inhibit the upstream steps that are critical for mTORCI activation controlling SLC7A11 expression (Figures 12A, 12B, 12C).
As was the case for IFNa, it turned out that priming with IL-3 was necessary for maximal chemokine production in response to CpG-A (Figure 15B). It was shown that JAK2 inhibition resulted in diminished expression of a range of chemokines. The majority of CCL3-, CCL17- and CXCL10- positive cells co-expressed IFNA2 and were susceptible to JAK2 inhibition, while only a portion of the CXCL8- and CXCL9-positive cells concomitantly expressed IFNA2.
Interestingly, the inventors have found that small molecule inhibitors of xc— and of ENPP2 were able to diminish cytokine production. Moreover, the combination of xc— and JAK2 inhibitors effectively switched off cytokine production by activated pDC. Particularly, small molecule inhibitors of xc — erastin and sulfasalazine were able to diminish cytokine production in pDC (Figure 13A - 13C).
The data provided herein demonstrate that a two-step process is required for pDC activation, in which IL-3/GM-CSF/JAK2/STAT5 lead to the sequential expression of amino acid transporter SLC5A5/SLC3A2 and system xc — that are critical for pDC to make inflammatory cytokines.
Of importance, the combination of SLC7A11 inhibitors and JAK2 inhibitors, which target SLC7A5:SLC3A2 transporter, effectively and synergistically switched off cytokine production by activated pDC (Figures 14A - 14B). This represents an
important advantage, as the inhibitors in the combination are effective at lower doses, which would be suboptimal or not effective when taken alone.
The data presented here highlight that simultaneous targeting of the two-step process, IL-3/GM-CSF/JAK2/STAT5/SLC7A5:SLC3A2 on one side, and system xc — on the other side, could offer a new and pDC-selective therapy for autoimmunity (Figure 21).
A valuable advantage of the present invention is that it can simultaneously target a set of cytokines, i.e. IFNa and TNF, whereas most prior art therapies are only directed to one of them, mostly IFNa, for example by using IFNa blocking antibodies.
Moreover, the combination therapy described herein targets two independent pathways, IL-3/GM-CSF/JAK2/STAT5/SLC7A5:SLC3A2, and system xc — on the other side, each critical for full pDC activation, in a single multi-hit approach. Targeting each pathway independently is shown to have significant inhibitory effects on cytokine production by activated pDCs, and targeting both pathways together results in synergistic inhibitory effects on cytokine production. This offers the possibility of a scaled step-up or step-down approach for therapy. In aggressive onset disease, both drugs could be administered initially to minimize organ damage, and then the treatment could be tapered by the removal of one of the drugs. The use of intensive therapy at the outset of disease could increase the rate of remission. Alternatively, in mild onset disease, treatment could be started with one drug before moving to combination therapy if required. The combination of two drugs targeting distinct pathways for synergistic inhibition of pDC activation may circumvent possible effects of the expression of multiple-drug resistance genes, a process that has been linked to the development of resistance to current therapies in diseases such as SLE.
Thus, the present invention is directed to a combination for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2.
Particularly, the present invention is directed to a combination for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells, wherein the combination consists of:
at least one inhibitor of antiporter system xc — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2 selected from: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5.
More particularly, the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
In one aspect, the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one a JAK2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
In another aspect, the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
In still another aspect, the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor targeting IL-3 receptor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
In a particular aspect, the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of:
at least one inhibitor of antiporter system xc — and at least one inhibitor targeting GM-CSF, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
In a further particular aspect, the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor targeting GM-CSF receptor alpha, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
In a further more particular aspect, the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor targeting STAT-5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
The inventors have further found that targeting the two independent pathways, IL-3/GM-CSF/JAK2/STAT5/SLC7A5:SLC3A2, and system xc — allows to dispense the use of further drugs, particularly chloroquines, such as hydroxychloroquine in the treatment of autoimmune diseases mediated by plasmacytoid dendritic cells. Hydroxychloroquine, although approved for medical use, suffers from dangerous side effects. Also, hydroxychloroquine should not be prescribed to individuals with known hypersensitivity to 4-aminoquinoline compounds as well as other contraindications. Therefore, alternative therapies without the use of hydroxychloroquine are desired.
Thus, the present invention is also directed to a combination for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2, wherein the combination does not comprise hydroxychloroquine.
Particularly, the present invention is directed to a combination for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells, wherein the combination consists of:
at least one inhibitor of antiporter system xc — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2 selected from: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the combination does not comprise hydroxychloroquine.
Definitions
"Plasmacytoid dendritic cells" pDCs have a unique role in linking innate and adaptive immunity. They have a lymphoid shape and a plasma cell morphology with an extensive endoplasmic reticulum, multiple mitochondria, and a small Golgi apparatus. pDCs have poor antigen presentation ability, in particular for exogenous antigens, but can acquire antigen-presenting cell function following activation with the expression of co-stimulatory molecules that can instruct T cells toward specific functional subsets. Once activated by TLRs, the expression of costimulatory molecules is induced in all pDCs, which confers T cell priming properties to these cells. Although pDCs can be activated through different cell surface receptors and cytosolic nucleic acid sensors, the sensing of nucleic acids through TLR7 and TLR9 seems to be the dominant mode of activation of these cells with respect to IFN production. Signaling through these two TLRs leads to the rapid and massive production of all type I and type III IFNs, which triggers the induction of IFN-stimulated genes (ISGs), many of them with antiviral properties. Because of these properties, it is postulated that the key function of pDCs is to act as antiviral cells. The activation of pDCs and the production of IFN-I can be important to the antiviral response and can promote tissue repair. However, the chronic or long-term persistent activation of these cells, which can be seen in autoimmunity and persistent viral infections, can lead or contribute to impaired immunity and disease progression, as discussed below.
As used herein, the term "in combination" refers to the use of more than one therapeutic agent (e.g., one inhibitor selected from a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor
targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, an inhibitor targeting STAT5, and a system xc — inhibitor). The use of the term "in combination" does not restrict the order in which said therapeutic agents are administered to a subject with a disease or disorder, e.g., an autoimmune disease.
As used herein, “antagonist” or “inhibitor” refers to a compound or combination of compounds that can reduce, minimize, suppress, block, or eliminate expression or function of a target molecule.
"Inhibitors" or "inhibitor compounds" contemplated by the present disclosure can take any of a variety of forms including natural compounds, chemical small molecule compounds or biological compounds. Exemplary compounds include a nucleic acid (e.g., an aptamer), a polypeptide, a peptide, a small molecule, an antibody, a monoclonal antibody, a polyclonal antibody, a chimeric antibody, an humanized antibody, an antigen binding fragment of an antibody, an antibody-drug conjugate, a fusion protein, multispecific antibodies, bispecific antibodies.
As used herein, the term “in vitro" or “ex vivo” refers to an artificial environment and to processes or reactions that occur within an artificial environment, for example, but not limited to, test tubes and cell cultures. The term “in vivo” refers to a natural environment (e.g., an animal or a cell) and to processes or reactions that occur within a natural environment.
“Immunoglobulin” or “antibody” is used broadly to refer to both antibody molecules and a variety of antibody-derived molecules and includes any member of a group of glycoproteins occurring in higher mammals that are major components of the immune system. The term “antibody” is used in the broadest sense and specifically covers monoclonal antibodies, antibody compositions with polyepitopic specificity, bispecific antibodies, diabodies, and single-chain molecules, as well as antibody fragments (e.g., Fab, F(ab')2, and Fv), so long as they exhibit the desired biological activity. An immunoglobulin molecule includes antigen binding domains, which each include the light chains and the end-terminal portion of the heavy chain, and the Fc region, which is necessary for a variety of functions, such as complement fixation. There are five classes of immunoglobulins wherein the primary structure of the heavy chain, in the Fc region, determines the immunoglobulin class. Specifically, the alpha, delta, epsilon, gamma, and mu chains correspond to IgA, IgD, IgE, IgG and IgM, respectively. As used herein
“immunoglobulin” or “antibody” includes all subclasses of alpha, delta, epsilon, gamma, and mu and also refers to any natural (e.g., IgA and IgM) or synthetic multimers of the four-chain immunoglobulin structure. Antibodies non-covalently, specifically, and reversibly bind an antigen.
The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that can be present in minor amounts. For example, monoclonal antibodies may be produced by a single clone of antibody-producing cells. Unlike polyclonal antibodies, monoclonal antibodies are monospecific (e.g., specific for a single epitope of a single antigen). The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
As used herein “chimerized” refers to an immunoglobulin, wherein the heavy and light chain variable regions are not of human origin and wherein the constant regions of the heavy and light chains are of human origin.
“Humanized” refers to an immunoglobulin such as an antibody, wherein the amino acids directly involved in antigen binding, the complementarity determining regions (CDR), of the heavy and light chains are not of human origin, while the rest of the immunoglobulin molecule, the framework regions of the variable heavy and light chains and the constant regions of the heavy and light chains, are of human origin.
“Fully human” refers to an immunoglobulin, such as an antibody, where the whole molecule is of human origin or consists of an amino acid sequence identical to a human form of the antibody.
Inhibitors of system xc~"
Thus, an "inhibitor of system xc — " refers to a compound or combination of compounds that can reduce, minimize, suppress, block, or eliminate expression or function of system xc~.
SLC7A11 (AB026891 , NM_014331 ) together with SLC3A2 form a heterodimer constituting the cystine/glutamate transporter system xc — , which provides in many cell types cystine for the synthesis of glutathione. It is Na+ independent and
electroneutral and obeys an obligatory exchange mode, exchanging extracellular anionic cystine (pH dependence) for glutamate with a stoichiometry of 1 :1 .
System xc — inhibitors for use in the present method include small molecule inhibitors such as, but not limited to, sulfasalazine (SAS), erastin and erastin analogs, azo-linked amino-naphthyl-sulfonate analogs (AANS) of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]- benzoate, 2-Hydroxy-5-[(E)-2-{4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]benzamide, 4-[(E)-2-(2-Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid,
4-nitro-N-phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate (L-[3-ODAP), L-alanosine, [3-N-methylamino-L-alanine (BMAA), L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate,
5-sulpho-l-cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, S-3-carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-naphthyl-4-bis-TFM-HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br-homoibotenate, S-2-naphthyl-ethyl-ACPA (NACPA), bis-trifluoromethyl-phenyl-isoxazole-4-hydrazone (TFMIH), 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone-dinitrophenol (NEIH), and sorafenib.
"Erastin" and "erastin analogs" are compounds which have the ability to induce ferroptosis through blocking the function of system xc — .
Examples for erastin analogs are preferably piperazine erastin (PE) and carbonyl erastin analogs (Larraufie et al., Bioorg Med Chem Lett. 2015; 25(21 ): 4787- 4792), such as: ketone erastin (KE), a-fluoro ketone erastin (FKE), trifluoroketone erastin (TFKE), morpholine ketone erastin (MKE), N-methylpiperazine ketone erastin (MPKE), N-allylpiperazine ketone erastin (APKE), N-p- methoxybenzylpiperazine ketone erastin (PMB-PKE), aldehyde erastin (AE), imidazole ketone erastin (IKE), piperazine ketone erastin (PKE).
Piperazine erastin has a piperazine moiety on the meta position of the aniline ring of erastin, whereas carbonyl erastin analogs have reactive carbonyl moieties in the meta position of the aniline-derived moiety of erastin.
The "azo amino-naphthylene sulfonic acid (AANS) analogs of sulfasalazine" have been described by Nesher et al, (Neurochemical research, 2020, 45, 1375) as potent inhibitor of system xc, and are named AANS #2 - 4, which are bis-AANS analogs, and AANS #5 - 7, which are symmetrical bis-azo analogues having dual AANS substituents positioned at the distal ends of the molecule. The structure of AANS #2-7 and SAS are reported in the following Table 1 , together with the respective IC50, as reported by Nesher et al. 2020.
The compounds ethyl 2-hydroxy-5-[(E)-2-4{4-[(pyridine-2-yl)sulfamoyl]phenyl}di- azen-1 -yl]-benzoate (4), 2-Hydroxy-5-[(E)-2-{4-[(pyridine-2-yl)sulfamoyl]phenyl}di- azen-1 -yl]benza-mide (5), 4-[(E)-2-(2-Hydroxynaphthalen-1 -yl)diazen-1 -
yl]benzene-1 -sulfonic acid (15), 4-nitro-N-phenylbenzene-1-sulfonamide(19), 2- Hydroxy-5-(3-phenylpropanamido)benzoic acid (12), are sulfasalazine analogs described by Patel at al, Drug Dev Res, 2019, 80, 758-777. The structure and IC50 of these sulfasalazine analogs are reported in the following Table 2.
Thus, a preferred embodiment of the invention is a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2- 4{4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)- 2-{4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]benza-mide, 4-[(E)-2-(2- Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, [3-N-methylamino-L-alanine, L-serine-O-sulphate, L-a- aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4- carboxyphenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, S-3-carboxy,3- hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]- phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-naphthyl-4-bis-TFM-HMICA, 5- 4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br-homoibotenate, S-2-naphthyl- ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4-hydrazone, 5- naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone-dinitrophenol, sorafenib.
A more preferred embodiment of the invention is a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine.
Second inhibitor component of the combination
The second component of the combination according to the present invention is at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5.
A "JAK2 inhibitor," as used herein, includes any compound that disrupts JAK2 activity or production and or the JAK2/STAT signaling pathway. Examples of JAK2 inhibitors include, but are not limited to, baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480.
The heterodimer "SLC7A5:SLC3A2" constitutes the system LAA (L-amino acids) transporter. The SLC7 family is divided into two sub-groups, the cationic amino acid transporters (the CAT family, SLC7A1-4) and the glycoprotein-associated amino acid transporters (the gpaAT family, SLC7A5-11 ), also called light chains or catalytic chains of the heterodimeric amino acid transporters (HAT). The CAT transporters subfamily members have 14 putative transmembrane (TM) segments and are glycosylated, whereas the gpaAT transporters have two TM segments
less, are not glycosylated, and need to associate with a glycoprotein of the SLC3 family, heavy chains 4F2hc (CD98, SLC3A2) or rBAT (related to bO,+AT-type amino acid transporter, where bO,+AT is the basic and neutral amino acid transporter) for surface expression.
SLC7A5 (also named LAT1 , L-type amino acid transporter-1 , NM_003486) was identified on the basis of its capability to transport large neutral aminoacids into Xenopus oocytes when expressed with SLC3A2 (NM_001012662.3). As expected for system L, this HAT protein also transports 2-(-)-endoamino-bicycloheptane-2- carboxylic acid (BCH) and its function is not Na+ sensitive. Its uptake selectivity range is relatively broad and the apparent affinity for the uptake of branched and aromatic amino acids is quite high (micromolar range). SLC7A5:SLC3A2 is an obligatory exchanger that does not mediate any measurable amino acid efflux in the absence of extracellular amino acids, i.e. no facilitated diffusion. Predominant substrates of SLC7A5:SLC3A2 are large neutral l-amino acids, T3, T4, L-DOPA, BCH.
"SLC7A5:SLC3A2 inhibitors" for use in the present method include small molecule inhibitors such as, but not limited to,
JPH203 (KYT-0353), a tyrosine derivative; triiodothyronine (T3) analogs: 3,3',5-triiodothyronine (L-T3), 3’,5’,3- triodothyronine (r L-T3), 3-iodo-L-tyrosine; 3,5-diiodo-L-tyrosine, SKN102- 105; tetraiodothyronine (L-T4), which is a thyroxine (T4) analog;
1.2.3-dithiazole derivatives, described below;
1.2.4-dithiazine derivatives, described below; phenylalanine ; phenylalanine derivates, described below; tryptophan analogs: tryptophan prodrug of valproic acid, L-tryptophan prodrug of benzoic acid;
2-aminobicyclo-(2,2,1 )-heptane-2-carboxylic acid, BCH;
(S)- 2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2-oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 (KMH-233);
2-amino-3-(3-benzylphenyl)propanoic acid, a phenylalanine analog 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid, a tyrosine analog HA-Phe, HA-Leu, HA-lle, HA-Met: hydroxamic acids (HA) conjugated to SLC7A5 substrates Phe, Tyr, Leu, lie, and Met, for example by replacing carboxylic acid in phenylalanine with HA;
baclofen, [3-(4-chlorophenyl)-Y-aminobutyric acid (P-(4-chlorophenyl)- GABA), is a derivative of the neurotransmitter y-aminobutyric acid (GABA); gabapentin, an analogue of the neurotransmitter GABA; acivicin, a glutamine analog, (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; fenclonine, also known as para-chlorophenylalanine (PCPA);
L-DOPA, also known as levodopa and L-3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of humans; KHK2898, a fully human anti CD98 (SLC3A2) monoclonal antibody, IGN523, a human anti CD98 (SLC3A2) monoclonal antibody
JPH203 (KYT-0353), is a tyrosine derivative and a known selective L-type amino acid transporter 1 inhibitor. JPH203 is the abbreviation for (S)-2-Amino-3-(4-((5- amino-2-phenylbenzo[d]oxazol-7-yl)methoxy)-3,5-dichlorophenyl)propanoic acid.
1.2.3-dithiazole derivatives are compounds which have 1 ,2,3-dithiazoles, primary aromatic or heteroaromatic amines or alcohols that are reacted with 4,5-dichloro-
1 .2.3-dithiazolium chloride (Appel’s salt) I, followed by treatment with a base (2 equiv) to give the corresponding [(4-chloro-5H-1 ,2,3-dithiazol-5- ylidene)amino]arenes or 2-(4-chloro-5H-1 ,2,3-dithiazol-5-ylidene)arene-1 (2H)- ones.
Examples for 1,2,3-dithiazole derivatives are compound 5, 10, 11 , 12, 16, 17, 19 described by Napolitano et al, (Biochemical Pharmacology, 2017, 143: 39- 52), shown in Table 3 below.
1.2.4-dithiazine derivatives are compounds synthetized by reaction of the appropriate (Z)-N-(4-chloro-5H-1 ,2, 3-dithiazol-5-ylidene)-1 H-pyrazol-5-amine III with diethylamine followed by treatment with concentrated H2SO4.
Example for 1 ,2,4-dithiazine derivatives is compound 59, described by Napolitano et al, (Biochemical Pharmacology, 2017, 143: 39-52), shown in Table 3 below.
Examples for phenylalanine derivatives are 3-([1 , 10-biphenyl]-3-yl)-2- aminopropanoic acid, and compounds 28, 36, 42 (reported below, Singh et al, Int J Mol Sci, 2019);
"Nitrogen mustard derivatives of phenylalanine" comprise p-N-di-(2 chloroethyl)aminophenylalanine, melphalan ((2S)-2-amino-3-{4-[bis(2 chloroethyl)amino]phenyl}propanoic acid), o-Sarcolysin, m-Sarcolysin
(sarcolysin is an isomeric form of melphalan), DL-2-NAM-7 ((2-amino-7-bis[(2- chloroethyl)amino]-1 ,2,3,4-tetrahydro-2-naphthoic acid).
IL-3 receptor is comprised of a ligand specific alpha subunit (IL3RA or IL3R- alpha) and a signal transducing beta subunit (IL3RB, or IL3R-beta) shared by the receptors for interleukin 3 (IL-3), colony stimulating factor 2 (CSF2/GM-CSF), and interleukin 5 (IL5). IL-3R-alpha is a type I transmembrane protein with a deduced molecular weight of about 41 kDa containing an extracellular domain involved in IL-3 binding, a transmembrane domain and a short cytoplasmic tail of about 50 amino acids.
An "inhibitor targeting IL-3 receptor alpha" is preferably an inhibitor able to interact with IL-3 receptor alpha chain and blocking its binding with the ligand IL-3. An "inhibitor targeting IL-3 receptor beta" is also preferably an inhibitor able to interact with IL-3 receptor beta chain causing blocking signal transduction upon binding of IL-3 to the receptor and the biological activities of IL-3.
An "inhibitor targeting IL-3 receptor alpha" as used in present invention is selected from the group comprising: CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, SGN-CD123A. An "inhibitor targeting IL-3 receptor beta" as used in present invention is preferably CSL311 antibody.
"Granulocyte macrophage-colony stimulating factor" or “GM-CSF” refers to a family of glycoprotein growth factors that control the production, differentiation, and function of granulocytes and monocytes-macrophages. GM-CSF was originally discovered as a protein with the capacity to generate both granulocyte and macrophage colonies from precursor cells in mouse bone marrow, and was accordingly named. Subsequent studies have demonstrated a role of GM-CSF in potentiating the function of mature macrophages and granulocytes, suggesting a role for GM-CSF in inflammatory responses. Moreover, GM-CSF has other functions arising from its ability to affect the properties of more mature myeloid cells such as granulocytes, macrophages and eosinophils. The functions of GM- CSF are mediated by binding to CD116, the granulocyte-macrophage colony stimulating factor receptor, also known as colony stimulating factor 2 receptor alpha (GM-CSFRa, GM-CSF receptor alpha) that binds GM-CSF with low affinity. The beta subunit, called CD131 , which is also shared with the IL-3 and IL-5 receptors, has no detectable binding activity for GM-CSF by itself but is necessary for high affinity binding when in association with the alpha subunit and plays a fundamental role in signal transduction.
An "inhibitor targeting GM-CSF" is a compound, more preferably an antibody, that can antagonize the activity of GM-CSF.
An "inhibitor targeting GM-CSF" as used in present invention is selected from otilimab (MOR103/GSK3196165), namilumab (MT203), lenzilumab (KB003), plonmarlimab (TJ003234 or TJM2), and gimsilumab.
An "inhibitor targeting GM-CSF receptor alpha" is a compound, more preferably an antibody or blocking antibody, that can neutralise the biological activity of GM- CSF receptor alpha by binding to GM-CSF receptor alpha or by inhibiting binding of GM-CSF to GM-CSF receptor alpha.
An "inhibitor targeting GM-CSF receptor alpha" as used in present invention is mavrilimumab.
In normal cells, STAT5 protein activation is tightly regulated by cytokines (IL-3, IL- 2, IL-5, IL-7, GM-CSF, erythropoietin, thrombopoietin and prolactin) and growth factors. Binding of these extracellular ligands to the target receptor induces activation of receptor-associated JAK kinase, which induces STAT5 phosphorylation. Phosphorylated STAT5 monomers form homo- or hetero-STAT5- STATX dimers due to the interaction between phosphorylated tyrosine and SH2. Activated STAT5 dimers migrate to the nucleus where they bind to STAT5 DNA response elements and Induces transcription of specific genes involved in controlled cell growth and division, cell proliferation, programmed cell death, or apoptosis, cell specialization, or differentiation and inflammation.
An "inhibitor targeting STAT5" is a compound that neutralizes biological activity of STAT5. As used herein, an "inhibitor targeting STAT5" is a monovalent small molecule that degrades STAT5. Preferably, an "inhibitor targeting STAT5" is selected from the group comprising:
- JPX1188, JPX0802, JPX1185 (Janpix, https://www.janpixbio.com)
Compound 17f
AC-4-130
- N'-((4-Oxo-4H-chromen-3-yl)methylene)nicotinohydrazide, also referred to as CAS 285986-31-4, (Muller et al., Chembiochem 2008, 9(5)723 - 727).
- BP-1-075, BP-1-107, BP-1-108, SF-1-087, SF-1-088 (Page et al., J. Med. Chem.
2012, 55, 3, 1047 - 1055), of general Formula:
wherein:
- N1 -(11 H-indolo[3,2-c]quinolin-6-yl)-N2,N2-dimethylethane-1 ,2-diamine, also referred to as IQDMA (Chien, et al., Chemico-Biological Interactions 2008, 176, 1 , 40-47), of Formula:
- pimozide, also referred to as CAS 2062-78-4, 1 -(1-(4,4-Bis(4-fluorophenyl)butyl) -4-piperidinyl)-1 ,3-dihydro-2H-benzimidazol-2-one, (Nelson et al., Blood 2011 , 117 (12): 3421-3429).
Thus, an "inhibitor targeting STAT5" is JPX1188, JPX0802, JPX1185, compound 17f , compound AC-4-130, CAS 285986-31 -4, BP-1-075, BP-1-107, BP- 1 -108, SF-1 -087, SF-1 -088, IQDMA, or CAS 2062-78-4.
A preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3-dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2- carboxylic acid; (S)- 2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2- oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)-
carbamoyl)phenyl)propanoic acid 1 ; 2-amino-3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids-isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid (|3-(4- chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4- dihydroxyphenylalanine; KHK2898 antibody, IGN523 antibody; or wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN- CD123A,; or wherein the inhibitor targeting IL-3 receptor beta is CSL311 antibody, or wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab; or wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab; or wherein the inhibitor targeting STAT5 is JPX1188, JPX0802, JPX1185, compound 17f, compound AC-4-130, CAS 285986-31-4, BP-1-075, BP-1-107, BP-1-108, SF-1-087, SF-1 -088, IQDMA, or CAS 2062-78-4.
A more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor JAK2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the at least one JAK2 inhibitor is baricitinib.
A still more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor JAK2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the at least one JAK2 inhibitor is delgocitinib.
In another aspect, the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and
wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3-dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2- carboxylic acid; (S)- 2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2- oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids-isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid (|3-(4- chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4- dihydroxyphenylalanine; KHK2898 antibody, IGN523 antibody.
In still another aspect, the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor targeting IL-3 receptor alpha or at least one inhibitor targeting IL-3 receptor beta wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN- CD123A; wherein the inhibitor targeting IL-3 receptor beta is CSL311 antibody.
In a particular aspect, the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor targeting GM-CSF, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab.
In a further particular aspect, the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor targeting GM-CSF receptor alpha,
wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab.
In a further more particular aspect, the present invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor targeting STAT-5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the inhibitor targeting STAT5 is JPX1188, JPX0802, JPX1185, compound 17f, compound AC-4-130, CAS 285986-31-4, BP-1-075, BP-1-107, BP-1-108, SF-1-087, SF-1 -088, IQDMA, or CAS 2062-78-4.
A further more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]benza-mide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, |3-N- methylamino-L-alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy- phenylglycine, S-3-carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5- naphthyl-4-bis-TFM-HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br- homoibotenate, S-2-naphthyl-ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4- hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone- dinitrophenol, sorafenib.
A further more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]benza-mide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, |3-N- methylamino-L-alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy- phenylglycine, S-3-carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5- naphthyl-4-bis-TFM-HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br- homoibotenate, S-2-naphthyl-ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4- hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone- dinitrophenol, sorafenib, and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3-dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )- heptane-2-carboxylic acid; (S)- 2-Amino-3-(3-((2,4-dicyano-3-(4-(2-
(methylamino)-2-oxoethoxy)phenyl) benzo[4,5]imidazo[1 , 2-a]pyrid in-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids-isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid (|3-(4- chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2-
oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4- dihydroxyphenylalanine; KHK2898 antibody, IGN523 antibody.
A still more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]benza-mide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, |3-N- methylamino-L-alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy- phenylglycine, S-3-carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5- naphthyl-4-bis-TFM-HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br- homoibotenate, S-2-naphthyl-ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4- hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone- dinitrophenol, sorafenib, and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3-dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine;
phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2- carboxylic acid; (S)- 2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2- oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids-isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid (|3-(4- chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4- dihydroxyphenylalanine; KHK2898 antibody, IGN523 antibody; or wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, SGN- CD123A; or wherein the inhibitor targeting IL-3 receptor beta is CSL311 antibody, or wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab; or wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab; or wherein the inhibitor targeting STAT5 is JPX1188, JPX0802, JPX1185, compound 17f, compound AC-4-130, CAS 285986-31-4, BP-1-075, BP-1-107, BP-1-108, SF-1-087, SF-1 -088, IQDMA, or CAS 2062-78-4.
A further preferred embodiment of the invention is a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or
wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3-dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2- carboxylic acid; (S)- 2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2- oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids-isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid (|3-(4- chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4- dihydroxyphenylalanine; KHK2898 antibody, IGN523 antibody; or wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN- CD123A; or wherein the inhibitor targeting IL-3 receptor beta is CSL311 antibody, or wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab; or wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab; or wherein the inhibitor targeting STAT5 is JPX1188, JPX0802, JPX1185, compound 17f, compound AC-4-130, CAS 285986-31-4, BP-1-075, BP-1-107, BP-1-108, SF-1-087, SF-1 -088, IQDMA, or CAS 2062-78-4.
A still more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]benza-mide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine,
ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, |3-N- methylamino-L-alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy- phenylglycine, S-3-carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5- naphthyl-4-bis-TFM-HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br- homoibotenate, S-2-naphthyl-ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4- hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone- dinitrophenol, sorafenib, and wherein the at least one JAK2 inhibitor is baricitinib.
A still more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]benza-mide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, |3-N- methylamino-L-alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy- phenylglycine, S-3-carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5- naphthyl-4-bis-TFM-HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br- homoibotenate, S-2-naphthyl-ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4- hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone- dinitrophenol, sorafenib, and wherein the at least one JAK2 inhibitor is delgocitinib.
A more preferred embodiment of the invention is a combination for use in the treatment of an autoimmune disease, wherein the combination consists of:
at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine, and wherein the at least one JAK2 inhibitor is baricitinib.
A further more preferred embodiment of the invention is a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine, and wherein the at least one JAK2 inhibitor is delgocitinib.
An "autoimmune diseases", as pertains to the present invention, is a disease or disorder arising from and directed against an individual's own tissues or a cosegregate or manifestation thereof or resulting condition therefrom. This class of disorders is highly varied, both between and within different kinds of autoimmune diseases, which complicates diagnosis and effective treatment. The causes of autoimmune diseases are also poorly understood, which results in courses of treatment that focus primarily on the symptoms. An "autoimmune disease mediated by plasmacytoid dendritic cells" refers to an autoimmune disease characterized by a chronic activation of plasmacytoid dendritic cells releasing high amounts of type I interferon (IFN-I). Thus, an "autoimmune disease mediated by plasmacytoid dendritic cells" is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug- induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott-Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid
diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
"Systemic Lupus Erythematosus" (SLE) is a debilitating autoimmune disease that can damage multiple organs, induce chronic renal failure, and lead to severe morbidity and mortality. A characteristic feature of SLE is the presence of antinuclear autoantibodies that form immune complexes with cellular debris and cause end-organ damage. Current treatment regimens are limited to non-specific immune suppression and management of inflammatory symptoms.
The term "lupus" as used herein is an autoimmune disease or disorder that in general involves antibodies that attack connective tissue. The principal form of lupus is a systemic one, systemic lupus erythematosus (SLE); including cutaneous SLE and subacutecutaneous SLE, as well as other types of lupus including nephritis, extrarenal, cerebritis, pediatric, non-renal, discoid, and alopecia. In certain embodiments, the term "systemic lupus erythematosus" refers to a chronic autoimmune disease that can result in skin lesions, joint pain and swelling, kidney disease (lupus nephritis), fluid around the heart and/or lungs, inflammation of the heart, and various other systemic conditions. In certain embodiments, the term "lupus nephritis" refers to inflammation of the kidneys that occurs in patients with SLE. Lupus nephritis may include, for example, glomerulonephritis and/or interstitial nephritis, and can lead to hypertension, proteinuria, and kidney failure. Lupus nephritis classes include class I (minimal mesangial lupus nephritis), class II (mesangial proliferative lupus nephritis), class 111 (focal lupus nephritis), class IV (diffuse segmental (IV-S) or diffuse global (IV-G) lupus nephritis), class V (membranous lupus nephritis), and class VI (advanced sclerosing lupus nephritis). The term "lupus nephritis" encompasses all of the classes.
The term "conditions induced by SLE" or "SLE-induced conditions" includes, for example serositis, malar rash (rash over the cheeks and bridge of the nose), discoid rash (scaly, disk-shaped sores on the face, neck and chest), sensitivity to light, alopecia, Raynaud's syndrome (sensitivity to cold), sores or ulcers (on the tongue, in the mouth or nose), abdominal pain, including peritonitis and bowel infarction, lupus hepatitis, hemolytic anemia, low lymphocytic count, low platelet count, leukopenia (low white blood cells count), the presence of antinuclear bodies
in the blood, skin lesions, central nervous system (CNS) effects including loss of memory, seizures, strokes and psychosis, CNS lupus, lung symptom s/effects including inflammation (pleuritis), chronic pneumonitis, chronic diffuse interstitial lung disease and scarring of the lungs, alternations in pulmonary vessel structure and function; hair loss, lupus nephritis, hematuria, proteinuria, fatigue, fever, nausea, dyspepsia, vomiting, diarrhoea, swollen glands, lack of appetite, weight loss, arthralgia and myalgia, arthritis, osteonecrosis, myopathy, atherosclerotic plaque, pericarditis, vasculitis, keratoconjunctivitis sicca, lupus retinopathy, pregnancy complications with increased rate of fetal death in utero, thyroid dysfunction,
Thus, an embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug- induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott-Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic
anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
A further embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein at least one inhibitor of the antiporter system xc — is selected from the group comprising erastin, imidazole ketone erastin, erastin analogs, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate (L-[3-ODAP), L-alanosine, |3-N- methylamino-L-alanine (BMAA), L-serine-O-sulphate, L-a-aminopimelate, L- homocysteate, S-sulpho-l-cysteine S-4-carboxy-phenylglycine, S-4-carboxy,3- hydroxy-phenylglycine, R,S-sulphothienylglycine, 5-benzyl-4-bis-TFM-HMICA, 5- naphthyl-4-bis-TFM-HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, (RS)-4-Br- homoibotenate, S-2-naphthyl-ethyl-ACPA (NACPA), bis-trifluoromethyl-phenyl- isoxazole-4-hydrazone (TFMIH), 5-naphthylethyl isoxazole-4-(2,4- dinitrophenol)hydrazone-dinitrophenol (NEIH), azo amino-naphthylene sulfonic acid (AANS) analogs, sulfasalazine, sulfasalazine derivatives, sorafenib; wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug- induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott-Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris;
myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
A preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott-Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic
anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
A more preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3-dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2- carboxylic acid; (S)- 2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2- oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids-isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid (|3-(4- chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4- dihydroxyphenylalanine; KHK2898 antibody, IGN523 antibody; or wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN- CD123A; or wherein the inhibitor targeting IL-3 receptor beta is CSL311 antibody, or wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab; or wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab; or
wherein the inhibitor targeting STAT5 is JPX1188, JPX0802, JPX1185, compound 17f, compound AC-4-130, CAS 285986-31 -4, BP-1 -075, BP-1 - 107, BP-1 -108, SF-1 -087, SF-1-088, IQDMA, or CAS 2062-78-4, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott-Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
A still more preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, wherein the at least one JAK2 inhibitor is baricitinib, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome;
Hyper-lgE syndrome; Wiskott-Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
A still more preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, wherein the at least one JAK2 inhibitor is delgocitinib, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott-Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
A further embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and
at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2- 4{4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)- 2-{4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]benza-mide, 4-[(E)-2-(2- Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, [3-N-methylamino-L-alanine, L-serine-O-sulphate, L-a- aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4- carboxyphenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, S-3-carboxy,3- hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]- phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-naphthyl-4-bis-TFM-HMICA, 5- 4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br-homoibotenate, S-2-naphthyl- ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4-hydrazone, 5- naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone-dinitrophenol, sorafenib, and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3-dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2- carboxylic acid; (S)- 2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2- oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids-isoleucine,
hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid (|3-(4- chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4- dihydroxyphenylalanine; KHK2898 antibody, IGN523 antibody; or wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN- CD123A; or wherein the inhibitor targeting IL-3 receptor beta is CSL311 antibody, or wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab; or wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab; or wherein the inhibitor targeting STAT5 is JPX1188, JPX0802, JPX1185, compound 17f, compound AC-4-130, CAS 285986-31 -4, BP-1 -075, BP-1 - 107, BP-1 -108, SF-1 -087, SF-1-088, IQDMA, or CAS 2062-78-4; and wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott- Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
An embodiment of the invention is a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and
at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3-dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2- carboxylic acid; (S)- 2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2- oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids-isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid (|3-(4- chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4- dihydroxyphenylalanine; KHK2898 antibody, IGN523 antibody; or wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN- CD123A; or wherein the inhibitor targeting IL-3 receptor beta is CSL311 antibody, or wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab; or wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab; or wherein the inhibitor targeting STAT5 is JPX1188, JPX0802, JPX1185, compound 17f, compound AC-4-130, CAS 285986-31 -4, BP-1 -075, BP-1 - 107, BP-1 -108, SF-1 -087, SF-1-088, IQDMA, or CAS 2062-78-4; and wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and
wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott- Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
A preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, wherein at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2- 4{4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)- 2-{4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]benza-mide, 4-[(E)-2-(2- Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, [3-N-methylamino-L-alanine, L-serine-O-sulphate, L-a- aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4- carboxyphenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, S-3-carboxy,3- hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]- phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-naphthyl-4-bis-TFM-HMICA, 5- 4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br-homoibotenate, S-2-naphthyl-
ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4-hydrazone, 5- naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone-dinitrophenol, sorafenib, and wherein the at least one JAK2 inhibitor is baricitinib, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott- Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
A more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, wherein at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2- 4{4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)- 2-{4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]benza-mide, 4-[(E)-2-(2- Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate,
L-alanosine, [3-N-methylamino-L-alanine, L-serine-O-sulphate, L-a- aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4- carboxyphenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, S-3-carboxy,3- hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]- phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-naphthyl-4-bis-TFM-HMICA, 5- 4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br-homoibotenate, S-2-naphthyl- ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4-hydrazone, 5- naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone-dinitrophenol, sorafenib, and wherein the at least one JAK2 inhibitor is delgocitinib, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott- Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
A more preferred embodiment of the invention is a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine and wherein the at least one JAK2 inhibitor is baricitinib,
wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott- Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
A still more preferred embodiment of the invention is a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine and wherein the at least one JAK2 inhibitor is delgocitinib, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic
dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott- Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
A more preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug- induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott-Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
A still more preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of:
at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]benza-mide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, |3-N- methylamino-L-alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy- phenylglycine, S-3-carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5- naphthyl-4-bis-TFM-HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br- homoibotenate, S-2-naphthyl-ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4- hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone- dinitrophenol, sorafenib, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug- induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott-Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic
anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
An embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott-Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
A preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor,
wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3-dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )- heptane-2-carboxylic acid; (S)- 2-Amino-3-(3-((2,4-dicyano-3-(4-(2-
(methylamino)-2-oxoethoxy)phenyl) benzo[4,5]imidazo[1 , 2-a]pyrid in-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids-isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid (|3-(4- chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4- dihydroxyphenylalanine; KHK2898 antibody, IGN523 antibody; wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott-Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
Thus, an embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of:
at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is systemic lupus erythematosus.
A further embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein at least one inhibitor of the antiporter system xc — is selected from the group comprising erastin, imidazole ketone erastin, erastin analogs, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate (L-[3-ODAP), L-alanosine, [3-N-methylamino-L-alanine (BMAA), L-serine-O-sulphate, L-a- aminopimelate, L-homocysteate, S-sulpho-l-cysteine S-4-carboxy- phenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, R,S- sulphothienylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-naphthyl-4-bis-TFM- HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, (RS)-4-Br-homoibotenate, S-2- naphthyl-ethyl-ACPA (NACPA), bis-trifluoromethyl-phenyl-isoxazole-4- hydrazone (TFMIH), 5-naphthylethyl isoxazole-4-(2,4- dinitrophenol)hydrazone-dinitrophenol (NEIH), azo amino-naphthylene sulfonic acid (AANS) analogs, sulfasalazine, sulfasalazine derivatives, sorafenib;
wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is systemic lupus erythematosus.
A preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is systemic lupus erythematosus.
A more preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3-dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2-
carboxylic acid; (S)-2-amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2- oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids-isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid (|3-(4- chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4- dihydroxyphenylalanine; KHK2898 antibody, IGN523 antibody; or wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN- CD123A; or wherein the inhibitor targeting IL-3 receptor beta is CSL311 antibody, or wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab; or wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab; or wherein the inhibitor targeting STAT5 is JPX1188, JPX0802, JPX1185, compound 17f , compound AC-4-130, CAS 285986-31 -4, BP-1-075, BP-1-107, BP- 1 -108, SF-1 -087, SF-1 -088, IQDMA, or CAS 2062-78-4, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is systemic lupus erythematosus.
A still more preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, wherein the at least one JAK2 inhibitor is baricitinib, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is systemic lupus erythematosus.
A still more preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, wherein the at least one JAK2 inhibitor is delgocitinib,
wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is systemic lupus erythematosus.
A further embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2- 4{4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)- 2-{4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]benza-mide, 4-[(E)-2-(2- Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, [3-N-methylamino-L-alanine, L-serine-O-sulphate, L-a- aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4- carboxyphenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, S-3-carboxy,3- hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]- phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-naphthyl-4-bis-TFM-HMICA, 5- 4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br-homoibotenate, S-2-naphthyl- ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4-hydrazone, 5- naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone-dinitrophenol, sorafenib, and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine;
1 ,2,3-dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2- carboxylic acid; (S)- 2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2- oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids-isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid (|3-(4- chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4- dihydroxyphenylalanine; KHK2898 antibody, IGN523 antibody; or wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN- CD123A; or wherein the inhibitor targeting IL-3 receptor beta is CSL311 antibody, or wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab; or wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab; or wherein the inhibitor targeting STAT5 is JPX1188, JPX0802, JPX1185, compound 17f, compound AC-4-130, CAS 285986-31 -4, BP-1 -075, BP-1 - 107, BP-1 -108, SF-1 -087, SF-1-088, IQDMA, or CAS 2062-78-4; and wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
An embodiment of the invention is a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine and
wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3-dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2- carboxylic acid; (S)- 2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2- oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids-isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid (|3-(4- chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4- dihydroxyphenylalanine; KHK2898 antibody, IGN523 antibody; or wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN- CD123A; or wherein the inhibitor targeting IL-3 receptor beta is CSL311 antibody, or wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab; or wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab; or wherein the inhibitor targeting STAT5 is JPX1188, JPX0802, JPX1185, compound 17f, compound AC-4-130, CAS 285986-31 -4, BP-1 -075, BP-1 - 107, BP-1 -108, SF-1 -087, SF-1-088, IQDMA, or CAS 2062-78-4; and wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
A preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, wherein at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2- 4{4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)-
2-{4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]benza-mide, 4-[(E)-2-(2- Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, [3-N-methylamino-L-alanine, L-serine-O-sulphate, L-a- aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4- carboxyphenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, S-3-carboxy,3- hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]- phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-naphthyl-4-bis-TFM-HMICA, 5- 4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br-homoibotenate, S-2-naphthyl- ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4-hydrazone, 5- naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone-dinitrophenol, sorafenib, and wherein the at least one JAK2 inhibitor is baricitinib, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
A more preferred embodiment of the invention is directed to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, wherein at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2- 4{4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)- 2-{4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]benza-mide, 4-[(E)-2-(2- Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, [3-N-methylamino-L-alanine, L-serine-O-sulphate, L-a- aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4- carboxyphenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, S-3-carboxy,3- hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]- phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-naphthyl-4-bis-TFM-HMICA, 5- 4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br-homoibotenate, S-2-naphthyl-
ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4-hydrazone, 5- naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone-dinitrophenol, sorafenib, and wherein the at least one JAK2 inhibitor is delgocitinib, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
A more preferred embodiment of the invention is a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine and wherein the at least one JAK2 inhibitor is baricitinib, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
A still more preferred embodiment of the invention is a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine and wherein the at least one JAK2 inhibitor is delgocitinib, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
A more preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is systemic lupus erythematosus.
A still more preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]benza-mide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, |3-N- methylamino-L-alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy- phenylglycine, S-3-carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5- naphthyl-4-bis-TFM-HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br- homoibotenate, S-2-naphthyl-ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4- hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone- dinitrophenol, sorafenib, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is systemic lupus erythematosus.
An embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is systemic lupus erythematosus.
A preferred embodiment of the invention relates to a combination for use in the treatment of an autoimmune disease, wherein the combination consists of: at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of: a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3-dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )- heptane-2-carboxylic acid; (S)- 2-Amino-3-(3-((2,4-dicyano-3-(4-(2-
(methylamino)-2-oxoethoxy)phenyl) benzo[4,5]imidazo[1 , 2-a]pyrid in-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids-isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid (|3-(4- chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4- dihydroxyphenylalanine; KHK2898 antibody, IGN523 antibody; wherein the autoimmune disease is mediated by plasmacytoid dendritic cells; and wherein the autoimmune disease is systemic lupus erythematosus.
PHARMACEUTICAL COMPOSITIONS
The disclosure also provides pharmaceutical compositions comprising one or more of the disclosed inhibitors in association with a pharmaceutically acceptable carrier.
Preferably, the present invention relates to a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent.
More preferably, the present invention relates to a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]benza-mide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, [3-N-methylamino-L- alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l- cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, S-3- carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4 - carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-naphthyl-4-bis-TFM- HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br-homoibotenate, S-2-naphthyl- ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4-hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone-dinitrophenol, sorafenib.
Still more preferably, the present invention relates to a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine.
An embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an
inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3- dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2-carboxylic acid; (S)-
2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2-oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-
3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids- isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid ([3- (4-chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4-dihydroxyphenylalanine, KHK2898 antibody, IGN523 antibody; or wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN-CD123A; or wherein the inhibitor targeting IL-3 receptor beta is CSL311 antibody, or wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab; or wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab; or wherein the inhibitor targeting STAT5 is JPX1188, JPX0802, JPX1185, compound 17f, compound AC-4-130, CAS 285986-31-4, BP-1-075, BP-1-107, BP-1 -108, SF-1- 087, SF-1-088, IQDMA, or CAS 2062-78-4.
A particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one JAK2 inhibitor is baricitinib.
A particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one JAK2 inhibitor is delgocitinib.
A more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]benza-mide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, [3-N-methylamino-L- alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l- cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, S-3- carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4 - carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-naphthyl-4-bis-TFM- HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br-homoibotenate, S-2-naphthyl- ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4-hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone-dinitrophenol, sorafenib, and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3- dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2-carboxylic acid; (S)-
2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2-oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-
3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids- isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid ([3- (4-chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4-dihydroxyphenylalanine, KHK2898 antibody, IGN523 antibody; or
wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN-CD123A; or wherein the inhibitor targeting IL-3 receptor beta is CSL311 antibody, or wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab; or wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab; or wherein the inhibitor targeting STAT5 is JPX1188, JPX0802, JPX1185, compound 17f, compound AC-4-130, CAS 285986-31-4, BP-1-075, BP-1-107, BP-1 -108, SF-1- 087, SF-1-088, IQDMA, or CAS 2062-78-4.
Another more preferred embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine, and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3- dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2-carboxylic acid; (S)-
2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2-oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-
3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids- isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid ([3- (4-chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4-dihydroxyphenylalanine, KHK2898 antibody, IGN523 antibody; or wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, SGN-CD123A; or wherein the inhibitor targeting IL-3 receptor beta is CSL311 antibody, or
wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab; or wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab; or wherein the inhibitor targeting STAT5 is JPX1188, JPX0802, JPX1185, compound 17f, compound AC-4-130, CAS 285986-31-4, BP-1-075, BP-1-107, BP-1 -108, SF-1- 087, SF-1-088, IQDMA, or CAS 2062-78-4.
A further embodiment of the present invention is a a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, , azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]benza-mide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, |3-N- methylamino-L-alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy- phenylglycine, S-3-carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5- naphthyl-4-bis-TFM-HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br- homoibotenate, S-2-naphthyl-ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4- hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone- dinitrophenol, sorafenib, and wherein the at least one JAK2 inhibitor is baricitinib.
Another still more preferred embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine, and wherein the at least one JAK2 inhibitor is baricitinib.
A further embodiment of the present invention is a a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one JAK2
inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, , azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]benza-mide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, |3-N- methylamino-L-alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy- phenylglycine, S-3-carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5- naphthyl-4-bis-TFM-HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br- homoibotenate, S-2-naphthyl-ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4- hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone- dinitrophenol, sorafenib, and wherein the at least one JAK2 inhibitor is delgocitinib.
Another still more preferred embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine, and wherein the at least one JAK2 inhibitor is delgocitinib.
A more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
A still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott- Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
A further more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
Another embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, , azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]benza-mide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, |3-N- methylamino-L-alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy- phenylglycine, S-3-carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5- naphthyl-4-bis-TFM-HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br- homoibotenate, S-2-naphthyl-ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4- hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone- dinitrophenol, sorafenib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
Another preferred embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, , azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]benza-mide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, |3-N- methylamino-L-alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy- phenylglycine, S-3-carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5- naphthyl-4-bis-TFM-HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br- homoibotenate, S-2-naphthyl-ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4- hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone- dinitrophenol, sorafenib; for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott- Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
Another more preferred embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting
GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, , azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1 -yl]benza-mide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, |3-N- methylamino-L-alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy- phenylglycine, S-3-carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5- naphthyl-4-bis-TFM-HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br- homoibotenate, S-2-naphthyl-ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4- hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone- dinitrophenol, sorafenib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
A particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
A more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor
targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott- Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
A still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
A further more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least
one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3- dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2-carboxylic acid; (S)-
2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2-oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-
3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids- isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid ([3- (4-chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4-dihydroxyphenylalanine, KHK2898 antibody, IGN523 antibody; or wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN-CD123A; or wherein the inhibitor targeting IL-3 receptor beta is CSL311 antibody, or wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab; or wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab; or wherein the inhibitor targeting STAT5 is JPX1188, JPX0802, JPX1185, compound 17f, compound AC-4-130, CAS 285986-31-4, BP-1-075, BP-1-107, BP-1 -108, SF-1- 087, SF-1-088, IQDMA, or CAS 2062-78-4; for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
A still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting
GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3- dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2-carboxylic acid; (S)-
2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2-oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-
3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids- isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid ([3- (4-chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4-dihydroxyphenylalanine, KHK2898 antibody, IGN523 antibody; or wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN-CD123A; or wherein the inhibitor targeting IL-3 receptor beta is CSL311 antibody, or wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab; or wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab; or wherein the inhibitor targeting STAT5 is JPX1188, JPX0802, JPX1185, compound 17f, compound AC-4-130, CAS 285986-31-4, BP-1-075, BP-1-107, BP-1 -108, SF-1- 087, SF-1-088, IQDMA, or CAS 2062-78-4; for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott- Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple
sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
Another still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3- dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2-carboxylic acid; (S)-
2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2-oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-
3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids- isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid ([3- (4-chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4-dihydroxyphenylalanine, KHK2898 antibody, IGN523 antibody; or wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN-CD123A; or wherein the inhibitor targeting IL-3 receptor beta is CSL311 antibody, or wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab; or wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab; or
wherein the inhibitor targeting STAT5 is JPX1188, JPX0802, JPX1185, compound 17f, compound AC-4-130, CAS 285986-31-4, BP-1-075, BP-1-107, BP-1 -108, SF-1- 087, SF-1-088, IQDMA, or CAS 2062-78-4, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
A further more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; and wherein the at least one JAK2 inhibitor is delgocitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
A still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; and wherein the at least one JAK2 inhibitor is delgocitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott-Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune- mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
Another still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; and wherein the at least one JAK2 inhibitor is delgocitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
A further more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; and wherein the at least one JAK2 inhibitor is baricitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
A still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; and wherein the at least one JAK2 inhibitor is baricitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott- Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive
hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
Another still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; and wherein the at least one JAK2 inhibitor is baricitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
A more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine, and wherein the at least one JAK2 inhibitor is baricitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
A more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine, and wherein the at least one JAK2 inhibitor is delgocitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
A further particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine, and wherein the at least one JAK2 inhibitor is baricitinib,
for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott- Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
A further more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine, and wherein the at least one JAK2 inhibitor is delgocitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott- Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated
glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
A particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine, and wherein the at least one JAK2 inhibitor is baricitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
A more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one JAK2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine, and wherein the at least one JAK2 inhibitor is delgocitinib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
Preferably, the present invention relates to a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent.
More preferably, the present invention relates to a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor
selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]benza-mide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, [3-N-methylamino-L- alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l- cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, S-3- carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4 - carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-naphthyl-4-bis-TFM- HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br-homoibotenate, S-2-naphthyl- ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4-hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone-dinitrophenol, sorafenib.
Still more preferably, the present invention relates to a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, and wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine.
An embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3- dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2-carboxylic acid; (S)-
2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2-oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1-yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-
3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids- isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid ([3- (4-chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4-dihydroxyphenylalanine, KHK2898 antibody, IGN523 antibody.
A more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]benza-mide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, [3-N-methylamino-L- alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l- cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, S-3- carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4 - carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-naphthyl-4-bis-TFM- HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br-homoibotenate, S-2-naphthyl- ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4-hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone-dinitrophenol, sorafenib, and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3- dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2-carboxylic acid; (S)- 2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2-oxoethoxy)phenyl)
benzo[4,5]imidazo[1 ,2-a]pyridin-1-yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino- 3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids- isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid ([3- (4-chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4-dihydroxyphenylalanine, KHK2898 antibody, IGN523 antibody.
Another more preferred embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine, and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3- dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2-carboxylic acid; (S)-
2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2-oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-
3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids- isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid ([3- (4-chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4-dihydroxyphenylalanine, KHK2898 antibody, IGN523 antibody.
A more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
A still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott-Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
A further more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
Another embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and
wherein the at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, , azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]benza-mide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, |3-N- methylamino-L-alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy- phenylglycine, S-3-carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5- naphthyl-4-bis-TFM-HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br- homoibotenate, S-2-naphthyl-ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4- hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone- dinitrophenol, sorafenib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
Another preferred embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, , azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]benza-mide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, |3-N- methylamino-L-alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy- phenylglycine, S-3-carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-
naphthyl-4-bis-TFM-HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br- homoibotenate, S-2-naphthyl-ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4- hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone- dinitrophenol, sorafenib; for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott- Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
Another more preferred embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4- [(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-
[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]benza-mide, 4-[(E)-2-(2-
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, |3-N-
methylamino-L-alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy- phenylglycine, S-3-carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5- naphthyl-4-bis-TFM-HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br- homoibotenate, S-2-naphthyl-ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4- hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone- dinitrophenol, sorafenib, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
A particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
A more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott- Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple
sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
A still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine, for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
A further more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3- dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2-carboxylic acid; (S)-
2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2-oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-
3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids- isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid ([3- (4-chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2-
oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4-dihydroxyphenylalanine, KHK2898 antibody, IGN523 antibody; for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
A still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent; and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3- dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2-carboxylic acid; (S)-
2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2-oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-
3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids- isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid ([3- (4-chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4-dihydroxyphenylalanine, KHK2898 antibody, IGN523 antibody; for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott- Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis;
inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
Another still more particular embodiment of the present invention is a pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent, and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3- dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2-carboxylic acid; (S)-
2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2-oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-
3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids- isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid ([3- (4-chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4-dihydroxyphenylalanine, KHK2898 antibody, IGN523 antibody; for use in the treatment of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
“Pharmaceutical composition” refers to a preparation in a form that allows the biological activity of the active ingredient(s) to be effective, and which contain no additional components which are toxic to the subjects to which the formulation is administered.
As used herein, the terms "pharmaceutically acceptable", "physiologically tolerable" and grammatical variations thereof, are used interchangeably and
represent that the materials are capable of administration to or upon a mammal without the production of undesirable physiological effects such as nausea, dizziness, gastric upset and the like.
“Pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical composition, other than an active ingredient, which is nontoxic to the subject to whom it is administered. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.
The pharmaceutical composition is designed to facilitate the administering of the inventive polypeptides comprising the single domain antibodies in an effective manner.
“Pharmaceutically acceptable vehicle” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to the subject to whom it is administered. A pharmaceutically acceptable vehicle includes, but is not limited to, a buffer, stabilizer, or preservative.
Examples of suitable vehicles or excipients include, without limitation, lactose, dextrose, sucrose, glucose, powdered sugar, sorbitol, mannitol, xylitol, starches, acacia gum, xanthan gum, guar gum, tara gum, mesquite gum, fenugreek gum, locust bean gum, ghatti gum, tragacanth gum, inositol, molasses, maltodextrin, extract of Irish moss, panwar gum, mucilage of isapol husks, Veegum, larch arabogalactan, calcium silicate, calcium phosphate, dicalcium phosphate, calcium sulfate, kaolin, sodium chloride, polyethylene glycol, alginates, gelatine, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, saline, syrup, methylcellulose, ethylcellulose, hydroxypropylnethylcellulose, carboxymethylcellulose, polyacrylic acids such as Carbopols, such as Carbopol941 , Carbopol980, Carbopol981 ,and gum bases such as Pharmagum™ (SPI Pharma Group; New Castle, Del.), and similar. Typically, the compositions of the present invention comprise from about 10% to about 90% by weight of the vehicle, the excipient or combinations thereof.
The pharmaceutical composition can be formulated into powders, granules, tablets, capsules, suspensions, emulsions, syrups, oral dosage form, external preparation, suppository or in the form of sterile injectable solutions, such as aerosolized in a usual manner, respectively. When formulated, it can be prepared
using a diluent or excipient such as generally used fillers, extenders, binders, wetting agents, disintegrating agents, surface active agents.
In the pharmaceutical composition, the solid preparation for oral administration may be a tablet, pill, powder, granule, or capsule. The solid preparation may further comprise an excipient. Excipients may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatine. In addition, the solid preparation may further comprise a lubricant, such as magnesium stearate, or talc. In the pharmaceutical composition, liquid preparations for oral administration may be best suspensions, solutions, emulsions, or syrups. The liquid formulation may comprise water, or liquid paraffin. The liquid formulation may, for excipients, for example, include wetting agents, sweeteners, aromatics or preservatives. For the purposes of parenteral administration, compositions containing the polypeptides of the invention are preferably dissolved in distilled water and the pH preferably adjusted to about 6 to 8.
Useful preparations of the compositions of the invention for parenteral administration also include sterile aqueous and non-aqueous solvents, suspensions and emulsions. Examples of useful non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oil, fish oil, and injectable organic esters.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutically acceptable carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to for a solid preformulation composition containing a homogeneous mixture for a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is mean that the active ingredient is dispersed evenly throughout the composition so that the composition may be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid pre-form ulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Typical unit dosage forms contain from 1 to 100 mg, for example, 1 , 2, 5, 0, 25, 5 or 00 mg, of the active ingredient. The tablets or pills can be coated o otherwise compounded to provide a dosage affording the advantage of prolonged action. For example, the tablet or pill can
comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which, serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, acetyl alcohol and cellulose acetate.
The liquid forms in which the composition of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oi suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium caboxymethylcellulose, luethylcellulose, polyvinylpyrrolidone or gelatin.
USES of the COMBINATIONS
Also described herein is a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system xc — , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
In particular, it is described a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system xc — , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]-benzoate, 2- Hydroxy-5-[(E)-2-{4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]benza-mide, 4-[(E)- 2-(2-Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid,
HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L-alanosine, [3-N-methylamino-L- alanine, L-serine-O-sulphate, L-a-aminopimelate, L-homocysteate, S-sulpho-l- cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, S-3- carboxy,3-hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4 - carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-naphthyl-4-bis-TFM- HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br-homoibotenate, S-2-naphthyl- ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4-hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone-dinitrophenol, sorafenib.
Also described herein is a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system xc — , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine.
Also described is a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system xc — , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3- dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2-carboxylic acid; (S)-
2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2-oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-
3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids- isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid ([3- (4-chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2-
oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4-dihydroxyphenylalanine; KHK2898 antibody, IGN523 antibody.
Also described herein is a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system xc — , and a therapeutically effective amount of at least one JAK2 inhibitor, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one JAK2 inhibitor is baricitinib.
Also described herein is a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system xc — , and a therapeutically effective amount of at least one JAK2 inhibitor, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one JAK2 inhibitor is delgocitinib.
Also described herein is a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system xc — , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions ; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott-Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune- mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s
disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhofs disease.
Also described herein is a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system xc~, and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
Also described herein is a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system xc — , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM- CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
In particular, it is described a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system xc — , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM- CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2-4{4-[(pyridine-2- yl)sulfamoyl]phenyl}diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2-{4-[(pyridine-2- yl)sulfamoyl]phenyl}diazen-1 -yl]benza-mide, 4-[(E)-2-(2-Hydroxynaphthalen-1 -
yl)diazen-1-yl]benzene-1 -sulfonic acid, 4-nitro-N-phenylbenzene-1 -sulfonamide, 2- Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3- diaminopropionate, L-alanosine, [3-N-methylamino-L-alanine, L-serine-O-sulphate, L- a-aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4-carboxyphenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, S-3-carboxy,3-hydroxy-phenylglycine, R,S- sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]-phenylglycine, 5-benzyl-4-bis-TFM- HMICA, 5-naphthyl-4-bis-TFM-HMICA, 5-4-TFM-benzyl-4-bis-TFM-HMICA, R,S-4- Br-homoibotenate, S-2-naphthyl-ethyl-ACPA, bis-trifluoromethyl-phenyl-isoxazole-4- hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone-dinitrophenol, sorafenib.
Also described herein is a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system xc — , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM- CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine.
Also described is a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system xc — , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM- CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the at least one JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at least one SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3- dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine
derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2-carboxylic acid; (S)-
2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2-oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1-yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-
3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids- isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid ([3- (4-chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4-dihydroxyphenylalanine; KHK2898 antibody, IGN523 antibody; or wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN- CD123A; or wherein the inhibitor targeting IL-3 receptor beta is CSL311 antibody, or wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab; or wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab; or wherein the inhibitor targeting STAT5 is JPX1188, JPX0802, JPX1185, compound 17f, compound AC-4-130, CAS 285986-31-4, BP-1-075, BP-1-107, BP-1-108, SF-1-087, SF-1 -088, IQDMA, or CAS 2062-78-4.
Also described herein is a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system xc — , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM- CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE- induced conditions ; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott-Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS);
immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease.
Also described herein is a method for the treatment of an autoimmune disease, comprising administering to a patient a combination consisting of a therapeutically effective amount of at least one inhibitor of antiporter system xc~, and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM- CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, or a pharmaceutical composition comprising said combination, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells, and wherein the autoimmune disease is systemic lupus erythematosus.
As used herein, the term "administering" refers to bringing a subject, tissue, organ or cells in contact with a therapeutically effective amount of a combination consisting of at least one inhibitor of antiporter system xc — , and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5, or of a pharmaceutical composition comprising said combination, as described in this disclosure. In certain embodiments, the present invention encompasses administering a therapeutically effective amount of a combination consisting of at least one inhibitor of antiporter system xc — , and at least one inhibitor selected from the group consisting of a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor, or of a pharmaceutical composition comprising said combination, as described in this disclosure to a patient or subject.
“Treatment”, “treat”, “treating”, "therapy" and/or "therapy regimen" refers to clinical intervention in an attempt to alter the natural course of a disease or disorder in the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desired results of treatment
can include, but are not limited to, preventing occurrence or recurrence of the disorder, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disorder, slowing or stopping the progression or worsening of a disease, disorder, or condition and/or the remission of the disease, disorder or condition, decreasing the rate of progression, amelioration or palliation of a disease state, and remission or improved prognosis. For example, treatment can include administration of a therapeutically effective amount of at least one inhibitor of antiporter system xc — , and a therapeutically effective amount of at least one inhibitor selected from the group consisting of a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, and an inhibitor targeting STAT5,or a pharmaceutical composition comprising said combination, to a subject to delay development or slow progression of an autoimmune disease, wherein the autoimmune disease is mediated by plasmacytoid dendritic cells.
“Concomitant administration,” “concurrent administration,” or “coadministration” as used herein includes administration of the active agents (e.g., monoclonal antibodies, small molecules, biomolecules), in conjunction or combination, together, or before or after each other. The multiple agent(s) may be administered by the same or by different routes, simultaneously or sequentially, as long as they are given in a manner sufficient to allow all agents to achieve effective concentrations at the site of action. A person of ordinary skill in the art would have no difficulty determining the appropriate timing, sequence, and dosages of administration for particular drugs and compositions of the present invention.
The term "effective amount" or "therapeutically effective amount" refers to the amount of an agent (or a pharmaceutical formulation) that is sufficient to achieve a desired therapeutic or prophylactic result, e.g., to treat or prevent a disease or disorder in a subject. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the seventy of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
The specific "effective amount" will vary depending on the particular agent chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, and the physical
delivery system in which it is carried. The specific "effective amount" will also vary with such factors as the particular condition being treated, the physical condition of the patient, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed. The optimum effective amounts can be readily determined by one of ordinary skill in the art using routine experimentation.
As used herein, the term "subject" and "patient" are used interchangeably herein and refer to both human and nonhuman animals. The term "nonhuman animals" of the disclosure includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dog, cat, horse, cow, chickens, amphibians, reptiles, and the like. Preferably, the subject is a human patient that is at for, or suffering from, an autoimmune disease.
The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the scope of the invention.
Further modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art in view of this description. Accordingly, this description is to be construed as illustrative only and is for the purpose of teaching those skilled in the art the general manner of carrying out the invention. It is to be understood that the forms of the invention shown and described herein are to be taken as examples of embodiments. Elements and materials may be substituted for those illustrated and described herein, parts and processes may be reversed, and certain features of the invention may be utilized independently, all as would be apparent to one skilled in the art after having the benefit of this description of the invention. Changes may be made in the elements described herein without departing from the scope of the invention as described in the following claims.
Description of the Figures
Figure 1 shows IL-3 priming of activated pDC for cytokine production. Isolated pDC maintained ± IL-3 were probed for: (A) IFNa and TNF production with IL-3 and CpG-A (for 5h) stimulation [r?=15 in 11 experiments (various time points)]; (B) live cells, where indicated cells were deprived from IL-3 for indicated time [n=4 in 2 experiments]; (C) IFNa and TNF production [IFNa: n=8 in 5 experiments and TNF: n=7 in 4 experiments]; (D) IFNA2 mRNA expression and IFNa production, n=3 in 3 experiments; (E) TNF mRNA expression and TNF production, n=3 in 3 experiments; (F) pS6 expression, n=6 in 2 experiments; (G) pS6 expression, n=8 in 3 experiments; (H) isolated pDC maintained in IL-3 with no FBS o/n were stimulated with SLE sera (1 :2) for 10 h and probed for pS6 expression, n=6 in 1 experiment; (I) Isolated pDC maintained ± IL-3 and indicated inhibitors o/n, then stimulated ± indicated TLRs agonists for 5 h were probed for IFNa or TNF production (n=6 in 2 experiments); (J) Isolated pDC maintained ± IL-3 and indicated inhibitors o/n, then stimulated ± indicated TLRs agonists for 5 h were probed for IFNa or TNF production (n=7 in 3 experiments). Bar graphs are shown as mean ± SD. Dots represent individual donors (/?).
Figure 2 shows IL-3 priming of activated pDC for mTORCI activation. (A) Isolated pDCs maintained ± IL-3 and indicated inhibitors o/n, then stimulated ± CpG-A (for 5h) and probed for pS6 (S235/236) expression [n=7 in 4 experiments]; (B) Isolated pDC maintained in IL-3 were probed for pS6 (S235/236) expression, where indicated cells were treated with rapamicin (RAP) inhibitor for indicated time [r?=5 in 4 experiments]; Isolated pDCs maintained ±- IL-3 and indicated inhibitors o/n, then stimulated ± CpG-A (for 5h) and probed for (C) IFNa (r?=4 in 2 experiments) and (D) TNF production (n=7 in 4 experiments); (E) isolated pDC maintained ± IL-3 o/n were stimulated ± indicated TLR9 or TLR7 agonists for 5 h and probed for CCL3, CXCL8, CXCL9, CXCL10 or CCL17 mRNA expression [n=4 in 2 experiments]; (F) isolated pDC maintained ± IL-3 o/n were stimulated ± indicated TLR9 or TLR7 agonists for 5 h and probed for live cells [n= 6 in 2 experiments]; (G) isolated pDC maintained ± IL-3 o/n were stimulated ± indicated TLR9 or TLR7 agonists for 5 h and probed for live cells [n=7 in 3 experiments]; (H) isolated pDC maintained in IL-3 with no FBS o/n were stimulated
with SLE sera (1 :2) for 10 h and probed for live cells [n=6 in 1 experiment]. Bar graphs are shown as mean ± SD. Dots represent individual donors (/?).
Figure 3 shows that pDC activation is coupled to mTORCI activity and changes in metabolism. Isolated pDC maintained in IL-3 were probed for: (A) protein synthesis measured by incorporation of puromycin analogue (OPP) in cells stimulated ± CpG-A for 10 h and indicated inhibitors, n=4 in 1 experiment; (B) glucose (r?=3 in 1 experiment) and (E) lactate (r?=3 in 1 experiment) levels in medium from cells stimulated ± CpG-A for 10 h, in (E) data shared with Figure 4A; (C) ECAR before and after addition of glucose (dashed line) in cells stimulated ± CpG-A for 5h after o/n rest, r?=3 in 2 experiments; (D) ECAR baseline levels measured by mitochondrial stress test in cells stimulated ± CpG-A for 10h (dashed line), n=7 in 6 experiments; (F) indicated metabolites shown as fractional contribution of newly synthesized 13C-glucose carbon-incorporation after 3 h stimulation ± CpG-A [n=5 in 2 experiments]; (G) OCR baseline levels using mitochondrial stress test in cells stimulated ± CpG-A, n=7 in 6 experiments; Bar graphs are shown as mean ± SD. Dots represent individual donors (n).
Figure 4 shows that pDC activation is coupled to mTORCI activity and changes in metabolism. Isolated pDC maintained in IL-3 were probed for: (A, D) lactate levels in medium from cells stimulated ± CpG-A and ± indicated inhibitors for 10 h, (A) n=5 in 2 experiments, (D) n=4 in 1 experiment; (B) protein synthesis measured by incorporation of puromycin analogue (OPP) in cells stimulated ± CpG-A for 10 h and indicated inhibitors, n=5 in 2 experiments, one experiment shown; (C) IFNa (r?=4 in 2 experiments) and TNF production (n=7 in 4 experiments), where indicated cells were pre-treated with inhibitor o/n and then stimulated ± CpG-A for 5h; (E) IFNa and TNF production in cells stimulated ± CpG-A and indicated inhibitors for 5h after o/n rest, n=5 in 2 experiments. Bar graphs are shown as mean ± SD. Dots represent individual donors (/?).
Figure 5 shows that IL-3 induces the expression of functional System LAA transporters that license mTORCI activation. (A) isolated pDC maintained in IL-3 o/n, then stimulated ± CpG-A for 5h were subjected for scRNA-seq analysis presented as UMAP plot coloured by clusters
and violin plots of SLC7A5 and SLC7A6 expression across clusters (r?=1 in 1 experiment); (B) SLC7A5 and SLC3A2 mRNA expression (n=7 in 4 experiments); (C) kynurenine uptake (r?=13-18 in 9 experiments); Bar graphs are shown in (B), (C) as geometric mean ± geometric SD, (D) ex vivo isolated pDC from healthy donor (HD) and SLE patients (SLE) were probed for SLC7A5 and SLC7A6 expression (n=6 in 1 experiment); (E) ex vivo isolated pDC from healthy donor were probed for kynurenine uptake (n=6 in 2 experiments); in (D) and (E) representative plots from individual donors (n) are shown. Bar graphs are shown as mean ± SD. Dots represent individual donors (n).
Figure 6 shows IL-3 induces the expression of functional System LAA transporters that license mTORCI activation. Isolated pDC maintained in IL-3 and indicated inhibitor o/n and then stimulated with CpG-A for 5h were probed for: (A) kynurenine uptake and pS6 (S235/236) expression (n=7-9 in 5-6 experiments); (B) kynurenine uptake and pS6 (Ser235/236) expression (n=3 in 3 experiments). (C) SLC7A5 mRNA expression and IFNa or TNF production (IFNa: n=6 in 4 experiments and TNF: n=3 in 2 experiments); (D) kynurenine uptake and IFNa or TNF production (IFNa: n=5-7 and TNF: n= 6-7 in 5 experiments); (E) isolated pDC maintained in regular or leucine free media plus IL-3 o/n, then stimulated ± CpG-A for 5 h were probed for pS6 expression (n=9 in 3 experiments); (F) isolated pDC maintained in regular or leucine free media plus IL-3 o/n, then stimulated ± CpG-A for 5 h were probed for IFNa or TNF production (n=9 in 3 experiments); (G) isolated pDC maintained with IL-3 ± JPH203 o/n, then stimulated ± CpG-A for 5 h were probed for kynurenine uptake and pS6 expression (n=8-9 in 3 experiments); (H) isolated pDC maintained with IL-3 ± JPH203 o/n, then stimulated ± CpG-A for 5 h were probed for IFNa or TNF production (n=8-9 in 3 experiments); (I) isolated pDC maintained ± IL-3 and indicated inhibitor o/n, then stimulated ± indicated TLR9 or TLR7 agonists for 5 h were probed for kynurenine uptake and pS6 expression [n=6-7 in 2-3 experiments]; (J) isolated pDC maintained in regular or methionine free media plus IL-3 o/n, then stimulated ± CpG-A for 5 h were probed for pS6 expression (n=10 in 3 experiments); (K) isolated pDC maintained in regular or methionine free media plus IL-3 o/n, then stimulated ± CpG-A for 5 h were probed for IFNa or TNF expression (n=10 in 3 experiments); (L) isolated pDC were transduced with Cas9
and control and SLC3A2 guide RNAs (SLC3A2 WT and SLC3A2 KO), maintained in IL-3 for 72 h and stimulated ± CpG-A for 5 h and probed for SLC3A2 surface expression [n=5 in 2 experiments]; (M) isolated pDC were transduced with Cas9 and control and SLC7A5 guide RNAs (SLC7A5 WT and SLC7A5 KO), maintained in IL-3 for 72 h and stimulated ± CpG-A for 5 h and probed for kynurenine uptake [n=8 in 4 experiments]; (N) isolated pDC were transduced with Cas9 and control and SLC3A2 guide RNAs (SLC3A2 WT and SLC3A2 KO), maintained in IL-3 for 72 h and stimulated ± CpG-A for 5 h and probed for IFNa or TNF production [n=5 in 2 experiments]; (O) isolated pDC were transduced with Cas9 and control and SLC7A5 guide RNAs (SLC7A5 WT and SLC7A5 KO), maintained in IL-3 for 72 h and stimulated ± CpG-A for 5 h and probed for IFNa or TNF production (IFNa: n=9 in 5 experiments, TNF: n=7 in 4 experiments). In (A) - (D) representative plots from individual donors (/?) are shown; in (F, l-O) bar graphs are shown as mean ± SD; in (G) bar graphs are shown as mean.
Figure 7 shows that inhibition of JAK2 prevents mTORCI activation and cytokine production. (A) - (G): Isolated pDC maintained ± IL-3 and indicated inhibitors o/n, then stimulated ± CpG-A for 5 h were probed for: (A) pSTAT5 (Y694) expression (r?=3-6 in 2-3 experiments); (B) SLC7A5 and SLC3A2 mRNA expression (r?=3-6 in 2 experiments); (C) kynurenine uptake (r?=5-13 donors in 3-6 experiments); (D) pS6 (S235/236) expression (r?=5-6 in 4 experiments); (E) kynurenine uptake and IFNa (r?=3 in 2 experiments) or TNF positive cells (r?=2-3 in 1-2 experiment); (F) kynurenine uptake and pS6 (S235/236) expression (n=5 in 3 experiments); (B - G) CpG-A and 50ng/ml IL-3 condition shared with Figures 5B, 5C, 6A, 6D; (G) IFNa positive cells (r?=4-5 in 2- 3 experiments); (H) isolated pDC from HD and RA patients treated with TOF or RIT were probed for SLC7A5 and SLC3A2 mRNA expression (n=8-10 in 2 experiments);. (A - C, E, F) Representative plots from individual donors (/?) are shown. Bar graphs are shown as (A - C, H) geometric mean ± geometric SD, (D, E) mean ± SD and (F) mean. Dots represent individual donors (/?).
Figure 8 shows that inhibition of JAK2 prevents mTORCI activation and cytokine production. Isolated pDC maintained ± GM-CSF and indicated inhibitors o/n, then stimulated ± CpG-A for 5h and probed for: (A) kynurenine
uptake and pS6 (S235/236) expression; (B) IFNa production. n=4 in 2 experiments. (A) Representative plots from individual donors (/?) are shown. Bar graphs are shown in (B) mean ± SD. Dots represent individual donors.
Figure 9 shows changes in activated vs untreated pDC. (A - D) isolated pDC maintained in IL-3 o/n, then stimulated ± CpG-A for 5h (in vitro pDC) were subjected to scRNA-seq analysis presented as: (A) LIMAP plot colored by clusters and separated by condition (numbers in red indicate cells that were sequenced); (B) bar graph of changes in cell frequencies across clusters after CpG-A stimulation; (C) LIMAP plot coloured by clusters and violin plot of IFNA2, IFNB1 , and IFNL1 ; (D) LIMAP plot coloured by clusters and violin plot of TNF expression across clusters; (E) LIMAP plot coloured by clusters and violin plot of SLC7A11 , ENPP2, and MYO1 E expression across clusters; (F) dot plot with the relative expression and percent expression of genes (x axis) across clusters in pDC (y axis).
Figure 10 shows in (A, B, C, H, I) re-analysed scRNA-seq data of pDC (SLE pDC) and other immune cells from kidney biopsies of lupus nephritis patients (in vivo SLE pDC) presented as UMAP plot colored by clusters and violin plots of (B, C) IL3RA, CSF2RA, CSF2RB, SLC7A5, SLC3A2 and (H) SLC7A11, ENPP2, and MY01E expression across clusters; (D, E) comparative analysis of differentially expressed genes from in vitro pDC and in vivo SLE pDC (C22) presented as (D) UpSet plot with the intersection of differentially expressed genes between pDC and SLE pDC; (E) dot plot with the relative expression and percent expression of genes (x axis) across clusters in pDC (y axis); (F) isolated pDC maintained in IL-3 o/n, then stimulated ± CpG-A for 5h (in vitro pDC) were subjected for scRNA-seq analysis presented as UMAP plot colored by clusters and violin plot of SLC7A11 expression across clusters; (G, I) bar graph with indicated frequencies of SLC7A11 , ENPP2, and MYO1 E expression expression within cluster of interest in (G) C2 and C9 in vitro pDC and (I) C22 in vivo SLE pDC; (C-E) n=1 in 1 experiment; (J) isolated pDC were maintained ± IL-3 and indicated inhibitors o/n, stimulated with indicated TLR9 or TLR7 inhibitors and probed for SLC7A11, ENPP2 or MY01E mRNA expression (n=4 in 2 experiments); (K) isolated pDC were maintained ± IL-3 and indicated
inhibitors o/n, stimulated with indicated TLR9 or TLR7 inhibitors and probed for SLC7A11, ENPP2 or MY01E mRNA expression; (L) isolated pDC were maintained ± IL-3 and indicated inhibitors o/n, stimulated with indicated TLR9 or TLR7 inhibitors and probed for IFNA2 and SLC7A11, ENPP2 or MY01E mRNA expression (n=4 in 2 experiments).
Figure 11 shows (A) expression of SLC7A11, detected with AF488 conjugated antibodies, in skin from healthy donors (HD) and skin from cutaneous lupus patients; (B) expression of SLC7A11 , detected as in (A), and IL- 3Ra (pink) on serial sections of skin from cutaneous lupus patients; scale bar 100pm, images representative of n=4 in 1 experiment, where n denotes individual donors. (C) ex vivo isolated pDC from healthy donor (HD) and SLE patients (SLE) were probed for SLC7A11 and SLC3A2 expression (r?=6 in 1 experiment, representative plot is shown); (D) ex vivo isolated pDC from healthy donor (HD) and SLE patients (SLE) were probed for ENPP2 or MY01E mRNA expression [n=4 in 1 experiment].
Figure 12 shows isolated pDC maintained ± IL-3 and indicated inhibitors o/n, then stimulated ± CpG-A for 5h and probed for: (A) SLC7A11 and SLC3A2 mRNA expression; (B) SLC7A11 and SLC7A5 mRNA expression; (C) SLC7A11 mRNA expression; (A - C) r?=5-6 in 3 experiments; (D) IFNa production, r?=3-4 in 2; (E, F) ENPP2 or MY01E mRNA expression (n=4 in 2 experiments); (G) FNA2 and ENPP2 or MY01E mRNA expression (n=4 in 2 experiments). (A, C) Representative plots from individual donors (/?) are shown. Bar graphs are shown as (B) geometric mean ± geometric SD, (D-F) mean ± SD, (G) mean. Dots represent individual donors (/?).
Figure 13 shows (A, C) isolated pDC maintained ± IL-3 and indicated inhibitors o/n, then stimulated ± CpG-A for 5h and probed for: IFNa production, (A) r?=9-13 in 3-5 experiments; (C) r?=5-9 in 2-4 experiments; and (A) TNF production, n=4 in 1 experiment; (B) kynurenine uptake and pS6 (S235/236) expression, r?=5-9 in 2-4 experiments; (D) isolated pDC maintained in IL-3 and indicated inhibitors o/n, then stimulated ± CpG-A for 5h were probed for live cells, r?=5-9 in 2-4 experiments; (E) isolated pDC were maintained in regular or cystine free media plus IL-3 o/n, then stimulated ± CpG-A for 5h and probed for IFNa or TNF production;
(F) isolated pDC were maintained in regular or cystine free media plus IL-3 o/n, then stimulated ± CpG-A for 5h and probed for kynurenine uptake and pS6 expression, (G) isolated pDC were maintained in regular or cystine free media plus IL-3 o/n, then stimulated ± CpG-A for 5h and probed for pS6 expression [(E-G) n=6 in 2 experiments]; (H) ENPP2 or MY01E mRNA expression [n=4 in 2 experiment]; (I) isolated pDC were maintained in HPLM ± IL-3 with indicated inhibitors o/n, then stimulated ± CpG-A for 5h and probed for kynurenine uptake and pS6 expression (n=7 in 2 experiments, 1 experiment shown); (J) isolated pDC were maintained in HPLM ± IL-3 with indicated inhibitors o/n, then stimulated ± CpG-A for 5h and probed for kynurenine uptake and pS6 expression (n=6-8 in 3 experiments); (K) isolated pDC were maintained in HPLM ± IL-3 with indicated inhibitors o/n, then stimulated ± CpG-A for 5h and probed for IFNa or TNF production (n=7 in 2 experiments, 1 experiment shown); (L) isolated pDC were maintained in HPLM ± IL-3 with indicated inhibitors o/n, then stimulated ± CpG-A for 5h and probed for IFNa or TNF production (n=6-8 in 3 experiments); Bar graphs are shown as mean ± SD. Dots represent individual donors (/?).
Figure 14 shows isolated pDC were maintained ± IL-3 and indicated inhibitors o/n, then stimulated ± CpG-A for 5h and probed for: (A) IFNa production, n=6 in 2 experiments, (B) TNF production, n=6 in 2 experiments; Bar graphs are shown as (A, B) geometric mean ± geometric SD. (C) isolated pDC maintained in IL-3 and indicated inhibitors o/n, then stimulated ± CpG-A for 5h were probed for live cells, n=6 in 2 experiments. (C) Bar graphs are shown as mean ± SD. Dots represent individual donors (/?).
Figure 15 shows isolated pDC maintained ± IL-3 and indicated inhibitors o/n, then stimulated ± indicated TLR9 or TLR7 agonists for 5 h were probed for: (A) IFNa production [n=6-7 in 2-3 experiments]; (B) IFNA2 and CCL3, CXCL8, CXCL9, CXCL10 or CCL17 mRNA expression [n=5 in 2 experiments]; (C) SLC7A5 and SLC3A2 mRNA expression [n=3 in 1 experiment]; (D) IFNa or TNF production [n=4 in 2 experiments]; (E) isolated pDC from HD and RA patients treated with TOF or RIT were probed for SLC7A5 and SLC3A2 mRNA expression [n=8-10 in 2 experiments]; (F) supernatants from isolated pDC maintained in IL-3 that were stimulated with CpG-A ± and indicated inhibitors for 24 h were
probed for: IFNa, IFNp, IFNA, TNF, CXCL8 or CXC10 secretion [n=3 in 1 experiment]; (G) IL-3Ra and GM-CSFRa surface expression by pDC and CD4 cells (negative control) gated from healthy donors PBMC [n=8 in 2 experiments]; (H) isolated pDC maintained ± GM-CSF o/n, then stimulated ± CpG-A for 5h were probed for live cells [n=5 in 3 experiments]. Representative plots from individual donors (n) are shown (B, E, G). Bar graphs are shown as (A, C, D, F, H) mean ± SD and (B) mean. Dots represent individual donors (n).
Figure 16 shows (A) isolated pDC were transduced with Cas9 and control and SLC7A11 guide RNAs (SLC7A11 WT and SLC7A11 KO), maintained in IL-3 for 72 h and stimulated ± CpG-A for 5 h and probed for IFNa or TNF production [n=5 in 3 experiments]; (B) isolated pDC maintained in regular or cystine free media plus IL-3 o/n, then stimulated ± CpG-A for 5 h were probed for kynurenine uptake [n=6 in 2 experiments]; (C, D) isolated pDC maintained in regular or cystine free media plus IL-3 and indicated inhibitor, then stimulated ± CpG-A for 5 h were probed for ENPP2 or MY01E mRNA expression [n=4 in 1 experiment]; (E, F) isolated pDC maintained in HPLM ± IL-3 and indicated inhibitors, then stimulated ± CpG-A for 5 h were probed for kynurenine uptake and pS6 expression [n=7 in 2 experiments]. Representative plots from individual donors (n) are shown (C, E, F). Bar graphs are shown as (A-D) mean ± SD. Dots represent individual donors (n).
Figure 17 Combination of STAT5 inhibitors and Sulfasalazine: Isolated pDC maintained in IL-3 and treated with indicated inhibitors o/n were then stimulated with CpG-A for 5 hours and probed for IFNa and TNF production: (A) AC-4-130 (AC) and SAZ [n=7-8 in 4 experiments]; (B) pimozide (PIM) and SAZ [n=5 in 3 experiments]; (C) IQDMA and SAZ [n=5-6 in 3 experiments]. Values are shown as normalized to GpG-A. Dots represent individual donors (n). Statistical analysis was performed using Prism 7 software (GraphPad) and results are represented as mean ± SD. One-way mixed analysis ANOVA was used. Designation of p-values were as follows: * < 0.05; ** < 0.01 ; *** < 0.001 ; **** < 0.00001 .
Figure 18 Combination of SLC7A5 inhibitor and Sulfasalazine: Isolated pDC maintained in IL-3 and treated with JPH203 o/n were then stimulated with CpG-A for 5 h and probed for IFNa and TNF production: JPH203
(JPH) and SAZ [n=6 in 4 experiments]. Values are shown as normalized to CpG-A. Dots represent individual donors (n). Statistical analysis was performed using Prism 7 software (GraphPad) and results are represented as mean ± SD. One-way mixed analysis ANOVA was used. Designation of p-values were as follows: * < 0.05; ** < 0.01 ; *** < 0.001 ; **** < 0.00001.
Figure 19 Combination of IGN523 (CD98 monoclonal Ab) and Sulfasalazine: Isolated pDC maintained in IL-3 and treated with IGN523 o/n were then stimulated with CpG-A for 5 h and probed for IFNa and TNF production: (A) IGN523 and SAZ [n=2-5 in 3 experiments]. At the time of IGN523 addition, crosslinking Ab was added at ratio 1 :5 as previously shown (Hayes, G.M. et al. (2015). Antitumor activity of an anti-CD98 antibody. Int J Cancer 137, 710-720). Values are shown as normalized to CpG-A. Dots represent individual donors (n). Statistical analysis was performed using Prism 7 software (GraphPad) and results are represented as mean ± SD. One-way mixed analysis ANOVA was used. Designation of p-values were as follows: * < 0.05; ** < 0.01 ; *** < 0.001 ; **** < 0.00001 .
Figure 20 Inhibition with methotrexate: Isolated pDC maintained in IL-3 and treated with methotrexate (MTX) o/n were then stimulated with CpG-A for 5 h and probed for IFNa and TNF production: MTX and SAZ [n=3-4 in 3 experiments]. Values are shown as normalized to CpG-A. Dots represent individual donors (n). Statistical analysis was performed using Prism 7 software (GraphPad) and results are represented as mean ± SD. One-way mixed analysis ANOVA was used. Designation of p- values were as follows: * < 0.05; ** < 0.01 ; *** < 0.001 ; **** < 0.00001 .
Figure 21 shows diagram illustrating the two-step model of pDC activation that leads to expression of SLC7A5:SLC3A2 and SLC7A11 and cytokine production.
EXAMPLES
Methods:
Specimen preparation:
PBMC from buffy coats from healthy blood donors were isolated by density gradient centrifugation using SepMate tubes and Lymphoprep (both STEMCELL Technologies). pDC were negatively selected from PBMC using the plasmacytoid dendritic cell isolation kit II (Miltenyi Biotec). Buffy coats were kindly provided by the Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg (donor consent, anonymized). Skin samples of lupus patients were obtained through the biobank of the SFB829 (Z4 project) with informed consent from all the subjects and ethical approval obtained from the Ethics Committee at the University of Cologne (votes 12-163 and 19-1146). SLE PBMC and sera were provided by ImmRheum biobank in Freiburg, a project that was approved by the local ethical committee (votes 507/16 and 624/14). All patients who provided blood to the biobank had provided written informed consent. RA PBMC were provided by the University Hospital Cologne, a project that was approved by the local ethical committee (number 13-091).
Cell culture
Isolated pDC were maintained in RPMI (Roswell Park Memorial Institute 1640 Medium, Gibco) supplemented with 10% FBS (HyClone), 4 mM L-Glutamine (Invitrogen), 100 U/ml Penicillin/Streptomycin (Invitrogen), 55 pM [3-Mercapto- ethanol (Sigma) and, where indicated, 50 ng/ml IL-3 (Peprotech) or 50 ng/ml GM- CSF (Peprotech). Where indicated, cells were cultured in RPMI without L-leucine and L-glutamine (MP Biomedicals) supplemented 2 mM L-glutamine (Invitrogen), or RPMI without methionine (Gibco), or RPMI without L-cystine, L-glutamine and L-methionine (MP Biomedicals) supplemented with 2 mM L-glutamine (Invitrogen) and 0.1 mM L-methionine (Sigma) or HPLM (Gibco). Amino acid free and HPLM media were supplemented with 10% dialyzed FBS (HyClone), 100 U/ml Penicillin/Streptomycin (Invitrogen), 55 pM [3-mercapto- ethanol (Sigma) and 50 ng/ml IL-3 (Peprotech). Cells were stimulated with 5 pM CpG-A (ODN2216) or 5 pM CpG-B (ODN2006) or 5 pM CpG-C (ODN2395) or 0.5 pg/ml R848 (resiquimod) or 5 pg/ml R837 (imiquimod) (all fromlnvivoGen) for times indicated. To detect intracellular cytokines, cells were treated with GolgiPlug (BD Bioscience) for the last 4 h of the culture. For overnight (o/n) incubations, cells
were plated at 0.5 - 1x106/ml. Where indicated, cells were treated with the following inhibitors for indicated times: 20 nM rapamycin, RAP (Calbiochem), 250 nM torinl , TOR (Tocris), 10pM heptelidic acid, HPA (Adipogen), 1 pM oligomycin (Sigma), 1 pM AZD1480, AZD (Selleckchem), 25 nM-1 pM baricitinib, BAR (LY3009104, Selleckchem), 200 ng/ml tofacitinib (CP690550, Tocris), 5 pM erastin, ERA (Sigma), 100 pM or 200 pM sulfasalazine, SAZ (Tocris) 5 or 10 pM JPH203 (KYT-0353, Selleckchem), 10, 15 or 30 pM ziritaxestat (MCE MedChemExprress) or sera from SLE patients at 1 :2 ratio for indicated times.
Flow cytometry
The following fluorochrome-conjugated monoclonal antibodies were used for staining cell surface markers: IL-3Ra (CD123) (Miltenyi Biotec, clone AC145), HLA-DR (BD Bioscience, clone G46-6), CD303 (BDCA2, BioLegend, clone 201A), CD116 (BD Bioscience, clone hGMCSFR-M1), CD4 (Biolegend, clone A161A1 ). Whole PBMC-staining was performed in 0.5% BSA in PBS for 30 min at 4° C, dead cells were excluded with the LIVE/DEAD Fixable Near-IR Dead Cell Stain Kit (Thermo scientific). Isolated pDC staining was performed in 0.5% BSA in PBS for 10 min at RT, dead cells were excluded with the LIVE/DEAD Fixable Near-IR or Aqua Dead Cell Stain Kits (Thermo scientific). Unspecific binding was blocked with FcR blocking reagent (Miltenyi). The following fluorochrome-conjugated Abs were used for intracellular staining: IFNa (Miltenyi, LT27:295), TNF (BioLegend, clone Mab11 ), pS6(S235/236; CST, clone D57.2.2e), pSTAT5 (Y694; CST, clone C71 E5). After surface staining, cells were fixed using Fixation/Permeabilization Kit (BD Bioscience) for 20 min at 4°C, and then additionally permeabilized in Perm/Wash solution for 30 min at 4°C, after which cells were incubated with antibodies against intracellular proteins, at previously determined antibody dilutions, for 30 min at RT.
De novo protein synthesis was measured using Click-iT™ Plus OPP Alexa Fluor™ 647 Protein Synthesis Assay Kit (Thermo scientific) on pDC stained with LIVE/DEAD Fixable Aqua Dead Cell Stain Kit (Thermo scientific). Cycloheximide (Sigma) at 100 pg/ml was used as a positive control for protein synthesis inhibition.
Kynurenine uptake was performed using pDC stained with antibody against IL-3Ra (Miltenyi) and LIVE/DEAD Fixable Near-IR Dead Cell Stain Kit (Thermo scientific), as described previous. Briefly, stained cells were incubated in HBSS (Gibco) with 200 pM kynurenine (Sigma) for 4 min at 37°C. Cells were then fixed and additional intracellular staining was performed as described above. Where indicated, at the
time of kynurenine uptake, cells were treated with 10 mM BCH (Tocris). The 405 nm laser and 450/50 BP filter were used for kynurenine fluorescence detection. Detection of intracellular mRNAs was performed using PrimeFlow RNA Assays according to manufacturer’s protocol (Thermo scientific). Isolated pDC were stained using LIVE/DEAD Fixable Aqua Dead Cell Stain Kit (Thermo scientific) and fixed with fixation buffer I. Where indicated, intracellular staining with IFNa and/or TNF was performed in perm/wash buffer at previously determined concentrations. Then, cells were fixed with fixation buffer II. Next, target-specific probes: IFNA2A (type 6), TNF (type 1 ), SLC7A5 (type 6), SLC3A2 (type 4), SLC7A11 (type 1 ), ENPP2 (type 4), MY01E (type 6), CCL3 (type 1 ), CCL17 (type 6), CXCL8 (type 1 ), CXCL9 (type 1 ), CXCL10 (type 1 ) were hybridized to the target RNA transcript and signal was amplified. All buffers and times of incubation were provided by the manufacturer.
In all cases, cells were analyzed using LSR Fortessa flow cytometers (BD Biosciences) and data were processed using FlowJo software v9.9.6 (Tristar).
Cytokine and chemokine measurements
Isolated pDC were plated at 1x106/ml and incubated in RPMI (Gibco) supplemented with 10% FBS (HyClone), 2 mM L-glutamine (Invitrogen), 100 ll/rnl Penicillin/Streptomycin (Invitrogen), 55 pM [3-mercaptoethanol (Sigma) containing 50 ng/ml IL-3 (Perprotech) and 5 pM CpG-A (InvivoGen) for 24 hours. Where indicated cells were treated with either AZD or BAR (both at 1 pM, Selleckchem). Type I IFN (IFNa, IFNp, IFNA), TNF, CXCL8 and CXCL10 secretion was measured from supernatants using the LEGENDplex human Anti-Virus responses panel (Biolegend, #7410390) according to the manufacturer protocol.
Metabolic assays
Extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were measured using mitochondrial stress test in a 96 well Extracellular Flux Analyzer (Seahorse Bioscience). Cells were plated at 0.15x106 per well on poly-D-lysine coated wells and preincubated at 37°C for a minimum of 45 min in the absence of CO2 in un-buffered RPMI (Gibco) with 25 mM glucose (Invitrogen), 1 mM pyruvate (Invitrogen) and 2 mM L-glutamine (Invitrogen). Media was supplemented with 10% FBS (HyClone) and 50 ng/ml IL-3. (Peprotech). OCR and ECAR were measured under basal conditions following the addition of CpG-A. Results were collected with Wave software version 2.4 (Agilent). In Figure 3C, ECAR was measured in real time first in the absence of glucose and then following the
addition of 10 mM glucose (Sigma). In this case data is presented as baseline- corrected.
Glucose and lactate were measured in cell culture supernatants using the Cedex Bio Analyzer (Roche) and data presented as mmol/L.
Stable-isotope tracing
Sample preparation and metabolite extraction: 10 mM uniformly-labelled deglucose (Sigma) was used to label isolated pDC maintained in RPMI (Gibco) supplemented with 10% FBS (HyClone), 4mM L-Glutamine (Invitrogen), 100 ll/rnl Penicilin/Streptomycin (Invitrogen), 55pM [3-Mercaptoethanol (Sigma) and 50 ng/ml IL-3 (Peprotech) for 3 h. For metabolite analysis, 0.6x106 pDC were washed in ice-cold PBS (Gibco) and metabolites were extracted using 30 pl extraction buffer (50:30:20, methanol:acetonitrile:water, Sigma) cooled on dry ice for 30 min beforehand. Samples were centrifuged at 2000 g for 3 min to remove protein debris and supernatants were stored at -80°C until acquisition.
Metabolite measurement by LC-MS: LC-MS was carried out using an Agilent 1290 Infinity II LIHPLC in-line with a Bruker Impact II QTOF operating in negative ion mode. Scan range was from 30 to 1050 Da. Mass calibration was performed at the beginning of each run. LC separation was on a Phenomenex Luna propylamine column (50 x 2 mm, 3 urn particles) using a solvent gradient of 100% buffer B (5mM ammonium carbonate in 90% acetonitrile) to 90% buffer A (10 mM NH4 in water). Flow rate was from 1000 to 750 pl/min. The Autosampler temperature was 5°C and injection volume was 2 pL. Metabolites were quantified using AssayR (Wills et al., Anal Chem 2017, 89, 9616 - 9619), and identified by matching accurate mass and retention time to standards.
Single cell RNA sequencing (scRNA-seq)
Single cell RNA sequencing was performed using a 10X Genomics Chromium Controller. Single cells were processed with GemCode Single Cell Platform using GemCode Gel Beads, Chip and Library Kits (v2) following the manufacturer’s protocol. An estimated 1400 cells were sequenced (~700 from each condition), with a mean of 64338 reads per cell and a mean of 2200 genes detected per cell. Libraries were sequenced on HiSeq 3000 (Illumina). Samples were demultiplexed and aligned using Cell Ranger 2.2 (10X genomics) to genome build GRCh38 to obtain a raw read count matrix of barcodes corresponding to cells and features corresponding to detected genes. Raw read count matrices from single cell RNA sequencing data from lupus nephritis patients were retrieved from ImmPort (accession SDY997) where the ethical approval, sample acquisition and
preparation, as well as library processing is described in detail (Arazi et al., Nat. Immunol. 2019, 20, 902 - 914). Read count matrices were processed, analyzed and visualized in R using Seurat v. 3 (Stuart et al., Cell 2019, 177, 1888- 19O2.e21.) and Uniform Manifold Approximation and Projection (UMAP) (Mclnnes et al., Journal of Open Source Software, 2018, 3(29), 861) as a dimensionality reduction approach. Differentially expressed genes, with greater than a 1.2 fold change and an adjusted p value of less than 0.05, were obtained and compared across clusters using the UpSet methodology (Conway et al., Bioinformatics 2017, 33, 2938-2940).
Data and software availability
Next generation sequencing data can be accessed at Gene Ontology Omnibus under GSE157305.
ChIP sequencing analysis
STAT5 binding sites were identified by retrieving raw sequencing data from Gene Expression Omnibus (accession GSE43119), which was produced from human T cells (Schmidl et al., Blood 2014, 123, e68-78). The analysis performed was limited specifically to conventional T cells (samples SRR639410 and SRR639408). Retrieved data were processed using the default settings of the snakePipe methodology developed by the Bioinformatics core at the Max-Planck-lnstitute for Immunobiology and Epigenetics which is described at https://snakepipes.readthedocs.io/en/latest/index.html. Samples were mapped to GRCh38 and binding sites were identified using "Model-based Analysis of ChlP- Seq" MACS2 (Zhang et al., Genome Biol, 2008, 9, R137) with the input control used as background.
Tissue Immunostaininq
Immunostaining for SLC7A11 and IL3-Ra (CD123) was performed on paraffin sections (6 mm). First, they were deparaffinized by xylol and ethanol incubations and washed in Tris-buffered saline (TBS). Heat-induced epitope retrieval was performed using Tris-EDTA buffer (10mM Tris, 1 mM EDTA, pH 9) for 20 min in a heated (95°C) water bath. Samples underwent incubation with primary antibodies against SLC7A11 (Abeam, ab37185), and IL-3Ra (Novocastra/Leica, clone BR4MS, name NCL-L-CD123) diluted in TBS, 1 % normal goat serum and 0.01 % Tween in a humid chamber o/n at 4°C. For the immunofluorescence, Alexa Fluor 488 conjugated secondary antibodies were used. Cell nuclei were counterstained with DAPI. Immunohistochemistry was performed in an automated system (Leica
BOND-MA, Leica Microsystem, Wetzlar, Germany). Images were captured using a BIOREVO BZ-9000 fluorescence microscope and associated software (Keyence, Neu-lsenburg, Germany).
CRISPR-Cas9 mediated gene deletion:
RNP complexes were prepared by annealing (5 min, 98°C) equimolar amounts of crRNA and tracrRNA (180 pmol each per donor, IDT), followed by incubation with 60 pmol Alt-R S.p. Cas9 Nuclease V3 (IDT). Two separate crRNAs per target were used and mixed. RNPs were delivered into purified human pDC by electroporation in P4 Primary Cell buffer (Lonza) in the presence of 2 pM enhancer (IDT) using the CM-137 program (4D-Nucleofector, Lonza). Cells were allowed to recover for 1 h in recovery medium (Lonza) and rested in RPMI (Gibco) supplemented with 10% FBS (HyClone), 2 mM L-Glutamine (Invitrogen), 100 U/ml Penicillin/Streptomycin (Invitrogen), 55 pM [3-Mercaptoethanol (Sigma) and 50 ng/ml IL-3 (Peprotech) for 72 h prior to stimulation with CpG-A. The following guides were used: Hs.Cas9.SLC7A11.1.AA, Hs.Cas9.SLC7A11 .1 .AE, Hs.Cas9.SLC7A5.1.AA, Hs.Cas9.SLC7A5.1 .AC, Hs.Cas9.SLC3A2.1 .AB, Hs.Cas9.SLC3A2.1.AE, Hs.Cas9.GCGAGGTATTCGCTCCGCG (non-targeting control).
Quantification and statistical analysis:
With the exception of scRNASeq, statistical analysis was performed using Prism 7 software (GraphPad) and results are represented as Mean ± SD or geometric SD (indicated in legends). Comparisons for two groups were calculated using unpaired two-tailed Student’s t tests (Figures 1 H, 3E; Figures 1 B, 2H, 3B, 5E). Comparisons of more than two groups were calculated using one-way ordinary paired (Figures 1 C, 1 F, 1 G, 11, 1 J, 2A, 2C, 2D, 3A, 4A-4D, 5B, 6E, 6F, 12E, 12F, 13A (TNF), 13E, 13G, 13H, 14A; Figures 2E-2G, 4E, 6J, 6K, 60, 10K, 16A, 16C, 16D) or nonmatched (Figures 5C, 6C, 6D, 6H, 7A-7E, 7H, 12C, 13A (IFNa); Figures 6L, 60, 13D, 15C, 15D, 15F, 15H, 16B) ANOVA with Tukeys multiple comparison tests or two-way paired (Figures 6I, 12G, 13F, 131, 15A, 15B) or nonmatched ANOVA (Figures 1 E, 6A, 6B, 6G, 7F, 7G, 8A, 8B, 12D, 13C, 13J, 13K) with Tukeys multiple comparison tests. Designations of p-values were as follows: * < 0.05; ** < 0.01 ; *** < 0.001 ; **** < 0.00001 .
Example 1. IL-3 primes pDC for cytokine production and mTORCI activation in response to CpG-A pDC produce type I IFN in response to stimulation through endosomal/lysosomal TLR7 or TLR9. To explore if this process is dependent on mTORCI , cytokine
production was measured over time by isolated pDC from healthy donors and cultured in medium containing IL-3, with or without the TLR9 agonist CpG-A (class A CpG-A oligonucleotides, ODN2216). Maximal IFNa secretion occurred between 10 h and 12 h post activation, during which time approx. 50% of the cells made this cytokine (Figure 1A). Stimulation also resulted in TNF production, which peaked at 8 h post activation, and declined rapidly thereafter (Figure 1A). Coproduction of TNF did not affect the amount of IFNa being made per cell, but maximal TNF production was associated with IFNa co-production (Figure 1A). Production of both cytokines ceased by approx. 24 h post activation (Figure 1A). Stimulation with CpG-A and other TLR agonists known to activate pDC (TLR9: CpG-B and CpG-C; TLR7: resiquimod (R848) and imiquimod (R837)) also induced the expression of a range of proinflammatory and homeostatic chemokines (Figure 2E).
To examine the role of IL-3 in pDC metabolism and function, pDC were maintained overnight in media with or without IL-3, after which they were either left untreated or stimulated with CpG-A. Results showed that cell death was increased in the absence of IL-3 (Figure 1B) and that the addition of CpG-A was unable to rescue viability (Figure 1B). The absence of IL-3 had a marked inhibitory effect on CpG- A-induced IFNa and TNF production (Figure 1C). This was not a reflection of cell death in the absence of IL-3, since cytokine measurements were made only in living cells. IL-3 was required for the CpG-A-induced transcription and translation of IFNa (Figure 1D). However, IL-3 alone was sufficient to drive TNF transcription, but this mRNA was translated only following stimulation with CpG-A (Figure 1E). Moreover, it was found that addition of other TLR9 or TLR7 agonists in the absence of IL-3, also led to increased cell death (Figures 2F and 2G) and diminished commitment to IFNa and TNF production compared to when pDC were cultured with IL-3 (Figures 11 and 1J).
Early work revealed that IL-3 acts as a growth factor to enhance anabolic pathways. Since anabolism is controlled centrally by mTORCI , and mTORCI has been shown to be important for pDC activation, regulation of mTORCI activity by IL-3 was evaluated by measuring phosphorylation of Ser235/236 of ribosomal protein S6 (pS6 (S235/236)), which provides a measure of activation of p70S6K, a direct mTORCI target. pS6 (S235/236) was found in <20% of pDC maintained without IL-3, and this was not increased by stimulation with CpG-A (Figure 2A). Maintenance in IL-3 alone did not increase pS6 (S235/236), but the combination of IL-3 followed by stimulation with CpG-A resulted in approx. 60% of pDC becoming
positive for pS6 (S235/236) (Figure 2A). Similarly, pDC maintained in IL-3 and stimulated with CpG-B or CpG-C (Figure 2F) and R848 or R837 (Figure 2G) had higher frequencies of pS6 positive cells compared to their IL-3 deprived counterparts. Moreover, sera from SLE patients, which have also been shown to activate pDC presumably due to the presence of DNA-containing immune complexes, also required IL-3 for induction of pS6 (Figure 1H) and sustaining cells viability (Figure 2H).
Then it was examined the effect of rapamycin (RAP), a selective mTORCI inhibitor, on activation-induced S6 phosphorylation, and found that it substantially limited the size of the pS6 (S235/236)-positive population (Figure 2B). Therefore, IL-3 plays a critical role in priming pDC to allow mTORCI activation upon TLR stimulation. Since pDC were unable to make cytokines in response to CpG-A and other TLR agonists in the absence of IL-3, it was reasoned that this could reflect the role of IL-3 in mTORCI priming. Consistent with this, RAP-mediated inhibition of S6 (S235/236) phosphorylation was sufficient to partially inhibit production of IFNa (Figure 2C) but also TNF (Figure 2D) by CpG-A-stimulated pDC.
Example 2. mTORCI primes pDC for metabolic changes critical for activation
As mTORCI controls protein synthesis through 4E-BP translation initiation factor, the inventors tested if mTORCI drives translation in activated pDC by measuring the incorporation of a puromycin analogue into newly translated protein. Compared to untreated cells, addition of CpG-A resulted in a significant increase in translation that was prevented by treatment with RAP (Figure 3A). In this regard, RAP was almost as effective as a selective mTORCI /2 inhibitor that blocks rapamycin-resistant functions of mTORCI , torin 1 (TOR) and the translation inhibitor cyclohexamide (CXH) (Figure 3A). mTORCI is recognized to promote anabolic metabolism linked to increased glycolysis. Consistent with this, activated pDC consumed more glucose than resting cells (Figure 3B). Moreover, the extracellular acidification rate (ECAR), a mark of lactate production, which can often accompany immune cell activation, was increased in activated vs. unstimulated pDC (Figures 3C, 3D). Increased ECAR was linked to increased release of lactate (Figure 3E), was glucosedependent (Figure 3C), and began to occur within minutes after the addition of CpG-A (Figure 3D). Elevated ECAR persisted for at least 10 h, in line with the time course of cytokine production and mTORCI activity. Tracing of carbon from
13C-labelled glucose supported the view that stimulation with CpG-A leads to increased incorporation of glucose carbon into lactate, but also revealed increased incorporation into TCA cycle intermediates (Figure 3F). Consistent with the latter, the mitochondrial oxygen consumption rate (OCR), a mark of mitochondrial oxidative phosphorylation, was also increased in CpG-A-stimulated pDC (Figure 3G)
The preceding findings indicated that metabolic changes occur early after pDC activation. To directly explore the role of increased glucose usage in pDC biology, CpG-A-stimulated cells were incubated with heptelidic (koningic) acid (HPA), a selective inhibitor of GAPDH, the central enzyme in the glycolysis pathway. HPA reduced secreted lactate levels to below those in cultures of unstimulated pDC (Figure 4A), and caused reductions in overall protein synthesis (Figure 4B) and production of IFNa and TNF (Figure 4C). Inhibition of mTORCI using RAP or TOR resulted in a decline in CpG-A-induced lactate release, supporting a link between stimulation-dependent mTORCI activation and increased glycolytic metabolism (Figure 4D). It was also found that the electron transport chain complex V ATP synthase inhibitor, oligomycin (OLI), inhibited IFNa production to approximately the same extent as HPA (Figure 4E), although it had no effect on TNF (Figure 4E). The combination of HPA and OLI inhibited IFNa and TNF production completely (Figures 4E).
Taken together, these data indicate that stimulation with CpG-A in pDC primed by exposure to IL-3, leads to an mTORCI -dependent increase in glucose metabolism that is critical for pDC activation.
3. IL-3 induces the expression of functional System L amino acid transporters that permit mTORCI activation in response to CpG-A mTORCI activation is dependent on the presence of sufficient environmental levels of amino acids, amongst which leucine and methionine are of particular importance. In T cells both of these amino acids are acquired from the environment via System LAA transporters comprising a heterodimer of the solute carriers SLC7A5 and SLC3A2 (CD98). Other System LAA transporters are composed of SLC7A6, SLC7A7 or SLC7A8 paired with SLC3A2.
Single cell RNA sequencing (scRNA-seq) revealed that the majority of pDC maintained in IL-3 primarily express SLC7A5, regardless of CpG-A stimulation (Figure 5A). SLC7A6 expression was limited in these cells (Figure 5A) and SLC7A7 and SLC7A8 transcripts were not detected.
Analysis by PrimeFlow RNA revealed that SLC7A5 and SLC3A2 were coexpressed in the majority of pDC cultured in IL-3 and stimulated with CpG-A (Figure 5B). This was a result of the signal delivered by IL-3, since approx. 97% of pDC cultured in IL-3 but not stimulated with CpG-A were also positive for SLC7A5 and SLC3A2 transcripts. In contrast, significantly fewer cells maintained without IL- 3 expressed these solute carriers and stimulation with CpG-A did not rescue their expression (Figure 5B).
To assess whether IL-3-induced expression of SLC7A5 and SLC3A2 allowed the assembly of a functional System LAA transporter, a flow cytometry-based assay was used that measures the ability of cells to take up kynurenine, a naturally fluorescing molecule that is transported into cells via SLC7A5; this can be used as a proxy measurement of large neutral amino acid (LNAA) uptake. It was found that the ability of pDC to take up kynurenine aligned with their expression of SLC7A5 and SLC3A2, and pinpointed IL-3 as being capable of conferring this capability (Figure 5C). Addition of BCH (2-Aminobicyclo[2.2.1]heptane-2-carboxylic acid), a System LAA transporter-specific inhibitor, abrogated transport of kynurenine in all of the conditions, confirming that uptake of this leucine surrogate is SLC7A5- dependent (Figure 5C). Of interest, freshly isolated pDC from PBMC of healthy donors and SLE patients also expressed System LAA transporters SLC7A5 and SLC3A2 (Figure 5D) and furthermore pDC from healthy donors had the ability to take up kynurenine immediately ex vivo, a process that was blocked by BCH (Figure 5E).
To confirm that functional System LAA transport is a prerequisite for mTORCI activation in response to CpG-A, the effects of IL-3 and CpG-A were examined on combined measurements of kynurenine uptake, S6 (S235/236) phosphorylation and cytokine production. The analysis revealed that in the absence of IL-3 the majority of cells were negative for kynurenine transport and pS6 (S235/236) (Figure 6A). Stimulation with CpG-A resulted in a slight increase in cells able to take up kynurenine and positive for pS6 (S235/236) (Figure 6A). As expected, maintenance in IL-3 allowed the majority of pDC to take up kynurenine (Figure 6A), but these cells remained negative for pS6 (S235/236). However, addition of CpG-A led to the emergence of a significant population of kynurenine and pS6 (S235/236) double positive cells (Figure 6A), in which S6 (S235/236) phosphorylation, but not kynurenine uptake, could be inhibited by RAP (Figure 6B). In line with the above results, stimulation with other TLR agonists in the presence of IL-3 also led to an increase in pS6 positive cells capable of taking up kynurenine (Figure 61).
It was further evaluated if cytokine production by activated pDC was linked to System LAA transporter activity. It was found that IFNa and TNF production occurred only in cells that expressed SLC7A5 (Figure 6C) and were therefore able to take up kynurenine (Figure 6D). Together, these data show that IL-3 is essential for induction of the System LAA transporters SLC7A5 and SLC3A2 and hence for active transport of LNAA into pDC, processes that prime subsequent activation of mTORCI and cytokine production in response to CpG-A.
To confirm the critical role of System LAA transport in pDC activation, cells in medium lacking leucine or methionine were cultured and it was found that phosphorylation of S6 and cytokine production were dependent on added leucine (Figures 6E and 6F), but not methionine (Figures 6J and 6K). Furthermore, cells in which SLC3A2 or SLC7A5 were deleted using CRISPR (Figure 6L and 6M), had diminished capacity to produce IFNa and TNF (Figures 6N and 60). Consistent with this, the SLC7A5-specific inhibitor JPH203, caused a marked dose-dependent reduction in pDC that were double positive for pS6 and kynurenine uptake (Figure 6G) and production of IFNa and TNF (Figure 6H). Together, these data show that IL-3 is essential for the induction of the System LAA transporters SLC7A5 and SLC3A2 in pDC, and that uptake of leucine, mediated by these transporters, is necessary for priming subsequent activation of mTORCI and cytokine production by pDC in response to CpG-A and other TLR agonists.
Example 4. IL-3 stimulation of SLC7A5:SLC3A2 and cytokine production is mediated by JAK2 and STAT5
IL-3 signals through a receptor comprised of the cytokine-binding IL-3Ra dimerized with common [3 chain (encoded by CSF2RB), which couples the receptor to the JAK2-STAT5 pathway. Using published data examining STAT5 chromatin immunoprecipitation sequencing in human CD4+ T cells, STAT5 DNA binding sites were found in both SLC7A5 and SLC3A2 loci. These data suggested that the JAK2-STAT5 pathway could be responsible for the IL-3 induced expression of these genes. Moreover, IL-3, but not CpG-A, was able to induce phosphorylation of STAT5 (Y694) (Figure 7A). Therefore, the effects of the selective JAK2 inhibitor AZD1480 (AZD) and the clinically used JAK2/1 inhibitor baricitinib (BAR) were examined on CpG-A-induced activation in pDC cultured in IL-3.
As expected, AZD and BAR inhibited IL-3-induced STAT5 (Y694) phosphorylation (Figure 7A). Consistent with a role for IL-3-induced JAK2 signaling in the expression of SLC7A5 and SLC3A2, both AZD and BAR significantly inhibited the expression of these genes (Figure 7B), and this was accompanied by reductions in the uptake of kynurenine (Figure 7C), and in the phosphorylation of S6 (S235/236) (Figure 7D).
JAK2 inhibition resulted in marked reductions in IFNa and TNF production that was linked to an inhibitor-induced decrease in the ability of activated pDC to take up kynurenine (Figure 7E). Thereafter it was observed that addition of JAK2 inhibitors led to the loss of cells that were positive for both kynurenine transport and mTORCI activity (Figure 7F), which was a similar outcome to that observed in IL-3-deprived cells (Figure 6A). Finally, only pDC with both high rates of kynurenine uptake and high mTORCI activity (S6 phosphorylation) made IFNa (Figures 7G and 15A), and that cytokine production was lost following JAK2 inhibition (Figure 7G), in agreement with results of Figure 7E.
As was the case for IFNa, priming with IL-3 was necessary for maximal chemokine production in response to CpG-A (Figure 15B). The majority of CCL3-, CCL17- and CXCL 70-positive cells co-expressed IFNA2, while only a portion of the CXCL8- and CXCL9-positive cells concomitantly expressed IFNA2 (Figure 15B). Absence of IL-3 priming prior to stimulation with CpG-A resulted in diminished chemokine and IFNA2 double positive populations (Figure 15B). This was likely the result of diminished JAK2-mediated signaling since AZD and BAR treatment also resulted in fewer pDC that were double positive for IFNA2 and CCL3, CCL17 or CXCL10, and almost complete loss of cells that were double positive for IFNA2 and CXCL8 or CXCL9 (Figure 15B).
Since System LAA transporters were expressed in pDC circulating in HD blood (Figure 5D), and their expression could be repressed by JAK2 inhibitors in vitro (Figure 7B), SLC7A5 and SLC3A2 were expressed in pDC from rheumatoid arthritis (RA) patients who had received monotherapy with tofacitinib (TOF), a first generation JAK inhibitor with activity against JAK1/3 and, to a lesser extent, JAK2. For comparison, pDC from HD and from RA patients treated with the B cell depleting Ab Rituximab (RIT) were used. It was validated that TOF, similarly to AZD or BAR, inhibited SLC7A5 and SLC3A2 expression (Figure 15C) and IFNa and TNF production (Figure 15D) in pDC stimulated with IL-3 plus CpG-A in vitro. Consistent with this, SLC7A5 and SLC3A2 positive pDC were less frequent in TOF-treated RA patients than in HD or RIT treated RA patients (Figures 7H and
15E). Moreover, no significant difference in SLC7A5 and SLC3A2 expression in pDC from RIT-treated RA patients versus HD was found (Figure 7H and 15E). It is then plausible that JAK2-regulated expression of System LAA transporters in vivo is responsible for modulating the production of cytokines in pDC driven pathologies.
The fact that pDC express SLC7A5 and SLC3A2 upon isolation (Figure 5D) and are able to take up kynurenine immediately ex vivo (Figure 5E) correlates with the ability of pDC to respond immediately ex vivo to CpG-A by making cytokines and chemokines even in the absence of added IL-3 (Figure 15F). Nevertheless, pDC activation in this setting was still inhibited by AZD and BAR (Figure 15F), indicating that the cells retain a functional memory of signaling initiated in vivo by the common [3c of the IL-3 receptor.
Example 5. GM-CSF stimulates activity of SLC7A5:SLC3A2 and cytokine production.
The common [3 subunit of the IL-3R is also the signaling component of the GM- CSF and IL-5 receptors. Human pDC express GM-CSFRa as well as IL-3Ra but do not express IL-5Ra, which is consistent with previous reports that pDC can respond to GM-CSF as well as to IL-3. It was found that, like IL-3, GM-CSF supported pDC survival, induced a population of cells with high rates of kynurenine uptake and mTORCI activity (Figure 8A) and that these cells were IFNa producers in response to CpG-A (Figure 8B). Moreover, all of these parameters were inhibited by AZD (Figures 8A, 8B).
Taken together, these data reveal the emergence of a subpopulation of pDC capable of making cytokines and chemokines in response to CpG-A and other TLR agonists. These cells express functional System LAA transporters and are able to activate mTORCI upon exposure to CpG-A. These processes are dependent on priming by IL-3 or GM-CSF through the JAK2-STAT5 pathway downstream of the common [3 subunit of the IL-3 and GM-CSF receptors. The data highlight JAK2 as a therapeutic target in conditions where pDC activation is implicated in disease.
Example 6. TLR stimulation induces selective expression of SLC7A11, ENPP2 and MYO1 E in type I IFN producing pDC
Even at peak cytokine production, only a subset of stimulated pDC was positive for pS6 (S235/236) and cytokine production (Figures 1A and 2B). Therefore, the
heterogeneity within the pDC population was explored through scRNA-seq. As in previous experiments, purified pDC maintained in IL-3 and stimulated with or without CpG-A were used. Individually sequenced cells were arranged into 12 transcriptionally distinct clusters (C). Based on transcriptional similarities, 12 clusters (C) of cells were identified in pDC cultured in IL-3, of which one, C9, was apparent only after stimulation with CpG-A (Figure 9A). In addition, the contributions of C2, C4 and C7 to the overall pDC population increased following stimulation with CpG-A (Figure 9B). Within these clusters, only C9 and C2, were enriched in type I IFN transcripts (Figure 9C). Of note, despite the expected broad expression of TNF, C9 in particular also appeared to be enriched in TNF transcripts (Figure 9D). Likewise, C9 was also enriched in expression of proinflammatory chemokines (Figure 9F). C2 and C9 had similar transcriptional profiles, evident by their proximity on the Uniform Manifold Approximation and Projection (UMAP) as well as in the clustering hierarchy (Figure 9D).
To identify similarities between in v/fro-activated pDC and in v/vo-activated pDC, activated pDC from the analysis were compared with recently reported scRNA-seq data from immune cells isolated from lupus nephritis kidney biopsies (Arazi et al. Nat Immunol 20, 902-914). The published data were reanalyzed and focusing specifically on the transcriptomes of pDC at the site of pathology (SLE pDC, C22, Figures 10A, 10B, 10C). Consistent with the findings described above regarding the importance of IL-3 or GM-CSF-initiated signaling and System LAA transporters expression for pDC activation, it was found that SLE pDC (C22) expressed IL3RA, CSF2RA, CSF2RB, SLC7A5 and SLC3A2 (Figures 10A, 10B, 10C). Indeed, expression of these genes was highest in pDC (C22) within the immune cell populations of nephritic kidney biopsies (Figures 10A, 10B, 10C). Next, differentially expressed genes in C2 and C9 from in v/fro-activated pDC and SLE pDC were identified compared to all other clusters in their respective datasets. Then, UpSet analysis (Conway et al., 2017) on these results was performed, in order to compare the transcriptional profile of activated pDC across these datasets. The analysis showed that of the 43 unrelated genes shared between C9, C2 and SLE pDC (Figure 10D), 21 were differentially regulated in C2 and C9 (Figure 10E), with expression of SLC7A11 increased in both clusters, but not in any other cluster from the in vitro dataset. Moreover, SLC7A11 together with ENPP2 and MY01E constituted a set of 3 genes coexpressed by all three groups of cells (Figure 10D) and not included in any other cluster. These genes were enriched in the type I IFN and TNF producing C9, and to a lesser degree C2 (Figures 9E and 10F), and a large percentage of the cells within these clusters
expressed the genes (Figure 10G). Moreover, amongst lesional immune cell populations from lupus nephritis kidney biopsies, SLC7A11 and ENPP2 were expressed almost exclusively in SLE pDC (C22), while MYO1E was expressed by SLE pDC (C22) and to lesser extent by two non-pDC clusters (Figure 10H). RNA- flow analysis confirmed that SLC7A11, ENPP2 and MYO1E were expressed when pDC were stimulated with CpG-A and also with other TLR agonists (Figure 10J). The majority of cells expressing these genes co-expressed IFNA2 when stimulated with CpG-A (Figure 10L).
As expression of SLC7A11, ENPP2 and MY01E seemed to mark type I IFN and TNF producing pDC, it was evaluated if SLC7A11 is detectable in pDC in other pathological sites in which pDC infiltration is implicated in disease. To this aim, sections from diseased skin from patients with cutaneous lupus were stained with antibodies against SLC7A11 and the IL-3Ra, a known marker of pDC in tissue sections. The microscopic analysis revealed a marked increase in SLC7A11- positive cells in the skin of cutaneous lupus patients compared to skin from healthy donors (HD, Figure 11 A) and the majority of these were IL-3Ra positive, although other cells, presently unidentified, also expressed SLC7A11 (Figure 11 B). Further analysis included testing pDC isolated from PBMC collected from SLE patients with varying degrees of disease activity (Systemic Lupus Erythematosus Disease Activity Index, SLEDAI, from 0 to 8), but results showed no evidence for SLC7A11 expression in these circulating cells (Figure 11 C). Further, no evidence of ENPP2 or MY01E expression in ex vivo pDC from HD was observed (Figure 11 D).
Taken together, these data suggest that SLC7A11, ENPP2 and MY01E expression are a mark of activated, cytokine-producing tissue-specific pDC.
Example 7. Inhibition of JAK2 potently blocks cytokine production by activated pDC
Unlike SLC7A5 and SLC3A2 (Figure 5D), SLC7A11, ENPP2 and MY01E (Figures 11C and 11 D) were not expressed by circulating pDC and therefore its expression was unlikely to be induced by signaling downstream of the common [3 chain of the IL-3 or GM-CSF receptors. This was confirmed by the finding that IL-3 alone was incapable of inducing expression of SLC7A11 (Figures 12A, 12B, 12C). Rather, this gene was expressed in response to stimulation with CpG-A (Figures 12A - 12C). SLC7A11 encodes the specific subunit of the cystine/glutamate exchanger xc — , which when chaperoned by SLC3A2 allows cells to take up cystine in exchange for glutamate. Expression of SLC7A11 was coupled to expression of SLC3A2 (Figure 12A), indicating that activated pDC can
express functional xc — transporter. While IL-3 alone was incapable of inducing SLC7A11 expression, it was critical for priming cells to express SLC7A11 in response to CpG-A, since JAK2 inhibition prevented this from happening (Figures 12A, C). This is likely the result of a requirement for IL-3 mediated System LAA transporter expression for optimal mTORCI activation, because TOR (torinl , Figures 12A and 12C) and RAP (Figure 10K) also inhibited SLC7A11 expression. Consistent with this, pDC maintained in IL-3 and stimulated with CpG-A had the highest frequencies of SLC7A11 and SLC7A5 double positive cells (Figure 12B), and as a result produced IFNa at full capacity (Figure 12D). In contrast, pDC deprived of IL-3 or treated with AZD or BAR lost expression of both transporters and hence IFNa production (Figures 12B, 12D). Again, treatment with TOR had similar, although less pronounced effect to AZD and BAR (Figures 12B, D).
As for SLC7A11, CpG-A-induced expression of ENPP2 and MY01E required priming of mTORCI by IL-3, since it was inhibited by AZD, BAR (Figure 12E), TOR (Figure 12F) and RAP (Figure 10K). Blunted ENPP2 and MY01E expression correlated with loss of IFNA2 expression (Figure 12G). Together, these data support the view that expression of SLC7A11, ENPP2 and MY01E correlates with type I IFN expression in activated pDC.
Example 8. Inhibition of xc~ potently blocks cytokine production by activated pDC
The finding that SLC7A11, ENPP2 and MY01E expression distinguishes activated tissue-specific pDC from circulating pDC makes it an attractive therapeutic target. The antiporter xc — , is a target of the small molecule inhibitors erastin (ERA) and sulfasalazine (SAZ). It was reasoned that inhibition of xc — , which comprises SLC7A11, might prevent the production of cytokines by pDC.
As predicted, both ERA and SAZ inhibited CpG-A- induced IFNa and TNF (Figure 13A) production. This was associated with reductions of cells that had both high rates of kynurenine uptake and S6 (S235/236) phosphorylation (Figure 13B), which is consistent with the fact that only pDC with both of these attributes make cytokines (Figure 13C). Inhibition occurred in the absence of appreciable cell death (Figure 13D). CRISPR deletion of SLC7A11 (Figure 16A), or the use of tissue culture medium that lacked cystine (Figures 13E-13G), the substrate for xc— had effects that were broadly similar to those exerted by ERA and SAZ (Figures 13A-13C), although there was less of an effect on kynerunine uptake in
the absence of extracellular cystine than there was in the presence of the inhibitors (Figure 16B).
It was found that ERA, SAZ (Figure 13H) or culture in cystine-free medium (Figure 16C) inhibited the expression of ENPP2 and MY01E in pDC stimulated with IL-3 plus CpG-A, indicating that SLC7A11 can regulate both of these genes. It was observed that ziritaxestat (ZIR), a small molecule ENPP2 inhibitor, inhibited the activation of pDC by IL-3 plus CpG-A (Figures 131, 13J and 16E), suggesting that the importance of SLC7A11 in pDC activation is linked to its ability to regulate ENPP2 expression.
Example 9. Coordinated inhibition of JAK2 and antiporter xc~ potently blocks cytokine production by activated pDCs.
Given the effectiveness of targeting JAK2 and xc — in limiting cytokine production, it was analysed whether a combinatorial approach of inhibiting both JAK2 and xc — might result in further loss of pDC function. An in vitro dose escalation was performed to define the effects of BAR on viability and cytokine production by activated pDC. Results showed that production of IFNa (Figure 14A) and TNF (Figure 14B) declined as BAR concentration rose from 25 to 100 nM, and that this was accompanied by increased cell death (Figure 14C). Moreover, the doses of BAR and SAZ that alone were suboptimal, synergized to increase the inhibition of both IFNa and TNF production (Figures 14A, 14B), without diminishing cell survival beyond that seen with BAR alone (Figure 14C).
To more closely model the situation in vivo, experiments in human plasma like medium (HPLM) were performed, which reflects the composition of human plasma. It was found that pDC activated with CpG-A in HPLM showed dependency on IL-3-mediated mTORCI activity for production of cytokines and that only cells with high rates of kynurenine uptake and high pS6 (Figures 13J and 16F) had the capacity to produce IFNa and TNF (Figure 13L). Moreover, individual JAK2 inhibitors (AZD or BAR), SLC7A11/xc — inhibitors (ERA and SAZ), the ENPP2 inhibitor ZIR (Figures 131, 13K and 16E), and combinations of BAR and SAZ (Figures 13J, 13L and 16F), were able to block pDC activation in HPLM.
Taken together, these data indicate that pDC activation is associated with the expression of SLC7A11 and, in an SLC7A H -dependent fashion, ENPP2 and MY0E1. Moreover inhibition of xc — or ENPP2 is able to suppress the ability of these cells to produce IFNa and TNF. Furthermore, a combinatorial approach for
suppressing pDC activation by targeting both JAK2 and xc , resulted in an additive inhibitory effect that essentially prevented cytokine production (Figure 21).
Example 10. Combination of STAT5 inhibitors and Sulfasalazine
Isolated pDC maintained in IL-3 and treated with indicated inhibitors o/n were then stimulated with CpG-A for 5 h and probed for IFNa and TNF production with AC-4-130 (AC) and SAZ [n=7-8 in 4 experiments]; pimozide (PIM) and SAZ [n=5 in 3 experiments]; and IQDMA and SAZ [n=5-6 in 3 experiments]. Results are shown in Figure 17A-17C. The data indicate a synergistic effect of STAT5 inhibitors with sulfasalazine in inhibition of cytokine production. Combinations of each inhibitor plus SAZ had synergistic effects compared to single suboptimal doses of either STAT5 inhibitors or SAZ alone, at inhibiting IFNa and TNF production by TLR9- activated pDC.
Example 11. Combination of SLC7A5 inhibitor and Sulfasalazine
Isolated pDC maintained in IL-3 and treated with JPH203 o/n were then stimulated with CpG-A for 5 h and probed for IFNa and TNF production with JPH203 (JPH) and SAZ [n=6 in 4 experiments]. Results are shown in Figure 18. Values are shown as normalized to CpG-A. Dots represent individual donors (n). The data indicate a synergistic effect of a combination of a SLC7A5 inhibitor with sulfasalazine in inhibition of cytokine production. Combination of JPH203 (JPH) plus SAZ had a synergistic effect compared to single suboptimal doses of either JPH203 or SAZ, at inhibiting IFNa and TNF by TLR9-activated pDC.
Example 12. Combination of IGN523 (CD98 monoclonal Ab) and Sulfasalazine
Isolated pDC maintained in IL-3 and treated with IGN523 o/n were then stimulated with CpG-A for 5 h and probed for IFNa and TNF production with IGN523 and SAZ [n=2-5 in 3 experiments]. At the time of IGN523 addition, crosslinking Ab was added at ratio 1 :5 as previously shown. Results are shown in Figure 19. Values are shown as normalized to CpG-A. Dots represent individual donors (n).
The data indicate a weak synergistic effect of a combination of an inhibitor targeting IL-3 receptor beta with sulfasalazine in inhibition of cytokine production.
A monoclonal Ab specific for SLC3A2 (CD98), IGN523 was tested. A single dose of IGN523 significantly abrogated production of IFNa and TNF by TLR9-activated activated pDC. IGN523 was maximally efficient at blocking cytokine production at the lowest tested Ab concentration (200 ng/ml). Combining IGN523 with SAZ
revealed a slight additive effect, compared to single doses of IGN523, at inhibiting IFNa and TNF by TLR9-activated pDC.
Example 12. Inhibition with methotrexate
Isolated pDC maintained in IL-3 and treated with methotrexate (MTX) o/n were then stimulated with CpG-A for 5 h and probed for IFNa and TNF production with MTX and SAZ [n=3-4 in 3 experiments]. Results are shown in Figure 20. Values are shown as normalized to CpG-A. Dots represent individual donors (n). Methotrexate (MTX) was tested over a broad range of concentrations (200 nM to 20 pM, which exceed plasma concentrations of MTX in patients treated with this drug), and found to have no ability to inhibit cytokine production by pDC stimulated with CpG in vitro.
Example 13. Combination of an inhibitor targeting GM-CSF receptor alpha and Sulfasalazine
Isolated pDC maintained in IL-3 and treated with mavrilimumab o/n were then stimulated with CpG-A for 5 h and probed for IFNa and TNF production with mavrilimumab and SAZ. The data indicate a synergistic effect of a combination of an inhibitor targeting GM-CSF receptor alpha with sulfasalazine in inhibition of cytokine production. Combination of mavrilimumab plus SAZ had a synergistic effect compared to single suboptimal doses of either mavrilimumab or SAZ, at inhibiting IFNa and TNF by TLR9-activated pDC.
Claims
1 . A combination of at least one inhibitor of antiporter system xc — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2 for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells.
2. The combination for use according to claim 1 , wherein the at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2 is selected from a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, or an inhibitor targeting STAT5.
3. The combination for use according to claim 2, wherein the combination consists of: at least one inhibitor of antiporter system xc — , a JAK2 inhibitor, and a SLC7A5:SLC3A2 inhibitor.
4. The combination for use according to any one of claims 1 to 3, wherein the at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2- 4{4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2- {4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]benza-mide, 4-[(E)-2-(2- Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L- alanosine, [3-N-methylamino-L-alanine, L-serine-O-sulphate, L-a- aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4- carboxyphenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, S-3-carboxy,3- hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]- phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-naphthyl-4-bis-TFM-HMICA, 5-4- TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br-homoibotenate, S-2-naphthyl-ethyl- ACPA, bis-trifluoromethyl-phenyl-isoxazole-4-hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone-dinitrophenol, sorafenib.
5. The combination for use according to any one of claims 1 — 4, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine.
6. The combination for use according to any one of the claims 2 - 5, wherein the JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3-dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2- carboxylic acid; (S)-2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2- oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)- propanoic acid 1 ; 2-amino-3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids-isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid (|3-(4- chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine;
L-3,4-dihydroxyphenylalanine; KHK2898 antibody, IGN523 antibody; or wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN- CD123A; or wherein the inhibitor targeting IL-3 receptor beta is CSL311 antibody, or wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab; or wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab; or wherein the inhibitor targeting STAT5 is JPX1188, JPX0802, JPX1185, compound 17f, compound AC-4-130, CAS 285986-31-4, BP-1-075, BP-1-107, BP-1-108, SF-1-087, SF-1 -088, IQDMA, or CAS 2062-78-4.
7. The combination for use according to any one of the claims 2 - 6, wherein the JAK2 inhibitor is baricitinib or delgocitinib.
8. The combination for use according to any one of the claims 1 - 7, wherein the autoimmune disease is selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced
150 lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott-Aldrich syndrome; ataxiatelangiectasia; immune mediated cancers; multiple sclerosis (MS); immune- mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease. The combination for use according to any one of the claims 1 - 8, wherein the autoimmune disease is systemic lupus erythematosus. A pharmaceutical composition consisting of at least one inhibitor of antiporter system xc — and at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2, together with at least one pharmaceutically acceptable vehicle, excipient and/or diluent. The pharmaceutical composition according to claim 10, wherein the at least one compound that inhibits expression or activity of System L amino acid transporter SLC7A5:SLC3A2 is selected from a JAK2 inhibitor, a SLC7A5:SLC3A2 inhibitor, an inhibitor targeting IL-3 receptor alpha, an inhibitor targeting IL-3 receptor beta, an inhibitor targeting GM-CSF, an inhibitor targeting GM-CSF receptor alpha, or an inhibitor targeting STAT5. The pharmaceutical composition according to claim 10 or 11 , wherein the at least one inhibitor of the antiporter system xc — is selected from the group comprising sulfasalazine, erastin, erastin analogs, , azo-linked amino-naphthyl-sulfonate analogs of sulfasalazine, ethyl 2-hydroxy-5-[(E)-2- 4{4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]-benzoate, 2-Hydroxy-5-[(E)-2- {4-[(pyridine-2-yl)sulfamoyl]phenyl}diazen-1-yl]benzamide, 4-[(E)-2-(2-
151
Hydroxynaphthalen-1 -yl)diazen-1 -yl]benzene-1 -sulfonic acid, 4-nitro-N- phenylbenzene-1 -sulfonamide, 2-Hydroxy-5-(3-phenylpropanamido)benzoic acid, HG106, glutamate a-aminoadipic acid, a-aminosuberic acid, cystathionine, ibotenate, quisqualate, L-[3-N-oxalyl-L-a,[3-diaminopropionate, L- alanosine, [3-N-methylamino-L-alanine, L-serine-O-sulphate, L-a- aminopimelate, L-homocysteate, S-sulpho-l-cysteine, S-4- carboxyphenylglycine, S-4-carboxy,3-hydroxy-phenylglycine, S-3-carboxy,3- hydroxy-phenylglycine, R,S-sulphothienylglycine, [(R,S)-4-[4'-carboxyphenyl]- phenylglycine, 5-benzyl-4-bis-TFM-HMICA, 5-naphthyl-4-bis-TFM-HMICA, 5-4- TFM-benzyl-4-bis-TFM-HMICA, R,S-4-Br-homoibotenate, S-2-naphthyl-ethyl- ACPA, bis-trifluoromethyl-phenyl-isoxazole-4-hydrazone, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazone-dinitrophenol, sorafenib. The pharmaceutical composition according to any one of claims 10 - 12, wherein the at least one inhibitor of the antiporter system xc — is sulfasalazine. The pharmaceutical composition according to any one of the claims 11 - 13, wherein the JAK2 inhibitor is selected from the group comprising baricitinib, delgocitinib, fedratinib, gandotinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, AZD1480; or wherein the at SLC7A5:SLC3A2 inhibitor is selected from the group comprising JPH203 (KYT-0353), triiodothyronine analogs; tetraiodothyronine; 1 ,2,3- dithiazole derivatives, 1 ,2,4-dithiazine derivatives; phenylalanine; phenylalanine derivates; tryptophan analogs; 2-aminobicyclo-(2,2,1 )-heptane-2-carboxylic acid; (S)- 2-Amino-3-(3-((2,4-dicyano-3-(4-(2-(methylamino)-2- oxoethoxy)phenyl) benzo[4,5]imidazo[1 ,2-a]pyridin-1 -yl)- carbamoyl)phenyl)propanoic acid 1 ; 2-amino-3-(3-benzylphenyl)propanoic acid; 2-amino-3-(3-benzyl-4-hydroxyphenyl)propanoic acid; hydroxamic acids- phenylalanine, hydroxamic acids-leucine, hydroxamic acids-isoleucine, hydroxamic acids-methionine; p-(4-chlorophenyl)-y-aminobutyric acid (|3-(4- chlorophenyl)-GABA); gabapentin; (2S)-Amino[(5S)-3-chloro-4,5-dihydro-1 ,2- oxazol-5-yl]ethanoic acid; para-chlorophenylalanine; L-3,4- dihydroxyphenylalanine, KHK2898 antibody, IGN523 antibody; or wherein the inhibitor targeting IL-3 receptor alpha is selected from the group comprising CSL362 antibody, flotetuzumab, IL3LDM, DT388IL3, and SGN- CD123A; or wherein the inhibitor targeting IL-3 receptor beta is CSL311 antibody, or
wherein the inhibitor targeting GM-CSF is otilimab, namilumab, lenzilumab, plonmarlimab, or gimsilumab; or wherein the inhibitor targeting GM-CSF receptor alpha is mavrilimumab; or wherein the inhibitor targeting STAT5 is JPX1188, JPX0802, JPX1185, compound 17f, compound AC-4-130, CAS 285986-31-4, BP-1-075, BP-1-107, BP-1-108, SF-1-087, SF-1 -088, IQDMA, or CAS 2062-78-4. The pharmaceutical composition according to any one of the claims 10 - 14, wherein the JAK2 inhibitor is baricitinib. The pharmaceutical composition according to any one of the claims 10 - 14, wherein the JAK2 inhibitor is delgocitinib. The pharmaceutical composition according to any one of the claims 10 - 16 for use in the treatment of an autoimmune disease mediated by plasmacytoid dendritic cells. The pharmaceutical composition according to any one of the claims 10 - 16 for use in the treatment of an autoimmune disease selected from the group comprising lupus; cutaneous lupus; systemic lupus erythematosus (SLE); neonatal lupus; drug-induced lupus; SLE-induced conditions; systemic sclerosis; cutaneous scleroderma; Sjogren’s syndrome; idiopathic inflammatory myopathy, juvenile and adult dermatomyositis; psoriasis; alopecia areata; lichen planus; lichen sclerosus; vitiligo; polymyositis; rheumatoid arthritis; ulcerative colitis; Crohn's disease; rejection of transplanted organs and tissues; rhinitis; chronic obstructive pulmonary diseases; sinusitis; atopic dermatitis; anaphylaxis; DiGeorge syndrome; Hyper-lgE syndrome; Wiskott-Aldrich syndrome; ataxia-telangiectasia; immune mediated cancers; multiple sclerosis (MS); immune-mediated or Type 1 Diabetes Mellitus; immune mediated glomerulonephritis; pemphigus; pemphigus vulgaris; myasthenia gravis; inflammatory bowel diseases (IBD); autoimmune thyroid diseases including Hashimoto’s disease and Grave’s disease; Goodpasture syndrome (GPS); myasthenia gravis pseudoparalytica; phacoantigenic uveitis; chronical aggressive hepatitis; primary biliary cholangitis; autoimmune hemolytic anemia; immune thrombocytopenia; osteoporosis; pernicious anemia; ophtalmia sympatica; Werlhof’s disease. The pharmaceutical composition according to any one of the claims 10 - 16 for use in the treatment of systemic lupus erythematosus.
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