Treatment of chronic kidney disease

Abstract

The disclosure relates to methods and compositions for the treatment of chronic kidney disease.

Description

Treatment of chronic kidney disease1. BACKGROUND

[0001] Chronic kidney disease (CKD) affects approximately 10% of the adult population worldwide [1]. The most common causes of CKD are diabetes, hypertension, and chronic glomerulonephritis. Current treatment for CKD includes the administration of angiotensin-converting enzyme inhibitors (ACE-ls) and angiotensin ll-receptor blockers (ARBs), lipid and blood pressure control, as well as tight glucose control in patients with diabetes.

[0002] Chronic kidney disease progression often leads to the complete destruction of functional kidney tissue, which ultimately can cause affected individuals to require life-long dialysis or to undergo renal allograft transplantation. Renal disease progression is characterized by fibrosis, which contributes to the destruction of the glomerulus (glomerulosclerosis) and renal tubules (tubulo-interstitial fibrosis).

[0003] The present invention solves one or more of the above-mentioned problems.2. SUMMARY

[0004] The present disclosure relates to the use of an inhibitor of type I IFN in the treatment chronic kidney disease. The invention is support by data, presented herein for the first time, providing a 3-gene type I IFN gene signature associated with chronic kidney disease. The inventors have identified a strong upregulation of the novel kidney specific IFNGS in the tubulointerstitium and glomerulus of patients with chronic kidney disease (CKD). These data provide evidence that dysregulated type I IFN may modulate disease pathogenesis in these compartments. In a randomized trial, type I IFN signaling blockade with anifrolumab strongly inhibited a 21-gene IFNGS in whole blood that included the 3 genes of the K_IFNGS [2]. These data suggest that an inhibitor of type I IFN such as anifrolumab would inhibit the K-IFNGS in the kidney, interfering with the immunopathogenesis of chronic kidney disease.3. BRIEF DESCRIPTION OF FIGURESFigure 1 : Expression of the K-IFNGS (IFI44L, MX1 , USP18) in the glomerular and tubulointerstitial compartments, including healthy controls and patients with chronic kidney diseases from the ERCB cohort.

[0005] IFI44L, MX1 , USP18 are upregulated in lupus nephritis and chronic kidney disease patients. *P<0.05; **P<0.01 ; ***P<0.001 . FSGS, focal and segmental glomerulosclerosis; GSVA, gene set variation analysis; IgA, immunoglobulin A; K_IFNGS, kidney interferon gene signature.4. DETAILED DESCRIPTION

[0006] The disclosure relates to a method of treating or preventing chronic kidney disease (CKD) in a subject in need thereof, comprising administering a therapeutically effective amount of an inhibitor of type I IFN signalling to the subject. The subject may have a type I IFN mediated disease. The type I IFN mediated disease comprises lupus nephritis (LN), SLE, CLE, myositis or scleroderma. The subject may be receiving standard of care for the type IFN mediated disease. The standard of care may comprise corticosteroids. The CKD may comprise basement membrane disease, membranous glomerulonephritis, focal and segmental glomerulosclerosis (FSGS), hypertensive renal disease, diabetic nephropathy, IgA nephropathy, minimal change disease, and / or kidney cancer.

[0007] The CKD may comprise kidney cancer, hypertensive renal disease and / or IgA nephropathy.

[0008] The CKD may comprise kidney cancer.

[0009] The inhibitor of type I IFN signalling may be a human monoclonal antibody specific for IFNAR1. The inhibitor of type I IFN signalling may be a human monoclonal antibody specific for IFN-a.

[0010] The inhibitor of type I IFN signalling may be an antibody specific for IFNAR1 . The inhibitor of type I IFN signalling may be an antibody specific for IFN-a.

[0011] The inhibitor of type I IFN signalling may be a human monoclonal antibody specific for IFNAR1 , comprising a heavy chain variable region complementarity determining region (HDCR) 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 3. The inhibitor of type I IFN signalling may be a human monoclonal antibody specific for IFNAR1 , comprising a HCDR2 comprising the amino acid sequence of SEQ ID NO: 4. The inhibitor of type I IFN signalling may be a human monoclonal antibody specific for IFNAR1 , comprising a HCDR3 comprising the amino acid sequence of SEQ ID NO: 5. The inhibitor of type I IFN signalling may be a human monoclonal antibody specific for IFNAR1 , comprising a light chain variable region complementarity determining region (LCDR) 1 comprising the amino acid sequence SEQ ID NO: 6 . The inhibitor of type I IFN signalling may be a human monoclonal antibody specific for IFNAR1 , comprising a LCDR2 comprising the amino acid sequence SEQ ID NO: 7. The inhibitor of type I IFN signalling may be a human monoclonal antibody specific for IFNAR1 , comprising a LCDR3 comprising the amino acid sequence SEQ ID NO: 8.

[0012] The monoclonal antibody may comprise a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 . The monoclonal antibody may comprise a human light chain variable region comprising the amino acid sequence of SEQ ID NO: 2.

[0013] The monoclonal antibody may comprise in the Fc region an amino acid substitution of L234F, as numbered by the EU index as set forth in Kabat and wherein said antibody exhibits reduced affinity for at least one Fc ligand compared to an unmodified antibody. The monoclonal antibody may comprise a human heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 1 1 . The monoclonal antibody may comprise a human light chain (LC) comprising the amino acid sequence of SEQ ID NO: 12.

[0014] The inhibitor of type I IFN mediated signalling may be anifrolumab or a functional variant thereof.

[0015] The inhibitor of type I IFN mediated signalling may be sifalimumab, Rontalizumab, QX006N, PF- 06823859, LABP-104, Eclitasertib, Litifilimab, Deucravacitinib, ABBV-599 or Baricitinib.

[0016] The subject may have an elevated 3-gene IFNGS score (K-IFNGS) at baseline. The elevated K- IFNGS may comprise an elevated IFI44L gene expression at baseline, optionally wherein IFI44L gene expression is elevated relative to gene expression of IFI44L in a healthy subject.

[0017] The elevated K-IFNGS may comprise elevated MX1 gene expression at baseline, optionally wherein MX1 gene expression is elevated relative to gene expression of MX1 in a healthy subject. The elevated K-IFNGS may comprise elevated USP18 gene expression at baseline, optionally wherein USP18 gene expression is elevated relative to gene expression of USP18 in a healthy subject. The elevated K- IFNGS may comprise elevated IFI44L, MX1 and USP18 gene expression at baseline, optionally wherein gene expression is elevated relative to gene expression in a healthy subject. The elevated K-IFNGS may be a composite gene set variation analysis (GSVA) score of IFI44, MX1 and USP18 gene expression in the subject. The elevated K-IFNGS may be a composite GSVA score of IFI44, MX1 and USP18 gene expression in the tubulointerstitium of the subject. The elevated K-IFNGS may be a composite GSVA score of IFI44, MX1 and USP18 gene expression in the kidney glomerulus of the subject. The composite GSVA score may be -0.5 to 1 .0. The GSVA score may be about 1 .0. The GSVA score may be 1 .0. The method may comprise determining whether the subject has an elevated K-IFNGS at baseline. The method may comprise determining whether the subject has an elevated K-IFNGS at baseline in the tubulointerstitium.

[0018] The disclosure also relates to a pharmaceutical composition for use in the method of any of the disclosure, wherein the pharmaceutical composition comprises an inhibitor of type I IFN signalling.

[0019] The disclosure also relates to the use of a pharmaceutical composition for the manufacturing of a medicament for use in the method of the disclosure, wherein the pharmaceutical composition comprises an inhibitor of type I IFN signalling. The inhibitor of type I IFN signalling may be anifrolumab.

[0020] The disclosure also relates to use of a type I IFN inhibitor in the preparation of medicament for the treatment of prevention of chronic kidney disease in a subject in need thereof. The disclosure also relates to an injection device comprising the pharmaceutical composition of the disclosure. The injection device may comprise a pre-filled syringe (PFS), accessorized pre-filed syringe (AFPS) or an auto-injector. The disclosure also relates to a kit comprising the injection device of the disclosure, and instructions for use. The instruction for use may specify that the subject has been diagnosed with chronic kidney disease.4.1. Chronic kidney disease

[0021] Chronic kidney disease is a gradual and progressive loss of the ability of the kidneys to excrete wastes, concentrate urine, and conserve electrolytes. The kidney functions in chronic kidney disease progress and deteriorate irreversibly towards end stage renal disease (ESRD). Patients suffering from ESRD cannot survive without dialysis or kidney transplantation.

[0022] Ch ronic kidney disease may be defined according to the presence or absence of kidney damage and the level of kidney function, regardless of the type (clinical diagnosis) of kidney disease. The primary measure of kidney function is glomerular filtration rate (GFR), which is often estimated as creatinine clearance from serum and urine creatinine concentrations. Chronic kidney disease or failure is defined by the US National Kidney Foundation as having glomerular filtration rate less than 60 ml / min for three months or more.4.2. Doses and methods of administration

[0023] The method may comprise administering an intravenous dose of anifrolumab or the functional variant thereof to the subject. The intravenous dose may be >300 mg anifrolumab or the functional variant thereof. The intravenous dose may be <1000mg. The intravenous dose may be about 300 mg, about 900 mg or about 1000 mg. The intravenous dose may be administered every four weeks (Q4W).

[0024] The method may comprise administering a subcutaneous dose of anifrolumab or the functional variant thereof. The subcutaneous dose may be >105 mg and <150 mg anifrolumab or the functional variant thereof. The subcutaneous dose may be <135 mg anifrolumab or the functional variant thereof. The subcutaneous dose may be about 120 mg. The subcutaneous dose may be administered in a single administration step. The subcutaneous dose may be administered at intervals of 6-8 days. The subcutaneous dose may be administered once per week. The subcutaneous dose may have a volume of about 0.5 to about 1 m. The subcutaneous dose may have a volume of about 0.8 ml.

[0025] The invention also relates to a unit dose for use in the methods of the invention, wherein the unit dose comprises >105 mg and <150 mg anifrolumab or a functional variant thereof. Unit doses of anifrolumab suitable for use in the method of the invention are described in WO2022223714 A1 [3], which is incorporated herein in its entirety.

[0026] The unit dose may comprise <135 mg (i.e., 135 mg or less) anifrolumab or the functional variant thereof. The unit dose may comprise about 120 mg anifrolumab or the functional variant thereof. The unit dose may comprise 120 mg anifrolumab or the functional variant thereof. The unit dose may consist essentially of >105 mg and <150 mg anifrolumab or the functional variant thereof. The unit dose may consist essentially of <135 mg anifrolumab or the functional variant thereof. The unit dose may consist essentially of about 120 mg anifrolumab or the or the functional variant thereof. The concentration of anifrolumab or the functional variant thereof in the unit dose may be about 150 mg / ml. The volume of the unit dose may be less than 1 ml. The dose or unit dose may have a volume of about 0.5 to about 1 ml. The concentration of the unit dose may be about 0.8 ml. The volume of the unit dose may be 0.8 ml. The unit dose may comprise a formulation of about 150 to 200 mg / ml anifrolumab or the functional variant thereof, about 25 to 150 mM of lysine sale and an uncharged excipient. The unit dose may comprise a formulation of 150 to 200 mg / ml anifrolumab or the functional variant thereof, 25 to 150 mM of lysine sale and an unchargedexcipient. The unit dose comprises a formulation of 25 mM histidine-HCL, 130 mM trehalose, and 0.05% w / v polysorbate 80. The formulation may have a pH of about 5.9.

[0027] A unit dose (also referred to as a unit dose form, a pharmaceutical unit dose or a pharmaceutical unit dose form) is a dose formed from a single unit. A unit dose (unit dose form) is suitable for administration to a subject in a single administration step. A unit dose (unit dose form) may be packaged in a single-unit container, for example a single-use pre-filled syringe or autoinjector. Unit doses provide the advantage that they can be ordered, packaged, handled and administered as single dose units containing a pre-determined amount of a drug. Unit doses decrease administration errors and reduce waste.4.3. Device

[0028] The invention also relates to an injection device comprising the pharmaceutical composition for use in the method of the invention. The injection device may be a pre-filled syringe (PFS). The injection device may be an accessorized pre-filed syringe (AFPS). The injection device may be an auto-injector (Al). The device may be used in the methods of the disclosure.4.4. Formulations

[0029] The invention also relates to pharmaceutical formulation comprising the type I IFN inhibitor for use in the methods of the disclosure. Formulations suitable for administration to subjects and comprising anifrolumab are described in detail in US Patent 10125195 B1 , which is incorporated herein in its in entirety.

[0030] The anifrolumab or the functional variant thereof may be comprised within a pharmaceutical composition. The pharmaceutical composition may comprise about 150 to 200 mg / ml anifrolumab or the functional variant thereof, about 25 to 150 mM of lysine sale and an uncharged excipient. The pharmaceutical composition may comprise 150 mg / mL anifrolumab or the functional variant thereof. The pharmaceutical composition may comprise 50 mM lysine HCI. The pharmaceutical composition may comprise 130 mM trehalose dihydrate. The pharmaceutical composition may comprise 0.05% polysorbate 80. The pharmaceutical composition may comprise 25 mM histidine / histidine HCI. The pharmaceutical composition may comprise 150 mg / mL anifrolumab or the functional variant thereof, 50 mM lysine HCI, 130 mM trehalose dihydrate, 0.05% polysorbate 80 and 25 mM histidine / histidine HCI.4.5. Inhibitors of type I IFN signaling

[0031] A “type I interferon receptor inhibitor” refers to a molecule that is antagonistic for the receptor of type I interferon ligands such as interferon-a and interferon- . Such inhibitors, subsequent to administration to a patient, may provide a reduction in the expression of at least 1 (preferably at least 4) pharmacodynamic (PD) marker genes selected from the group consisting of IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1 , IFIT1 , HERC5, ISG15, LAMP3, OAS3, OAS1 , EPST1 , IFIT3, LY6E, OAS2, PLSCR1 , SIGLECI, USP18, RTP4, and DNAPTP6. The at least 4 genes may suitably be IFI27, IFI44, IFI44L, and RSAD2. The “type I interferon receptor” is preferably interferon-a / p receptor (IFNAR).

[0032] For example, the type I interferon receptor inhibitor may be an antibody or antigen-binding fragment thereof that inhibits type I IFN activity (by inhibiting the receptor). An example of a suitable antibody or antigen-binding fragment thereof (that inhibits type I IFN activity) is an interferon-a / p receptor (IFNAR) antagonist. The type I interferon receptor inhibitor may be an antibody or antigen-binding fragment thereof that inhibits type I IFN activity. Additionally or alternatively, the type I interferon receptor inhibitor may be a small molecule inhibitor of a type I interferon receptor (e.g. for pharmacological inhibition of type I interferon receptor activity).

[0033] The IFNAR1 inhibitor may be a human monoclonal antibody specific for IFNAR1. The IFNAR1 inhibitor may be a modified IgG 1 class human monoclonal antibody specific for IFNAR1 .

[0034] Inhibition of type I IFN signaling may be achieved by directly targeting the ligands binding to the type I IFN receptor. For example, PF 06823859 is a recombinant humanized antibody that binds and neutralizes the Type I IFN receptor ligand IFN-p. Rontalizumab is a humanized monoclonal antibody inhibiting the Type I IFN receptor ligand IFN-a.

[0035] Alternatively, type I IFN signaling may be inhibited by targeting molecules downstream of the type I IFN receptor. LABP-104 is a small molecule agonist of the surface membrane-associated receptor LanC-like Glutathione S-Transferase 2 (LANCL2). SAR443122, also called Eclitasertib, is a small molecule inhibitor of receptor-interacting protein kinase 1 (RIPK1). Litifilimab is a humanized lgG1 monoclonal antibody inhibiting blood dendritic cell antigen 2 (BDCA2). The small molecule Deucravacitinib is a selective allosteric tyrosine kinase 2 (TYK2) inhibitor. ABBV-599 is a combination of small molecule inhibitors of Bruton’s Tyrosine Kinase (BTK) and Janus kinase 1 (JAK1). The small molecule Baricitinib is an JAK1 and Janus kinase 2 (JAK2) tyrosine kinase inhibitor.4.5.1. Anifrolumab

[0036] Anifrolumab (MEDI-546, anifro, ANI) is a human immunoglobulin G1 kappa (IgGl K) monoclonal antibody (mAb) directed against subunit 1 of the type I interferon receptor (IFNAR1). Anifrolumab downregulates IFNAR signaling and suppresses expression of IFN-inducible genes. Disclosures related to anifrolumab can be found in U.S. Patent No. 7662381 and U.S. Patent No. 9988459, which are incorporated herein by reference in their entirety. Sequence information for anifrolumab is provided in Error! Reference source not found.Table 1: Anifrolumab Sequences

[0037] Anifrolumab is an immunoglobulin comprising an HCDR1 , HCDR2 and HCDR3 of SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, respectively (or functional variant thereof); and an LCDR1 , LCDR2 and LCDR3 of SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively (or functional variant thereof). Anifrolumab is an immunoglobulin comprising a VH of SEQ ID NO: 1 and a VL of SEQ ID NO: 2.

[0038] The constant region of anifrolumab has been modified such that anifrolumab exhibits reduced affinity for at least one Fc ligand compared to an unmodified antibody. Anifrolumab is a modified IgG class monoclonal antibody specific for IFNAR1 comprising in the Fc region an amino acid substitution of L234F, as numbered by the EU index as set forth in Kabat (1991 , NIH Publication 91-3242, National Technical Information Service, Springfield, Va.). Anifrolumab is a modified IgG class monoclonal antibody specific for IFNAR1 comprising in the Fc region an amino acid substitution of L234F, L235E and / or P331 S, as numbered by the EU index as set forth in Kabat (1991 , NIH Publication 91-3242, National Technical Information Service, Springfield, Va.). Anifrolumab is an antibody comprising a light chain constant region of SEQ ID NO: 9. Anifrolumab is an antibody comprising a heavy chain constant region of SEQ ID NO: 10. Anifrolumab is an antibody comprising a light chain constant region of SEQ ID NO: 9 and a heavy chain constant region of SEQ ID NO: 10. Anifrolumab is an antibody comprising a heavy chain of SEQ ID NO: 11. Anifrolumab is an antibody comprising a light chain of SEQ ID NO: 12. Anifrolumab is an antibody comprising a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12.

[0039] Functional variants of anifrolumab are sequence variants that perform the same function as anifrolumab. Functional variants of anifrolumab are variants that bind the same target as anifrolumab and have the same effector function as anifrolumab. Functional anifrolumab variants include antigen-binding fragments of anifrolumab and antibody and immunoglobulin derivatives of anifrolumab. Functional variants include biosimilars and interchangeable products. The terms biosimilar and interchangeable product are defined by the FDA and EMA. The term biosimilar refers to a biological product that is highly similar to an approved (e.g., FDA approved) biological product (reference product, e.g., anifrolumab) in terms of structure and has no clinically meaningful differences in terms of pharmacokinetics, safety and efficacy from the reference product. The presence of clinically meaningful differences of a biosimilar may be assessed in human pharmacokinetic (exposure) and pharmacodynamic (response) studies and an assessment of clinical immunogenicity. An interchangeable product is a biosimilar that is expected to produce the same clinical result as the reference product in any given patient.

[0040] The antibody according to the disclosure may comprise a heavy chain variable region complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 3 . The antibody may comprise a heavy chain variable region complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 4. The antibody may comprise a heavy chain variable region complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 5. The antibody may comprise a light chain variable region complementarity determining region 1 (LCDR1) comprising the amino acid sequence SEQ ID NO: The antibody may comprise a light chain variable region complementarity determining region 2 (LCDR2) comprising the amino acid sequence SEQ ID NO: 7. The antibody may comprise a light chain variable region complementarity determining region 3 (LCDR3) comprising the amino acid sequence SEQ ID NO: 8.

[0041] The antibody may comprise a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 . The antibody may comprise a human light chain variable region comprising the amino acid sequence of SEQ ID NO: 2. The antibody may comprise a human light chain constant region comprising the amino acid sequence of SEQ ID NO: 9. The antibody may comprise a human heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 10. The antibody may comprise in the Fc region an amino acid substitution of L234F, as numbered by the EU index as set forth in Kabat and wherein said antibody exhibits reduced affinity for at least one Fc ligand compared to an unmodified antibody. The antibody may comprise a human heavy chain comprising the amino acid sequence of SEQ ID NO: 11 . The antibody may comprise a human light chain comprising the amino acid sequence of SEQ ID NO: 12.

[0042] The antibody may comprise: (a) a heavy chain variable region complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 3 ; (b) a heavy chain variable region complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 4; c) a heavy chain variable region complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 5; (d) a light chain variable region complementarity determining region 1 (LCDR1) comprising the amino acid sequence SEQ ID NO: 6 ; (b) a light chain variable region complementarity determining region 2 (LCDR2) comprising the amino acid sequence SEQ ID NO: 7; c) a light chain variable region complementarity determining region 3 (LCDR3) comprising the amino acid sequence SEQ ID NO: 8.

[0043] The antibody may comprise (a) a human heavy chain comprising the amino acid sequence of SEQ ID NO: 1 1 ; and (b) a human light chain comprising the amino acid sequence of SEQ ID NO: 12.

[0044] The IFNAR1 inhibitor may be anifrolumab or a functional variant thereof.

[0045] Anifrolumab safety has been evaluated in 8 blinded or open-label intravenous (IV) and subcutaneous (SC) studies: 6 studies in patients with SLE (Study 05, Study 04, Study 1013, Study 1 145, and Study 08), 1 study in patients with systemic sclerosis (SSc) (Study MI-CP180), and 1 study in healthy volunteers (Study 06) (Error! Reference source not found.). Of these studies, two (Studies 08 and 06) employed SC anifrolumab administration. Two studies are ongoing: 1 study in patients with SLE (Study 09) and 1 study in patients with lupus nephritis (LN) (Study 07).Table 2: Clinical studies

[0046] Study MI-CP151 is described in further detail in Higgs et al. 2013 [5]. Study 1013 is described in further detail in Furie et al. 2017 [6], which is incorporated herein by reference in its entirety. Study 04 is described in further detail in Furie et al. 2019 [7], which is incorporated herein by reference in its entirety. The results of Study 05 are presented in Morand et al. 2020 [8], herein incorporated by reference in its entirety. A full summary of the evidence for intravenous anifrolumab clinical efficacy in SLE is provided in Tanaka et al., 2020 [9], which is incorporated herein by reference in its entirety.4.5.2. Anifrolumab variant

[0047] A variant of the reference (anifrolumab) antibody may comprise: a heavy chain CDR1 having at most 2 amino acid differences when compared to SEQ ID NO: 3; a heavy chain CDR2 having at most 2 amino acid differences when compared to SEQ ID NO: 4; a heavy chain CDR3 having at most 2 amino acid differences when compared to SEQ ID NO: 5; a light chain CDR1 having at most 2 amino acid differences when compared to SEQ ID NO: 6; a light chain CDR2 having at most 2 amino acid differences when compared to SEQ ID NO: 7; and a light chain CDR3 having at most 2 amino acid differences when compared to SEQ ID NO: 8; wherein the variant antibody binds to the target of anifrolumab (e.g. IFNAR) and preferably with the same affinity.

[0048] A variant of the reference (anifrolumab) antibody may comprise: a heavy chain CDR1 having at most 1 amino acid difference when compared to SEQ ID NO: 3; a heavy chain CDR2 having at most 1amino acid difference when compared to SEQ ID NO: 4; a heavy chain CDR3 having at most 1 amino acid difference when compared to SEQ ID NO: 5; a light chain CDR1 having at most 1 amino acid differences when compared to SEQ ID NO: 6; a light chain CDR2 having at most 1 amino acid difference when compared to SEQ ID NO: 7; and a light chain CDR3 having at most 1 amino acid difference when compared to SEQ ID NO: 8; wherein the variant antibody binds to the target of anifrolumab (e.g. IFNAR) optionally with the same affinity.

[0049] A variant antibody may have at most 5, 4 or 3 amino acid differences total in the CDRs thereof when compared to a corresponding reference (anifrolumab) antibody, with the proviso that there is at most 2 (optionally at most 1) amino acid differences per CDR. A variant antibody may have at most 2 (optionally at most 1) amino acid differences total in the CDRs thereof when compared to a corresponding reference (anifrolumab) antibody, with the proviso that there is at most 2 amino acid differences per CDR. A variant antibody may have at most 2 (optionally at most 1) amino acid differences total in the CDRs thereof when compared to a corresponding reference (anifrolumab) antibody, with the proviso that there is at most 1 amino acid difference per CDR.

[0050] A variant antibody may have at most 5, 4 or 3 amino acid differences total in the framework regions thereof when compared to a corresponding reference (anifrolumab) antibody, with the proviso that there is at most 2 (optionally at most 1) amino acid differences per framework region. Optionally a variant antibody has at most 2 (optionally at most 1) amino acid differences total in the framework regions thereof when compared to a corresponding reference (anifrolumab) antibody, with the proviso that there is at most 2 amino acid differences per framework region. Optionally a variant antibody has at most 2 (optionally at most 1) amino acid differences total in the framework regions thereof when compared to a corresponding reference (anifrolumab) antibody, with the proviso that there is at most 1 amino acid difference per framework region.

[0051] A variant antibody may comprise a variable heavy chain and a variable light chain as described herein, wherein: the heavy chain has at most 14 amino acid differences (at most 2 amino acid differences in each CDR and at most 2 amino acid differences in each framework region) when compared to a heavy chain sequence herein; and the light chain has at most 14 amino acid differences (at most 2 amino acid differences in each CDR and at most 2 amino acid differences in each framework region) when compared to a light chain sequence herein; wherein the variant antibody binds to the same target antigen as the reference (anifrolumab) antibody (e.g. IFNAR) and preferably with the same affinity.

[0052] The variant heavy or light chains may be referred to as “functional equivalents” of the reference heavy or light chains. A variant antibody may comprise a variable heavy chain and a variable light chain as described herein, wherein: the heavy chain has at most 7 amino acid differences (at most 1 amino acid difference in each CDR and at most 1 amino acid difference in each framework region) when compared to a heavy chain sequence herein; and the light chain has at most 7 amino acid differences (at most 1 amino acid difference in each CDR and at most 1 amino acid difference in each framework region) when comparedto a light chain sequence herein; wherein the variant antibody binds to the same target antigen as the reference (anifrolumab) antibody (e.g. IFNAR) and preferably with the same affinity.

[0053] Functional variants of anifrolumab include the antibodies described in WO 2018 / 023976 A1 , incorporated herein by reference (Error! Reference source not found.).Table 3: anti-IFNAR antibody sequences

[0054] Functional variants include antibodies comprising the VH amino acid sequence SEQ ID NO: 13. Functional variants include antibodies comprising the VH amino acid sequence SEQ ID NO: 16. Functional variants include antibodies comprising the VL amino acid sequence SEQ ID NO: 14. Functional variants include antibodies comprising the VL amino acid sequence SEQ ID NO: 15. Functional variants include antibodies comprising the VL amino acid sequence SEQ ID NO: 16. Functional variants include antibodies comprising the VH sequence SEQ ID NO: 13 and VL amino acid sequence SEQ ID NO: 16. Functional variants include antibodies comprising the VH sequence SEQ ID NO: 13 and VL amino acid sequence SEQ ID NO: 15. Functional variants include antibodies comprising the VH sequence SEQ ID NO: 16 and VL amino acid sequence SEQ ID NO: 15. Functional variants include antibodies comprising the VH sequence SEQ ID NO: 16 and VL amino acid sequence SEQ ID NO: 14.

[0055] IFNAR inhibitors may be a monoclonal antibody comprising the VH amino acid sequence SEQ ID NO: 13. The anti-IFNAR antibodies may comprise the VH amino acid sequence SEQ ID NO: 16. The anti- IFNAR antibodies may comprise the VL amino acid sequence SEQ ID NO: 14. The anti-IFNAR antibodies may comprise the VL amino acid sequence SEQ ID NO: 15. The anti-IFNAR antibodies may comprise the VL amino acid sequence SEQ ID NO: 16. The anti-IFNAR antibodies may comprise the VH sequence SEQ ID NO: 13 and VL amino acid sequence SEQ ID NO: 16. The anti-IFNAR antibodies may comprise the VH sequence SEQ ID NO: 13 and VL amino acid sequence SEQ ID NO: 15. The anti-IFNAR antibodies may comprise the VH sequence SEQ ID NO: 16 and VL amino acid sequence SEQ ID NO: 15. The anti-IFNAR antibodies may comprise the VH sequence SEQ ID NO: 16 and VL amino acid sequence SEQ ID NO: 14.4.5.3. Sifalimumab

[0056] Sifalimumab is an inhibitor of type I IFN mediated signaling. Sifalimumab (MEDI-545) is a fully human, immunoglobulin G1 K monoclonal antibody that binds to and neutralizes the majority of IFN-a subtypes

[0010] . Sifalimumab is described US patent 7,741 ,449, which is incorporated herein by reference in its entirety. The efficacy and safety of sifalimumab were assessed in a phase lib, randomised, double-blind, placebo-controlled study (NCT01283139) of adults with moderate to severe active systemic lupus erythematosus (SLE). 431 patients were randomised and received monthly intravenous sifalimumab (200 mg, 600 mg or 1200 mg) or placebo in addition to standard-of-care medications. The primary efficacy end point was the percentage of patients achieving an SLE responder index response at week 52. Compared with placebo, a greater percentage of patients who received sifalimumab (all dosages) met the primary end point (placebo: 45.4%; 200 mg: 58.3%; 600 mg: 56.5%; 1200 mg 59.8%).4.5.4. QX006N

[0057] Functional variants of anifrolumab and anti-IFNAR antibodies include the QX006N antibody described in CN 1 1327807, incorporated herein by reference. QX006N is an inhibitor of type I IFN signalling.Table 4: QX006N antibody sequences

[0058] IFNAR inhibitors may be a monoclonal antibody comprising the VH amino acid sequence SEQ ID NO: 17. The anti-IFNAR antibodies may comprise the VL amino acid sequence SEQ ID NO: 18.

[0059] QX006N is an immunoglobulin comprising an HCDR1 , HCDR2 and HCDR3 of SEQ ID NO: 19, SEQ ID NO: 20, and SEQ ID NO: 21 , respectively (or functional variant thereof); and an LCDR1 , LCDR2 and LCDR3 of SEQ ID NO: 22, SEQ ID NO: 23, and SEQ ID NO: 23, respectively (or functional variant thereof). QX006N is an immunoglobulin comprising a VH amino acid sequence SEQ ID NO: 17 the VL amino acid sequence SEQ ID NO: 18.4.5.5. Other inhibitors of type I IFN signaling

[0060] In addition to the inhibitors described above, inhibition of type I IFN signaling may be achieved by directly targeting the ligands binding to the type I IFN receptor. For example, PF 06823859 is a recombinant humanized antibody that binds and neutralizes the Type I IFN receptor ligand IFN- . Rontalizumab is a humanized monoclonal antibody inhibiting the Type I IFN receptor ligand IFN-a.

[0061] Alternatively, type I IFN signaling may be inhibited by targeting molecules downstream of the type I IFN receptor. LABP-104 is a small molecule agonist of the surface membrane-associated receptor LanC- like Glutathione S-Transferase 2 (LANCL2). SAR443122, also called Eclitasertib, is a small molecule inhibitor of receptor-interacting protein kinase 1 (RIPK1). Litifilimab is a humanized lgG1 monoclonal antibody inhibiting blood dendritic cell antigen 2 (BDCA2). The small molecule Deucravacitinib is a selective allosteric tyrosine kinase 2 (TYK2) inhibitor. ABBV-599 is a combination of small molecule inhibitors of Bruton’s Tyrosine Kinase (BTK) and Janus kinase 1 (JAK1). The small molecule Baricitinib is an JAK1 and Janus kinase 2 (JAK2) tyrosine kinase inhibitor.4.6. Kit

[0062] In another aspect the invention relates to a kit comprising a unit dose of the invention and instructions for use, wherein the instructions for use comprise instructions for subcutaneous administration of the unit dose to a subject.

[0063] In another aspect the invention relates to a kit comprising the pharmaceutical composition for the use of the invention, wherein the instructions for use comprise instructions for subcutaneous administration of the pharmaceutical composition to a subject.

[0064] In another aspect the invention relates to a kit comprising the injection device of any of the invention, and instructions for use, wherein the instruction for use comprise instructions for use of the injection device to subcutaneously administer the unit dose or pharmaceutical composition to the subject.

[0065] The kit of the invention may comprise packaging, wherein the packaging is adapted to hold the injection device and the instructions for use. The instructions for use may be attached to the injection device. The instruction for use may comprise instructions for administration of >105 mg and <150 mg anifrolumab or functional variant thereof. The instruction for use may comprise instructions for administration of <135 mg anifrolumab or the functional variant thereof. The instruction for use may comprise instructions for administration of 120 mg anifrolumab or the functional variant thereof. The instruction for use may comprise instructions for administration of 120 mg anifrolumab or the functional variant thereof every 4 weeks. The instructions for use may define the subject as having a type I IFN mediated disease. The instructions may define the subject as having LP. The instructions for use may be written instructions. The instructions for use may be attached to the injection device. The instructions may specify that the type I IFN inhibitor is for use in the treatment of LP in a patient. The instructions for use may explain that a type I IFN inhibitor maybe used to treat LP in a subject. The instructions for use may specify that the subject has an elevated type I IFN gene signature.

[0066] The instructions for use may specify that the injection device, unit dose and / or pharmaceutical composition are for use in the treatment of LP. The instructions for use comprise instructions for administration of 120 mg anifrolumab or the functional variant thereof every week.4.7. Lupus Nephritis

[0067] Lupus nephritis (LN) is one of the most prevalent severe disease manifestations of lupus, occurring in approximately 40% of SLE patients

[0011] . LN is more prevalent in African Americans, Hispanics, and Asians compared with patients of European descent

[0012] , The accumulation of immune complexes and the subsequent inflammatory response in kidney tissue can lead to irreversible glomerular and tubulointerstitial damage

[0011] . LN is strongly associated with the increased morbidity and pre-mature mortality in SLE with the standardized mortality ratio being about 3-fold higher in LN patients compared with patients with non- renal SLE and 6- to 9-fold higher compared with the general population. According to the World Health Organization (WHO) histological classification, proliferative LN includes patients with focal Class III and diffuse Class IV proliferative glomerulonephritis

[0013] , a subset of patients with poor prognosis, with up to 45% of patients progressing to end-stage kidney disease within 15 years of diagnosis

[0014] .

[0068] The ultimate treatment goal for patients with active, proliferative LN is to prevent end-stage kidney failure and death

[0015] . Persistent proteinuria and / or acute kidney dysfunction indicate renal inflammation and are risk factors for progressive kidney damage and worse long-term outcomes

[0011] . Therefore, shortterm treatment goals include attenuating proteinuria, measured using the urine protein-creatinine ratio (UPCR), and stabilizing / improving the estimated glomerular filtration rate (eGFR)

[0015] .

[0069] Histopathological classes III and IV represent proliferative LN that generally requires intensive immunosuppressive therapy to achieve the treatment goal of renal remission, preserved renal function, and ultimately prevention of end-stage renal disease (ESRD). Such immunosuppressive therapy with Mycophenolate mofetil (MMF) or cyclophosphamide (CYC), in combination with glucocorticoids, is the current recommended off-label standard of care treatments for proliferative LN in international guidelines, for which an unmet therapeutic need clearly remains; the treatment typically consists of an initial intensive immunosuppressive period for 3 to 6 months followed by less intensive therapy for several years to maintain remission

[0015] . However, not all patients respond to this therapy: only 10% to 40% achieve remission after one year

[0016] and disease flares are common

[0017] . Furthermore, the current treatments have significant side effects, such as the risk of pre-mature menopause induced by CYC and organ damage from long-term glucocorticoid use.

[0070] The Food and Drug Administration (FDA) approved belimumab in 2020 and voclosporin in 2021 for the treatment of patients with LN based on positive efficacy results beyond standard therapy. However, in phase 3 trials, less than 50% of patients achieved a complete renal response (CRR) following treatmentwith belimumab (CRR; requiring urine protein-creatinine ratio (UPCR) <0.5 mg / mg) [18-20]. As such, there remains a need for additional treatment options to further increase response rates while reducing glucocorticoid exposure.

[0071] LN diagnosis is made by renal biopsy and histopathological classification according to the 2003 ISN / RPS classification criteria

[0013] and the histopathological classification also guides treatment. Active Class III and Class IV LN generally requires initially intensive immunosuppressive therapy combined with high dose glucocorticoids followed by several years of continued immunosuppressive treatment to achieve the clinically important treatment goals of renal remission, preserved renal function, and ultimately prevention of ESKD. The currently recommended immunosuppressive therapy for Class III and IV LN (used as off-label in most regions) consists of MMF or cyclophosphamide in combination with glucocorticoids

[0015] .

[0072] Even if renal outcomes have improved after introduction immunosuppressive treatment only 10% to 40% achieve remission after 1 year

[0016] and disease flares are common. Importantly, up to 20% of LN patients develop ESKD within 10 years of initial diagnosis despite treatment and therapy is associated with significant side effects including organ damage from long-term glucocorticoid use. Despite recent approvals of belimumab in US and EU and voclosporin in US for treatment of adult patients with active a large unmet need remains since more than half of patients don’t respond to these therapies. Thus, new effective and safe therapies targeting novel pathways for treatment of active LN remains in order to achieve clinical treatment goals, i.e., improve renal remission rates, reduce flares, and prevent of ESKD, while reducing the need for glucocorticoids.

[0073] The unmet need for LN thus remains substantial, with the need for novel, targeted therapies for improved renal responses, reduced flares, and prevention of ESRD, as well as reduced need for glucocorticoids. LN remission rates remain suboptimal

[0018] , and patients are at high risk of developing endstage kidney disease

[0014] and drug-related toxicity, particularly relating to prolonged, high-dose glucocorticoid use

[0015] .4.8. Subject

[0074] The subject may be a human subject. The subject may be an adult.4.9. Type I IFN mediated disease

[0075] Type I IFN mediated disease may be defined as a disease characterized by dysregulation of type I IFN [9] The type I IFN disease may be a type I IFN-mediated autoimmune disease. The type I IFN disease may be a type I IFN-mediated systemic autoimmune disease. Type I IFN-mediated diseases include lupus (including SLE, LN and CLE). The type I IFN-mediated disease may be lupus nephritis. The type I IFN- mediated diseases include cutaneous lupus erythematosus. Type I IFN-mediated diseases include myositis. Type I IFN-mediated disease include scleroderma. Type I IFN-mediated diseases include Sjogren’s syndrome.

[0076] Type I IFN-mediated diseases include interferonopathies. The Type I IFN-mediated disease may be characterized by association with a high 21 -gene IFNGS compared to healthy subjects. The Type I IFN- mediated disease may be characterized by association with a high 4 gene-IFNGS compared to healthy subjects. The Type I IFN-mediated disease may be characterized by association with a high 5 gene-IFNGS compared to healthy subjects.4.9.1. Myositis

[0077] Myositis (also known as idiopathic inflammatory myopathies (I MM)) , like SLE, is a connective tissue disease with strong type 1 IFN involvement. Myositis is a rare, progressive and debilitating disease. Myositis is a type I IFN mediated disease. In particularly, type I IFN-inducible genes are overexpressed in whole blood and muscle in patients with myositis [10,11]. Type I IFN gene expression correlates with myositis disease activity [10,11]. Furthermore, type I IFN-secreting plasmacytoid DC (pDC) are present in the target tissues of patients with myositis [12,13]. Additionally, myositis is induced de novo or worsened with IFN treatment [13,14]. Finally, the anti-IFN-a monoclonal antibody, sifalimumab, neutralized IFN gene expression in both DM and PM in muscle, which was associated with improved muscle function. The clinical manifestations of fatigue, rash, photosensitivity and joint pain are common to both lupus and myositis.4.9.2. Scleroderma

[0078] Systemic Sclerosis (Scleroderma, SSc), like SLE, is a connective tissue disease with strong type 1 IFN involvement. Systemic sclerosis is a multi-system autoimmune disease, characterized by functional and structural abnormalities of small blood vessels and fibrosis of skin and internal organs. Type 1 IFN pathway is a pathogenic driver in SSc. Evidence of the central role of Type I IFNs in pathogenesis of SSc (inflammatory and fibrotic processes) includes multiple associated genetic polymorphisms that implicate the type-1 IFN pathway in SSc

[0015] . Furthermore, SSc auto-antibodies have been found to directly amplify the type-1 IFN response

[0016] , and there is evidence of type-1 IFN contribution to TGF- dependent and independent fibrosis in lungs and skin of SSc patients

[0017] . Additionally, digital ulcers due to vascular lesions of small vessels in SSc are associated with high IFN signature

[0018] .4.10. Type I IFN gene signature (IFNGS)

[0079] Type I IFN is considered to play a central role SLE disease pathogenesis and inhibition of this pathway is targeted by anifrolumab. To understand the relationship between type I IFN expression and response to anti-IFN therapy, it is necessary to know if a subject’s disease is driven by type I IFN activation. However, direct measurement of type I IFN remains a challenge. As such, a transcript-based marker was developed to evaluate the effect of over expression of the target protein on a specific set of mRNA markers. The expression of these markers is easily detected in whole blood and demonstrates a correlation with expression in diseased tissue such as skin in SLE. The bimodal distribution of the transcript scores for SLE subjects supports defining an IFN test high and low subpopulation. The type I IFN test is described in WO201 1028933 A1 , which is incorporated herein by reference in its entirety. The type I IFN gene signaturemay be used to identify a subject has a type I IFN gene signature (IFNGS)-test high patient or an IFNGS- test low patient. The IFNGS test measures expression of the genes IFI27, IFI44, IFI44L, and RSAD2 compared with 3 reference genes: 18S, ACTB and GAPDH in the whole blood of the subject. The result of the test is a score that is compared with a pre-established cut-off that classifies patients into 2 groups with low or high levels of IFN inducible gene expression.

[0080] The expression of the genes may be measured by RT-PCR. Suitable primers and probes for detection of the genes may be found in WO2011028933. A suitable kit for measuring gene expression for the IFNGS test is the QIAGEN therascreen® IFIGx RGQ RT-PCR kit (IFIGx kit), as described in Brohawn et al. [4], which is incorporated herein by reference in its entirety. The type I IFN gene signature test measures the mRNA expression of 4 type I IFN-inducible genes (IFI27, IFI44, IFI44L, and RSAD2) relative to 3 housekeeping genes (ACTB, 18S, and GAPDH).

[0081] The type I IFNGS test may be conducted at a designated central laboratory using the QIAGEN therascreen IFN-inducible gene expression (IFIGx) Rotor-Gene Q (RGQ) reverse transcriptase PCR (RT- PCR) system. This expression system consists of collection tubes and

[0082] RNA isolation kits described above, along with a therascreen IFIGx RGQ RT-PCR kit used with RGQ molecular diagnostic platform with IFIGx software. The IFIGx kit measures the expression of four type I IFN-inducible genes (IFI27, IFI44, IFI44L and RSAD2) relative to three housekeeping genes (ACTB, 18S and GAPDH) and generates a qualitative diagnostic score of positive or negative. The result is expressed as a score that is compared with a pre-established delta Ct-based cut-off, in the trough of the bimodal distribution, and classifies patients into one of two groups representing low or high IFIGx [5] (Figure 1).

[0083] The analytical validation of the four-gene test as a measurement of IFIGx has been reported and was in two phase III studies of anifrolumab forthe treatment of SLE (NCT02446899 and NCT02446912) [6]. Patients with SLE, who present heterogeneous disease activity and symptoms, are commonly stratified by low or high levels of IFIGx [7,8].

[0084] Type I IFN gene signature may be calculated alternatively using a 5-gene IFNGS score [9].5. CLAUSES

[0085] The Examples that follow are illustrative of specific embodiments of the disclosure, and various uses thereof. They are set forth for explanatory purposes only and should not be construed as limiting the scope of the disclosure in any way.Clause 1) A method of treating or preventing chronic kidney disease (CKD) in a subject in need thereof, comprising administering a therapeutically effective amount of an inhibitor of type I IFN signalling to the subject.Clause 2) The method of clause 1 , wherein the subject has a type I IFN mediated disease.Clause 3) The method of clause 2, wherein the type I IFN mediated disease comprises lupus nephritis (LN).Clause 4) The method of any preceding clause, wherein the subject is receiving standard of care for the type IFN mediated disease.Clause 5) The method of clause 4, wherein standard or care comprises corticosteroids.Clause 6) The method of any preceding clause, wherein the chronic kidney disease comprises basement membrane disease, membranous glomerulonephritis, focal and segmental glomerulosclerosis (FSGS), hypertensive renal disease, diabetic nephropathy, IgA nephropathy, minimal change disease, and / or kidney cancer.Clause 7) The method of any preceding clause, wherein the CKD comprises kidney cancer, hypertensive renal disease and / or IgA nephropathy.Clause 8) The method of any preceding clause, wherein the CKD comprises kidney cancer.Clause 9) The method of any preceding clause, wherein the inhibitor of type I IFN signalling is a human monoclonal antibody specific for IFNAR1 or IFN-a.Clause 10) The method of any preceding clause, wherein the inhibitor of type I IFN signalling is a human monoclonal antibody specific for IFNAR1 , comprising: a. a heavy chain variable region complementarity determining region (HDCR) 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 3 ; b. a HCDR2 comprising the amino acid sequence of SEQ ID NO: 4; c. a HCDR3 comprising the amino acid sequence of SEQ ID NO: 5; d. a light chain variable region complementarity determining region (LCDR) 1 comprising the amino acid sequence SEQ ID NO: 6 ; e. a LCDR2 comprising the amino acid sequence SEQ ID NO: 7; and f. a LCDR3 comprising the amino acid sequence SEQ ID NO: 8.Clause 1 1) The method of clause 9 or 10, wherein the monoclonal antibody comprises: (a) a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 ; and (b) a human light chain variable region comprising the amino acid sequence of SEQ ID NO: 2.Clause 12) The method of any of clauses 9 to 11 , wherein the monoclonal antibody comprises in the Fc region an amino acid substitution of L234F, as numbered by the EU index as set forth in Kabat and wherein said antibody exhibits reduced affinity for at least one Fc ligand compared to an unmodified antibody.Clause 13) The method of any of any of clauses 9 to 112, wherein the monoclonal antibody comprises: (a) a human heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 1 1 ; and (b) a human light chain (LC) comprising the amino acid sequence of SEQ ID NO: 12.Clause 14) The method of any preceding clause, wherein the inhibitor of type I IFN mediated signalling is anifrolumab or a functional variant thereof.Clause 15) The method of any preceding clause, wherein the inhibitor of type I IFN mediated signalling is sifalimumab, Rontalizumab, QX006N, PF-06823859, LABP-104, Eclitasertib, Litifilimab, Deucravacitinib, ABBV-599 or Baricitinib.Clause 16) The method of any preceding clause, wherein the subject has an elevated 3-gene IFNGS score (K-IFNGS) at baseline.Clause 17) The method of clause 16, wherein the elevated K-IFNGS comprises elevated IFI44L gene expression at baseline, optionally wherein IFI44L gene expression is elevated relative to gene expression of IFI44L in a healthy subject.Clause 18) The method of clause 16 or 17, wherein the elevated K-IFNGS comprises elevated MX1 gene expression at baseline, optionally wherein MX1 gene expression is elevated relative to gene expression of MX1 in a healthy subject.Clause 19) The method of any of clauses 16 to 18, wherein the elevated K-IFNGS comprises elevatedUSP18 gene expression at baseline, optionally wherein USP18 gene expression is elevated relative to gene expression of USP18 in a healthy subject.Clause 20) The method of any of clauses 16 to 19, wherein the elevated K-IFNGS comprises elevatedIFI44L, MX1 and USP18 gene expression at baseline, optionally wherein gene expression is elevated relative to gene expression in a healthy subject.Clause 21) The method of any of clauses 16 to 20, wherein the elevated K-IFNGS is a composite gene set variation analysis (GSVA) score of IFI44, MX1 and USP18 gene expression in the subject.Clause 22) The method of clause 16 or 21 , wherein the elevated K-IFNGS is a composite GSVA score of IFI44, MX1 and USP18 gene expression in the tubulointerstitium of the subject.Clause 23) The method of any of clause s 16 to 22, wherein the elevated K-IFNGS is a compositeGSVA score of IFI44, MX1 and USP18 gene expression in the kidney glomerulus of the subject.Clause 24) The method of any of clause s 21 to 23, wherein the composite GSVA score is -0.5 to 1 .0.Clause 25) The method of clause 24, wherein the GSVA score is about 1 .0.Clause 26) The method of any preceding clause, comprising determining whether the subject has an elevated K-IFNGS at baseline.Clause 27) The method of clause 26, comprising determining whether the subject has an elevated K- IFNGS at baseline in the tubulointerstitium.Clause 28) A pharmaceutical composition for use in the method of any of clauses 1 to 27, wherein the pharmaceutical composition comprises an inhibitor of type I IFN signalling.Clause 29) The use of a type I IFN inhibitor for the preparation of medicament for the treatment of prevention of chronic kidney disease in a subject in need thereof.Clause 30) An injection device comprising the pharmaceutical composition of clause 28.Clause 31) The injection device of clause 31 , wherein the injection device comprises a pre-filled syringe (PFS), accessorized pre-filed syringe (AFPS) or an auto-injector.Clause 32) A kit comprising the injection device of clause 31 or 32, and instructions for use.Clause 33) The kit of clause 33, wherein the instructions for use specify that the subject was diagnosed with chronic kidney disease.6. EXAMPLE 1 : Type I Interferon Pathway is Upregulated in Glomerular and Tubulointerstitial Kidney Compartments of Patients with Renal Diseases6.1. Objectives

[0086] The inventors evaluated IFNGS expression in the kidney glomeruli and tubules of patients with lupus nephritis (LN), and in a broader set of chronic kidney diseases (CKDs).6.2. Methods

[0087] The inventor ran a Gene Set Enrichment Analysis for the Human Gene Set “HALLMARK_INTERFERON_ALPHA_RESPONSE” (ID: M591 1) in two “LN vs Control” public transcriptomic datasets, GSE32591 and GSE98422 [21 ,22]. The top three common genes upregulated in LN vs controls in both training datasets were combined to generate a kidney-specific type I IFNGS (KJFNGS). The Gene Set Variation Analysis (GSVA) composite score for the KJFNGS was evaluated in a third LN dataset (ERCB), which included LN and other CKDs

[0044] (accessed from Lindenmeyer M, et al. European Renal cDNA Bank (ERCB)-Nephromine-EuRenOmics Database. 2014. hltps: / / doi.org / 10.6084 / m9.figshare.940987.v1 , accessed 2 Jan 2024) and in an LN single-cell RNA sequencing (scRNA-seq) dataset

[0023] . The GSVA score was compared in patients with kidney diseases vs healthy individuals using Wilcoxon signed-rank tests (with Benjamini-Hochberg P-value adjustment).6.3. Results

[0088] The “HALLMARK_INTERFERON_ALPHA_RESPONSE” gene signature was upregulated in kidney biopsies of patients with LN compared with healthy controls in both GSE32591 and GSE98422 datasets; the top three common genes upregulated in LN in both training datasets were IFI44L (log foldchange [logFC]=3.83 and 2.29, in GSE32591 and GSE98422, respectively), MX1 (3.21 and 1.75), USP18 (2.31 and 1.08) (all adjusted P-values<0.01). These genes formed the KJFNGS, which was validated in the ERCB dataset, showing a consistent significant upregulation in both the tubulointerstitial and the glomerular kidney compartments of patients with LN compared with healthy individuals (P<0.001 in both compartments; Figure 1). Other CKDs had numerically higher GSVA scores in the kidney glomerulus, and there was significant (P<0.05) upregulation of the KJFNGS in the tubulointerstitium for hypertensive renal disease, diabetic nephropathy, and IgA nephropathy, vs healthy controls (Figure 1). In the scRNA-seq dataset, IFI44L and MX1 were also upregulated in multiple cell populations of the kidney in LN vs controls.6.4. Conclusions

[0089] The inventors have identified a strong upregulation of a novel kidney-specific IFNGS in the tubulointerstitium and glomerulus of patients with LN. Surprisingly, the inventors have also identified a strong upregulation of the novel kidney-specific IFNGS in the tubulointerstitium of patients with other CKDs. These data provide evidence that dysregulated type I IFN may modulate disease pathogenesis in these compartments. In a randomized trial, type I IFN signaling blockade with anifrolumab strongly inhibited a 21 - gene IFNGS in whole blood that included the 3 genes of the KJFNGS [2]. These data suggest that an inhibitor of type I IFN such as anifrolumab would inhibit the K-IFNGS in the kidney, interfering with the immunopathogenesis chronic kidney disease.REFERENCESAll publications mentioned in the specification are herein incorporated by reference in their entirety.[1] K.-U. Eckardt et a / ., Lancet Lond. Engl. 382, 158 (2013).[2] D. Jayne et al., Ann. Rheum. Dis. 81 , 496 (2022).[3] C. LINDHOLM et al., WO2022223714A1 (27 October 2022).[4] R. Tummala et al., Lupus Sci. Med. 5, e000252 (2018).[5] B. W. Higgs et al., Ann. Rheum. Dis. 73, 256 (2014).[6] R. Furie et al., Arthritis Rheumatol. Hoboken Nj 69, 376 (2017).[7] R. A. Furie et al., Lancet Rheumatol. 1 , e208 (2019).[8] E. F. Morand et al., N. Engl. J. Med. 382, 211 (2020).[9] Y. Tanaka and R. Tummala, Mod. Rheumatol. 0, 1 (2020).

[0010] M. Khamashta et al., Ann. Rheum. Dis. 75, 1909 (2016).

[0011] J. G. Hanly et al., Rheumatol. Oxf. Engl. 55, 252 (2016).

[0012] E. C. Baechler et a / ., Proc. Natl. Acad. Sci. U. S. A. 100, 2610 (2003).

[0013] J. J. Weening et al., Kidney Int. 65, 521 (2004).

[0014] N. Maroz and M. S. Segal, Am. J. Med. Sci. 346, 319 (2013).

[0015] A. Fanouriakis et al., Ann. Rheum. Dis. 79, 713 (2020).

[0016] E. M. Ginzler, A. J. Bollet, and E. A. Friedman, Annu. Rev. Med. 31 , 463 (1980).

[0017] H.-J. Anders et al., Nat. Rev. Dis. Primer 6, 7 (2020).

[0018] R. Furie et al., N. Engl. J. Med. (2020).

[0019] C. Arriens et al., Ann. Rheum. Dis. 79, 172 (2020).

[0020] B. H. Rovin et al., Kidney Int. 95, 219 (2019).

[0021] C. C. Berthier et al., J. Immunol. Baltim. Md 1950 189, 988 (2012).

[0022] Z. Liao et al., Front. Immunol. 10, (2019).

[0023] E. Der et al., Nat. Immunol. 20, 915 (2019).

Claims

CLAIMS1. A method of treating or preventing chronic kidney disease (CKD) in a subject in need thereof, comprising administering a therapeutically effective amount of an inhibitor of type I IFN signalling to the subject.

2. The method of claim 1 , wherein the subject has a type I IFN mediated disease.

3. The method of claim 2, wherein the type I IFN mediated disease comprises lupus nephritis (LN).

4. The method of any preceding claim, wherein the subject is receiving standard of care for the type IFN mediated disease.

5. The method of claim 4, wherein standard or care comprises corticosteroids.

6. The method of any preceding claim, wherein the chronic kidney disease comprises basement membrane disease, membranous glomerulonephritis, focal and segmental glomerulosclerosis (FSGS), hypertensive renal disease, diabetic nephropathy, IgA nephropathy, minimal change disease, and / or kidney cancer.

7. The method of any preceding claim, wherein the CKD comprises kidney cancer, hypertensive renal disease and / or IgA nephropathy.

8. The method of any preceding claim, wherein the CKD comprises kidney cancer.

9. The method of any preceding claim, wherein the inhibitor of type I IFN signalling is a human monoclonal antibody specific for IFNAR1 or IFN-a.

10. The method of any preceding claim, wherein the inhibitor of type I IFN signalling is a human monoclonal antibody specific for IFNAR1 , comprising:(a) a heavy chain variable region complementarity determining region (HDCR) 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 3 ;(b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 4; c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 5;(d) a light chain variable region complementarity determining region (LCDR) 1 comprising the amino acid sequence SEQ ID NO: 6 ;(e) a LCDR2 comprising the amino acid sequence SEQ ID NO: 7; and(f) a LCDR3 comprising the amino acid sequence SEQ ID NO: 8.11 . The method of claim 9 or 10, wherein the monoclonal antibody comprises: (a) a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 ; and (b) a human light chain variable region comprising the amino acid sequence of SEQ ID NO: 2.

12. The method of any of claims 9 to 11 , wherein the monoclonal antibody comprises in the Fc region an amino acid substitution of L234F, as numbered by the EU index as set forth in Kabat and wherein said antibody exhibits reduced affinity for at least one Fc ligand compared to an unmodified antibody.

13. The method of any of any of claims 9 to 12, wherein the monoclonal antibody comprises: (a) a human heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 1 1 ; and (b) a human light chain (LC) comprising the amino acid sequence of SEQ ID NO: 12.

14. The method of any preceding claim, wherein the inhibitor of type I IFN mediated signalling is anifrolumab or a functional variant thereof.

15. The method of any preceding claim, wherein the inhibitor of type I IFN mediated signalling is sifalimumab, Rontalizumab, QX006N, PF-06823859, LABP-104, Eclitasertib, Litifilimab, Deucravacitinib, ABBV-599 or Baricitinib.

16. The method of any preceding claim, wherein the subject has an elevated 3-gene IFNGS score (K- IFNGS) at baseline.

17. The method of claim 16, wherein the elevated K-IFNGS comprises elevated IFI44L gene expression at baseline, optionally wherein IFI44L gene expression is elevated relative to gene expression of IFI44L in a healthy subject.

18. The method of claim 16 or 17, wherein the elevated K-IFNGS comprises elevated MX1 gene expression at baseline, optionally wherein MX1 gene expression is elevated relative to gene expression of MX1 in a healthy subject.

19. The method of any of claims 16 to 18, wherein the elevated K-IFNGS comprises elevated USP18 gene expression at baseline, optionally wherein USP18 gene expression is elevated relative to gene expression of USP18 in a healthy subject.

20. The method of any of claims 16 to 19, wherein the elevated K-IFNGS comprises elevated IFI44L, MX1 and USP18 gene expression at baseline, optionally wherein gene expression is elevated relative to gene expression in a healthy subject.21 . The method of any of claims 16 to 20, wherein the elevated K-IFNGS is a composite gene set variation analysis (GSVA) score of IFI44, MX1 and USP18 gene expression in the subject.

22. The method of claim 16 or 21 , wherein the elevated K-IFNGS is a composite GSVA score of IFI44, MX1 and USP18 gene expression in the tubulointerstitium of the subject.

23. The method of any of claims 16 to 22, wherein the elevated K-IFNGS is a composite GSVA score of IFI44, MX1 and USP18 gene expression in the kidney glomerulus of the subject.

24. The method of any of claims 21 to 23, wherein the composite GSVA score is -0.5 to 1 .0.

25. The method of claim 24, wherein the GSVA score is about 1 .0.

26. The method of any preceding claim, comprising determining whether the subject has an elevated K-IFNGS at baseline.

27. The method of claim 26, comprising determining whether the subject has an elevated K-IFNGS at baseline in the tubulointerstitium.

28. A pharmaceutical composition for use in the method of any of claims 1 -27, wherein the pharmaceutical composition comprises an inhibitor of type I IFN signalling.

29. The use of a pharmaceutical composition for the manufacturing of a medicament for use in the method of any claims 1 to 28, wherein the pharmaceutical composition comprises an inhibitor of type I IFN signalling.

30. The use of a type I IFN inhibitor in the preparation of medicament for the treatment of prevention of chronic kidney disease in a subject in need thereof.31 . An injection device comprising the pharmaceutical composition of claim 28.

32. The injection device of claim 31 , wherein the injection device comprises a pre-filled syringe (PFS), accessorized pre-filed syringe (AFPS) or an auto-injector.

33. A kit comprising the injection device of claim 31 or 32, and instructions for use.

34. The kit of claim 33, wherein the instructions for use specify that the subject was diagnosed with chronic kidney disease.

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