Treatment of iGA nephropathy using endothelin receptor antagonists and APRIL binding antibodies

Abstract

The present disclosure relates to the use of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof, as well as isolated antibodies that bind to human APRIL, including antigen binding fragments of the antibodies, for the treatment of IgA nephropathy.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of the filing dates of U.S. Provisional Application No. 63 / 420,305, filed on October 28, 2022, and U.S. Provisional Application No. 63 / 420,504, filed on October 28, 2022. The content of each application is hereby incorporated by reference in its entirety.

[0003] Sequence Listing

[0004] This document includes an electronic format sequence listing submitted via an electronic filing system to the United States Patent and Trademark Office. The XML file (incorporated by reference herein) is titled "sequence.xml", created on October 27, 2022, and is 50.2 bytes in size. Technical Field

[0005] This disclosure relates to the use of endothelin receptor antagonists or pharmaceutically acceptable salts thereof, and isolated antibodies (including fragments thereof) that bind to human APRIL for the treatment of IgA nephropathy. Background Art

[0006] IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Aberrant glycosylation of IgA1 leads to elevated serum levels of galactose - deficient IgA1 (Gd - IgA1), which can be recognized by glycan - specific IgA and IgG autoantibodies. Aggregates of immune complexes form in situ and / or deposit in the glomerular mesangium. This promotes mesangial cell proliferation, increased synthesis of extracellular matrix proteins, cytokines, chemokines, and infiltration of immune cells into the surrounding tissue. Thus, disease progression involves (1) the production of Gd - IgA1; (2) its recognition by anti - glycan autoantibodies; (3) the formation of immune complexes in the kidney; and (4) the activation of mesangial cells. See, e.g., Penfold et al., Int. J. Nephrol. and Renovascular Dis. 11, pp. 137 - 148 (2017).

[0007] Unlike other progressive kidney diseases such as diabetic nephropathy, IgAN mainly occurs in subjects in their 20s and 30s who are otherwise healthy. Patients exhibit a range of symptoms, typically including microscopic or gross hematuria and increased protein excretion in the urine. Patients may also exhibit hypertension due to ongoing kidney damage. Current treatment methods only provide supportive care, including administration of the maximum tolerated dose of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, or administration of immunosuppressive drugs, the benefits of which are largely offset by adverse reactions. Ultimately, 30%-40% of patients will develop end-stage renal disease (ESRD) within 20-30 years of being diagnosed with IgAN. During this period, patients will experience many symptoms in addition to declining kidney function, which will significantly reduce their quality of life. Patients with IgAN typically exhibit a significant increase in the expression of endothelin 1 (ET-1) and ET-RA in the kidney. Increased endothelin expression is positively correlated with proteinuria, which is one of the hallmark symptoms of IgAN.

[0008] APRIL is expressed as a type II transmembrane protein, but unlike most other TNF family members, it is mainly processed as a secreted protein and is cleaved in the Golgi apparatus where it is cleaved by the furin convertase to release the soluble active form (Lopez-Fraga et al., 2001, EMBO Rep [EMBO Report] 2:945-51). APRIL assembles as a non-covalently linked homotrimer and has similar structural homology to many other TNF family ligands in terms of protein folding (Wallweber et al., 2004, Mol Biol [Molecular Biology] 343, 283-90). APRIL binds two TNF receptors: B cell maturation antigen (BCMA) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) (reviewed in Kimberley et al., 2009, J Cell Physiol. [Journal of Cellular Physiology] 218(1):1-8). In addition, APRIL has recently been shown to bind heparan sulfate proteoglycan (HSPG) (Hendriks et al., 2005, Cell Death Differ [Cell Death and Differentiation] 12, 637-48). APRIL has been shown to play a role in B cell signaling and drives the proliferation and survival of human and murine B cells in vitro (reviewed in Kimberley et al., 2009, J Cell Physiol. [Journal of Cellular Physiology] 218(1):1-8).

[0009] APRIL is expressed mainly by immune cell subsets such as monocytes, macrophages, dendritic cells, neutrophils, B cells, and T cells, many of which also express BAFF. In addition, APRIL can be expressed by non-immune cells such as osteoclasts, epithelial cells, and a variety of tumor tissues (reviewed in Kimberley et al., 2009, J Cell Physiol. 218(1):1-8). In fact, APRIL was initially identified based on its expression in cancer cells (Hahne et al., 1998, J Exp Med 188, 1185-90). High levels of APRIL mRNA were found in a panel of tumor cell lines as well as in human primary tumors such as colon cancer and lymphoma. Elevated serum levels of APRIL were found in patients with IgA nephropathy (McCarthy et al., 2011, J.Clin.Invest. 121(10):3991-4002).

[0010] Serum Gd-IgA1 levels have been reported to be significantly higher in IgAN patients than in disease controls and healthy controls. In patients with IgAN, serum Gd-IA1 levels were significantly correlated with estimated glomerular filtration rate, serum IgA levels, and tubulointerstitial atrophy / interstitial fibrosis. CKD progression was more frequent in IgAN patients with higher serum Gd-IgA1 levels than in IgAN patients with lower serum Gd-IgA1 levels. The Cox proportional hazards model showed that high GdIgA1 levels were an independent risk factor for CKD progression after adjusting for several confounding factors. Kim et al., J.Clin.Med. November 4, 2020;9(11):3549.doi:10.3390 / jcm9113549.

[0011] The established standard of care for most patients with IgA nephropathy involves providing supportive measures, which include the use of renin-angiotensin-aldosterone system blockade. Although there is clear evidence that the benefits of these therapies outweigh the risks, many patients also receive corticosteroid therapy or other immunosuppressive agents.

[0012] To improve the care of patients with IgAN, at least two antibodies against APRIL, BION-1301 and sibeprenlimab (VIS649), are in clinical trials for treating IgAN. See, for example, U.S. ClinicalTrials.gov identifiers NCT05508204, NCT03945318, NCT03719443, NCT05248659, and NCT05248646. Similarly, the endothelin receptor antagonists atrasentan and sparsentan are in clinical trials for treating IgAN. See, for example, U.S. ClinicalTrials.gov identifiers NCT04573478, NCT05834738, NCT04573920, and NCT04663204. In addition, a subgroup analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial provides early evidence that dapagliflozin (an SGLT-2 inhibitor) may be a safe and effective addition to current standard of care for IgA nephropathy. Wheeler et al., Kidney International (2021) 100:215–224. SUMMARY OF THE INVENTION

[0013] Atracurium is a selective endothelin A (ETA) receptor antagonist (ETA Ki is approximately 34 pM; ETB Ki is approximately 63 nM, and the ETA selectivity is approximately 1800x). See, for example, Wu-Wong et al., Clin. Sci. (London), 103(48), pp. 107s-111s (2002). Selective ETA receptor antagonists block ETA function while having minimal effect on the ETB receptor, providing beneficial renal effects, including vasodilation and reduced inflammation, while still being able to clear ET-1. See, for example, Jandeleit-Dahm and Watson, Curr. Opin. Nephrol. Hypertens., 21(1), pp. 66-71 (2012); also see, Nakamura et al., Nephron, vol. 72, pp. 454-460 (1996). Although ETA receptor antagonists increase renal sodium and water retention, this is typically clinically manageable. See, for example, Saleh et al., J. Pharm. Exp. Ther., 338(1), pp. 263-270 (2011). Atracurium has been shown to be effective in patients with diabetic kidney disease (DKD), significantly reducing the risk of renal events defined as doubling of serum creatinine or end-stage kidney disease. See, for example, Heerspink et al., The Lancet, 393, pp. 1937-1947 (2019).

[0014] Sparsentan is a dual-action angiotensin II subtype 1 receptor blocker ("ARB") and ETA receptor antagonist. Trachtman et al., J. Am. Soc. Nephrol., vol. 29, no. 11, pp. 2745-2754 (2018).

[0015] IgA nephropathy is considered a primary glomerular disease in which there is local or intrinsic renal pathology. Unlike, for example, diabetic kidney disease (“DKD”), the peak incidence of IgA nephropathy is in young individuals in their second or third decade of life and is a disease originating from autoimmunity. IgA nephropathy is caused by the deposition of pathogenic IgA / immune complexes in the glomerular mesangium. See, e.g., Lai, et al., Nature Reviews Disease Primers, 2, p. 16001, 2016. Diagnosis requires a kidney biopsy and confirmation of mesangial IgA deposition by immunofluorescence microscopy. Recent advances in understanding the initiating events that trigger IgA nephropathy have shown that abnormal mucosal immune responses stimulate the production of galactose-deficient IgA1, which is recognized as an autoantigen by circulating antiglycan autoantibodies. Immunorecognition leads to the formation of nephritogenic immune complexes that deposit in the kidney and activate mesangial cells. Activated mesangial cells proliferate and produce excessive extracellular matrix components, cytokines, and chemokines. See, e.g., Suzuki, et al., J. Am. Soc. Nephrol., Vol. 22, pp. 1795-1803 (2011). Up to 40% of patients with biopsy-proven IgA nephropathy will develop end-stage kidney disease at some point during long-term follow-up. As further described herein, atrasentan can be administered at an effective dose with acceptable toxicity and with appropriate selectivity to minimize unwanted side effects while still treating underlying IgAN and improving the quality of life of the subject. Some embodiments provide a method of inhibiting mesangial cell activation in a subject having IgA nephropathy, the method comprising administering to the subject an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0016] Most subjects with IgAN first present with single or episodic gross hematuria, or present after microscopic hematuria and / or proteinuria are detected during routine urinalysis. In some cases, the subject presents with acute kidney injury, such as caused by crescentic IgAN or gross hematuria causing tubular obstruction. Diagnosis of IgAN is typically determined by kidney biopsy, along with immunofluorescence and / or immunoperoxidase studies of IgA deposits. Marked globular IgA deposits in the mesangium (sometimes accompanied by C3 and IgG) and less prominent deposits along the glomerular capillary wall are hallmarks of IgAN. Certain histopathological features associated with long-term outcomes include mesangial hyperplasia, endocapillary hyperplasia, segmental scarring, and tubular atrophy.

[0017] Some embodiments provide a method for treating IgA nephropathy, the method comprising administering to a subject an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0018] Some embodiments provide a method for inhibiting mesangial cell activation in a subject having IgA nephropathy, the method comprising administering to the subject an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0019] In some embodiments, inhibition of mesangial cell activation comprises reducing mesangial cell inflammation and / or the activity of one or more biomarkers indicative of mesangial cell proliferation.

[0020] In some embodiments, reducing mesangial cell inflammation comprises decreasing the expression and / or activity of one or more of IL6, MCP1, or other biomarkers indicative of mesangial cell inflammation.

[0021] In some embodiments, inhibition of mesangial cell activation comprises reducing the profibrotic response in mesangial cells.

[0022] In some embodiments, mesangial cell activation is induced by IgA immune complexes.

[0023] In some embodiments, mesangial cell activation is associated with the presence of IgA immune complexes.

[0024] Some embodiments provide a method for reducing renal inflammation and / or fibrosis in a subject having IgA nephropathy, the method comprising administering to the subject an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0025] Some embodiments provide a method for reducing the occurrence of renal hematuria in a subject having IgA nephropathy, the method comprising administering to the subject an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0026] Some embodiments provide a method for stabilizing eGFR in a subject having IgA nephropathy, the method comprising administering to the subject an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0027] Some embodiments provide a method for reducing the number of episodes of IgA nephropathy-related diseases in a subject having IgA nephropathy, the method comprising administering to the subject an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0028] Some embodiments provide a method for delaying the onset of end-stage renal disease (ESRD) in a subject with IgA nephropathy, the method comprising administering to the subject an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0029] Some embodiments provide a method for reducing proteinuria in a subject with IgA nephropathy, the method comprising administering to the subject an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0030] Some embodiments provide a method for reducing fatigue in a subject with IgA nephropathy, the method comprising administering to the subject an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0031] In some embodiments, the step of determining IgA immune complex deposition in the kidney of the subject occurs before the administration step. In some embodiments, the step of determining an elevated level of mesangial cell activation in the subject occurs before the administration step. In some embodiments, the step of determining an elevated level of IgA immune complexes in the kidney of the subject occurs before the administration step.

[0032] In some embodiments, the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is selected from the group consisting of tezosentan, spysentan, bosentan, sparsentan, macitentan, ambrisentan, sitaxentan, atriopeptine, atrasentan, and pharmaceutically acceptable salts of any of the foregoing, and combinations thereof.

[0033] In some embodiments, the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is sparsentan or a pharmaceutically acceptable salt thereof, and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0034] In some embodiments, the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, atrasentan is administered as a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt of atrasentan is atrasentan hydrochloride or atrasentan mandelate. In some embodiments, the pharmaceutically acceptable salt of atrasentan is atrasentan hydrochloride. In some embodiments, the pharmaceutically acceptable salt of atrasentan is atrasentan mandelate. In some embodiments, atrasentan is administered as a free base.

[0035] In some embodiments, the APRIL-binding antibody or an antigen-binding fragment thereof comprises:

[0036] Heavy chain complementarity-determining region-1 (HC CDR1), which comprises an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 1;

[0037] Heavy chain complementarity-determining region-2 (HC CDR2), which comprises an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 2;

[0038] Heavy chain complementarity-determining region-3 (HC CDR3), which comprises an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 3;

[0039] Light chain complementarity-determining region-1 (LC CDR1), which comprises an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 4;

[0040] Light chain complementarity-determining region-2 (LC CDR2), which comprises an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 5; and

[0041] Light chain complementarity-determining region-3 (LC CDR3), which comprises an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 6.

[0042] In some embodiments, the APRIL-binding antibody or an antigen-binding fragment thereof comprises:

[0043] Heavy chain complementarity-determining region-1 (HC CDR1), which comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 1;

[0044] Heavy chain complementarity-determining region-2 (HC CDR2), which comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 2;

[0045] Heavy chain complementarity-determining region-3 (HC CDR3), which comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 3;

[0046] Light chain complementarity-determining region-1 (LC CDR1), which comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 4;

[0047] Light chain complementarity-determining region-2 (LC CDR2), which comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 5; and

[0048] Light chain complementarity-determining region-3 (LC CDR3), which comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 6.

[0049] In some embodiments, the APRIL-binding antibody or an antigen-binding fragment thereof comprises:

[0050] Heavy chain complementarity-determining region-1 (HC CDR1), which comprises the amino acid sequence of SEQ ID NO:1;

[0051] Heavy chain complementarity-determining region-2 (HC CDR2), which comprises the amino acid sequence of SEQ ID NO:2;

[0052] Heavy chain complementarity-determining region-3 (HC CDR3), which comprises the amino acid sequence of SEQ ID NO:3;

[0053] Light chain complementarity-determining region-1 (LC CDR1), which comprises the amino acid sequence of SEQ ID NO:4;

[0054] Light chain complementarity-determining region-2 (LC CDR2), which comprises the amino acid sequence of SEQ ID NO:5; and

[0055] Light chain complementarity-determining region-3 (LC CDR3), which comprises the amino acid sequence of SEQ ID NO:6.

[0056] In some embodiments, the APRIL-binding antibody or an antigen-binding fragment thereof comprises a heavy chain variable region that comprises an amino acid sequence having at least 80% sequence identity with SEQ ID NO:8, 10, 12, 14, 16, 18, 20, 22 or 24.

[0057] In some embodiments, the APRIL-binding antibody or an antigen-binding fragment thereof comprises a heavy chain variable region that comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:8, 10, 12, 14, 16, 18, 20, 22 or 24.

[0058] In some embodiments, the APRIL-binding antibody or an antigen-binding fragment thereof comprises a heavy chain variable region that comprises the amino acid sequence of SEQ ID NO:8, 10, 12, 14, 16, 18, 20, 22 or 24.

[0059] In some embodiments, the APRIL-binding antibody or an antigen-binding fragment thereof comprises a light chain variable region that comprises an amino acid sequence having at least 80% sequence identity with SEQ ID NO:26.

[0060] In some embodiments, the APRIL-binding antibody or an antigen-binding fragment thereof comprises a light chain variable region that comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:26.

[0061] In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof comprises a light chain variable region that comprises the amino acid sequence of SEQ ID NO:26.

[0062] In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof comprises a heavy chain that comprises an amino acid sequence having at least 80% sequence identity with SEQ ID NO:28.

[0063] In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof comprises a heavy chain that comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:28.

[0064] In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof comprises a heavy chain that comprises the amino acid sequence of SEQ ID NO:28.

[0065] In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof comprises a light chain that comprises an amino acid sequence having at least 80% sequence identity with SEQ ID NO:30.

[0066] In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof comprises a light chain that comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:30.

[0067] In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof comprises a light chain that comprises the amino acid sequence of SEQ ID NO:30.

[0068] In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof comprises a heavy chain secretory leader sequence that comprises an amino acid sequence having at least 80% sequence identity with SEQ ID NO:32.

[0069] In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof comprises a heavy chain secretory leader sequence that comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:32.

[0070] In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof comprises a heavy chain secretory leader sequence that comprises the amino acid sequence of SEQ ID NO:32.

[0071] In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof comprises a light chain secretory leader sequence comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 34.

[0072] In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof comprises a light chain secretory leader sequence comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 34.

[0073] In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof comprises a light chain secretory leader sequence comprising the amino acid sequence of SEQ ID NO: 34.

[0074] In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof is generated from a nucleic acid comprising one of SEQ ID NO: 7, 9, 11, 13, 15, 17, 19, 21, or 23.

[0075] In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof is generated from a nucleic acid comprising SEQ ID NO: 25.

[0076] In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof is generated from a nucleic acid comprising SEQ ID NO: 27.

[0077] In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof is generated from a nucleic acid comprising SEQ ID NO: 29.

[0078] In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof is generated from a nucleic acid comprising SEQ ID NO: 31.

[0079] In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof is generated from a nucleic acid comprising SEQ ID NO: 33.

[0080] In some embodiments, the method comprises administering to a subject an amount of atrasentan or a pharmaceutically acceptable salt thereof equivalent to about 0.20 mg to about 1.50 mg of atrasentan free base. In some embodiments, the method comprises administering to a subject an amount of atrasentan hydrochloride equivalent to about 0.20 mg to about 1.50 mg of atrasentan free base.

[0081] In some embodiments, the method comprises administering to a subject an amount of atrasentan or a pharmaceutically acceptable salt thereof equivalent to about 0.25 mg to about 1.25 mg of atrasentan free base. In some embodiments, the method comprises administering to a subject an amount of atrasentan hydrochloride equivalent to about 0.25 mg to about 1.25 mg of atrasentan free base.

[0082] In some embodiments, the method comprises administering to a subject an amount of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof equivalent to about 0.40 mg to about 0.85 mg of atrasentan free base. In some embodiments, the method comprises administering to a subject an amount of atrasentan hydrochloride equivalent to about 0.40 mg to about 0.85 mg of atrasentan free base.

[0083] In some embodiments, the method comprises administering to a subject an amount of atrasentan or a pharmaceutically acceptable salt thereof equivalent to about 0.50 mg of atrasentan free base. In some embodiments, the method comprises administering to a subject an amount of atrasentan hydrochloride equivalent to about 0.50 mg of atrasentan free base.

[0084] In some embodiments, the method comprises administering to a subject an amount of atrasentan or a pharmaceutically acceptable salt thereof equivalent to about 0.75 mg of atrasentan free base. In some embodiments, the method comprises administering to a subject an amount of atrasentan hydrochloride equivalent to about 0.75 mg of atrasentan free base.

[0085] In some embodiments, the method comprises administering to a subject an amount of sparsentan or a pharmaceutically acceptable salt thereof equivalent to about 200 mg of sparsentan free base.

[0086] In some embodiments, the method comprises administering to a subject an amount of sparsentan or a pharmaceutically acceptable salt thereof equivalent to about 400 mg of sparsentan free base.

[0087] In some embodiments, the method comprises administering to a subject an amount of sparsentan or a pharmaceutically acceptable salt thereof equivalent to about 600 mg of sparsentan free base.

[0088] In some embodiments, the method comprises administering to a subject an amount of sparsentan or a pharmaceutically acceptable salt thereof equivalent to about 800 mg of sparsentan free base.

[0089] In some embodiments, the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is administered orally, buccally or parenterally. For example, the dosage forms for the oral route can be tablets, capsules, powders, pills, granules, suspensions, solutions and solution pre-concentrates, emulsions and emulsion pre-concentrates, and the dosage forms for the parenteral route can be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, transdermal, transmucosal administration.

[0090] In some embodiments, the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is administered once daily.

[0091] In some embodiments, the APRIL-binding antibody or an antigen-binding fragment thereof is administered by a parenteral route, such as intravenously, intraperitoneally, intradermally, subcutaneously, intramuscularly, intracranially, intrathecally, transdermal permeation, transmucosal administration.

[0092] In some embodiments, the APRIL-binding antibody or an antigen-binding fragment thereof is formulated as a solution, a lyophilized agent, or a powder for injection.

[0093] In some embodiments, the APRIL-binding antibody or an antigen-binding fragment thereof is administered once every 2, 3, 4, 5, 6, 7, 8, 9, or 10 days or once every 1, 2, or 3 weeks; alternatively, the APRIL-binding antibody or an antigen-binding fragment thereof can be administered once daily for five consecutive days per week followed by a two-day interval.

[0094] In some embodiments, about 0.05 mg / kg to about 8 mg / kg of the APRIL-binding antibody or an antigen-binding fragment thereof is administered to a subject.

[0095] In some embodiments, about 0.05 mg / kg to about 4 mg / kg of the APRIL-binding antibody or an antigen-binding fragment thereof is administered to a subject.

[0096] In some embodiments, about 2 mg / kg to about 6 mg / kg of the APRIL-binding antibody or an antigen-binding fragment thereof is administered to a subject.

[0097] In some embodiments, about 4 mg / kg to about 8 mg / kg of the APRIL-binding antibody or an antigen-binding fragment thereof is administered to a subject.

[0098] In some embodiments, about 0.05 mg / kg, about 0.1 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, or about 8 mg / kg of the APRIL-binding antibody or an antigen-binding fragment thereof is administered to a subject.

[0099] In some embodiments, the method includes repeating the administration of the APRIL-binding antibody or an antigen-binding fragment thereof in a regimen of at least once a week (QW) for at least 2 dosing cycles.

[0100] In some embodiments, the method includes repeating the administration of the APRIL-binding antibody or an antigen-binding fragment thereof in a regimen of at least once every two weeks (Q2W) for at least 2 dosing cycles.

[0101] In some embodiments, the method comprises repeating the administration of an APRIL-binding antibody or antigen-binding fragment thereof in a regimen of at least once every 4 weeks (Q4W) or once monthly (QMT) for at least 2 dosing cycles.

[0102] In some embodiments, each administration event administers a total dose of an APRIL-binding antibody or antigen-binding fragment thereof between about 10 mg and about 1350 mg of the APRIL-binding antibody or antigen-binding fragment thereof.

[0103] In some embodiments, each administration delivers a formulation of about 2 mL at a concentration of about 150 mg / mL of the APRIL-binding antibody or antigen-binding fragment thereof, and each administration event comprises one or more of said administrations.

[0104] In some embodiments, each administration delivers a formulation of about 4 mL at a concentration of about 150 mg / mL of the APRIL-binding antibody or antigen-binding fragment thereof, and each administration event comprises one or more of said administrations.

[0105] In some embodiments, the formulation of the APRIL-binding antibody or antigen-binding fragment thereof is administered subcutaneously into a site on the thigh, abdomen, or upper arm of an individual.

[0106] In some embodiments, the formulation of the APRIL-binding antibody or antigen-binding fragment thereof is administered intravenously.

[0107] In some embodiments, 15 mL of a formulation at a concentration of 20 mg / mL is added to 235 mL of 0.9% saline to provide an intravenous dose at a concentration of 1.2 mg / mL.

[0108] In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof is administered by a loading / maintenance dosing regimen. In some embodiments, the loading component of the loading / maintenance dosing regimen comprises administering the APRIL-binding antibody or antigen-binding fragment thereof one or more times at a concentration higher than the concentration of the APRIL-binding antibody or antigen-binding fragment thereof in the maintenance component of the loading / maintenance dosing regimen. In some embodiments, the loading component of the loading / maintenance dosing regimen comprises administering the APRIL-binding antibody or antigen-binding fragment thereof one or more times at a frequency higher than the frequency of administration of the APRIL-binding antibody or antigen-binding fragment thereof in the maintenance component of the loading / maintenance dosing regimen.

[0109] In some embodiments, it has been determined that the subject has controlled serum glucose levels.

[0110] In some embodiments, the subject is concurrently receiving an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), or a combination thereof.

[0111] In some embodiments, the ACE inhibitor is selected from the group consisting of quinapril, fosinopril, perindopril, captopril, enalapril, enalaprilat, ramipril, cilazapril, delapril, fosenpril, zofenopril, indolapril, benazepril, lisinopril, spirapril, trandolapril, borodipine, pentopril, moexipril, resinamyl, and pivopril.

[0112] In some embodiments, the ACE inhibitor is selected from the group consisting of quinapril, fosinopril, captopril, enalapril, and lisinopril.

[0113] In some embodiments, the ARB is selected from the group consisting of candesartan, candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan, olmesartan medoxomil, telmisartan, valsartan, azilsartan medoxomil, and BRA-657.

[0114] In some embodiments, the ARB is selected from the group consisting of candesartan, losartan, olmesartan, and valsartan.

[0115] In some embodiments, the method further comprises administering a therapeutically effective amount of an SGLT-2 inhibitor.

[0116] In some embodiments, the SGLT-2 inhibitor is selected from the group consisting of dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, bempagliflozin, luseogliflozin, galpagliflozin (XZP-5695), tofogliflozin, ertugliflozin, hengagliflozin (SHR-3824), inagliflozin (DWP-16001), TA-1887 (3-(4-cyclopropylbenzyl)-4-fluoro-1-(β-D-glucopyranosyl)-1H-indole), indole-N-glycoside 18 (3-(4-ethylbenzyl)-1-(β-D-glucopyranosyl)-1H-indole), sotagliflozin, luseogliflozin, sergliflozin etabonate, remogliflozin, remogliflozin etabonate, and T-1095 (((2R,3S,4S,5R,6S)-6-(2-(3-(benzofuran-5-yl)propanoyl)-3-hydroxy-5-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl) etabonate).

[0117] In some embodiments, the SGLT-2 inhibitor is selected from the group consisting of bempagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin, sergliflozin, sotagliflozin, and tofogliflozin.

[0118] In some embodiments, the SGLT-2 inhibitor is canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin.

[0119] In some embodiments, the administration combination comprises administering an APRIL-binding antibody or an antigen-binding fragment thereof and one or both of an endothelin receptor antagonist and an SGLT-2 inhibitor simultaneously, separately, or sequentially.

[0120] In some embodiments, the administration combination comprises administering an APRIL-binding antibody or an antigen-binding fragment thereof and an endothelin receptor antagonist by different administration routes.

[0121] In some embodiments, the APRIL-binding antibody or an antigen-binding fragment thereof is administered intravenously or subcutaneously, and the endothelin receptor antagonist is administered orally.

[0122] In some embodiments, the APRIL-binding antibody or an antigen-binding fragment thereof and the endothelin receptor antagonist are administered according to different dosing regimens.

[0123] In some embodiments, an SGLT-2 inhibitor and one or more ACE inhibitors and / or one or more ARBs are administered to a subject.

[0124] In some embodiments, an SGLT-2 inhibitor and one or more ACE inhibitors are administered to a subject.

[0125] In some embodiments, an SGLT-2 inhibitor and an ACE inhibitor are administered to a subject.

[0126] In some embodiments, an SGLT-2 inhibitor and one or more ARBs are administered to a subject.

[0127] In some embodiments, an SGLT-2 inhibitor and an ARB are administered to a subject.

[0128] In some embodiments, the SGLT-2 inhibitor is administered orally, buccally, or parenterally. In some embodiments, the dosage forms for the oral route are selected from the group consisting of tablets, capsules, powders, pills, granules, suspensions, solutions and solution pre-concentrates, emulsions and emulsion pre-concentrates. In some embodiments, the parenteral route is selected from the group consisting of intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, transdermal, transmucosal administration.

[0129] In some embodiments, prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject excretes an average of about 0.5 grams or more of protein in the urine per day.

[0130] In some embodiments, prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the subject excretes an average of about 1 gram or more of protein in the urine per day.

[0131] In some embodiments, prior to the first administration of atrasentan or a pharmaceutically acceptable salt thereof, the mean eGFR of the subject is at least about 30 mL / min / 1.73m 2 .

[0132] Some embodiments provide a kit comprising: an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, wherein the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and the APRIL-binding antibody or an antigen-binding fragment thereof can be in the same dosage form and / or in separate dosage forms. In some embodiments, the kit may further comprise an SGLT-2 inhibitor.

[0133] Some embodiments provide a kit comprising: an SGLT-2 inhibitor and an APRIL-binding antibody or an antigen-binding fragment thereof, wherein the SGLT-2 inhibitor and the APRIL-binding antibody or an antigen-binding fragment thereof can be in the same dosage form and / or in separate dosage forms.

[0134] All publications, patents, patent applications, and information available on the Internet mentioned in this specification are incorporated herein by reference to the extent as if each individual publication, patent, patent application, or information item were specifically and individually indicated to be incorporated by reference. If the publications, patents, patent applications, and information items incorporated by reference conflict with the disclosure contained in this specification, this specification is intended to supersede and / or take precedence over any such conflicting material.

[0135] Various embodiments of the features of the present disclosure are described herein. However, it should be understood that such embodiments are provided by way of example only, and that many variations, changes, and substitutions can be made by those skilled in the art without departing from the scope of the present disclosure. It should also be understood that various alternatives to the specific embodiments described herein are also within the scope of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0136] Figure 1 Shows the study protocol of a phase 3, randomized, double-blind, placebo-controlled study of BION-1301 in adults with IgA nephropathy. DETAILED DESCRIPTION

[0137] A. DEFINITIONS

[0138] To more readily understand the present disclosure, certain terms are first defined. As used in this application, unless otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the application.

[0139] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd Edition, 2002, CRC Press; Dictionary of Cell and Molecular Biology, 3rd Edition, 1999, Academic Press; and Oxford Dictionary Of Biochemistry And Molecular Biology, Revised Edition, 2000, Oxford University Press provide a general dictionary of many of the terms used in this disclosure. For the purposes of this disclosure, the following terms are defined.

[0140] Units, prefixes, and symbols are expressed in their accepted form of the International System of Units (Système International d'Unités) (SI). Numerical ranges include the numbers defining the range. The headings provided herein are not limitations of the different aspects of this disclosure, and these aspects can be obtained by referring to the specification as a whole. Thus, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

[0141] When referring to a number or numerical range, the term "about" means that the referenced number or numerical range is an approximation, e.g., within experimental variability and / or statistical experimental error, and thus the number or numerical range can vary by up to ±10% of the referenced number or numerical range.

[0142] "Treatment" or "therapy" of a subject refers to any type of intervention or process in which an active agent is administered to or performed on the subject, the goal of which is to reverse, alleviate, improve, inhibit, or slow the onset, progression, development, severity, or recurrence of symptoms, complications, conditions, or biochemical markers associated with a disease.

[0143] "Subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents (e.g., mice, rats, and guinea pigs). In some embodiments, the subject is a human. The terms "subject", "patient", and "individual" are used interchangeably herein.

[0144] The phrase "effective amount" or "therapeutically effective amount" means an amount of a compound which, when administered to a subject in need of such treatment, is sufficient to (i) treat the indicated disease or disorder, (ii) attenuate, mitigate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. When used to refer to treatment with more than one therapeutic agent, each agent may be administered independently at a therapeutically effective amount (e.g., an amount therapeutically effective as a monotherapy), or one or more therapeutic agents may together be a therapeutically effective amount (e.g., a therapeutically effective amount for a combination therapy) for treating the indicated disease or disorder. In other words, the amounts of the components in a therapeutically effective amount of a combination therapy may be independently administered at less than the therapeutically effective amount when administered as a monotherapy (in combination). A therapeutically effective amount of an agent typically reduces symptoms by at least 10%; usually at least 20%; preferably at least about 30%; more preferably at least 40%, and most preferably at least 50%.

[0145] The term "synergistic effect" or "synergistic" as used herein means that the action of the combination of two therapeutic agents in a combination therapy described herein is greater than the sum of the actions of each agent when administered alone (i.e., as a monotherapy).

[0146] Determination of the synergistic interaction between two combination formulations can ultimately be measured by administering to a subject in need of treatment combination formulations in different w / w (weight / weight) ratios and doses to determine the optimal range for the effect and the absolute dose range for each component for the effect. However, the synergistic effect observed in an in vitro model or in vivo model can predict the effect in humans and other species, and as described herein, there are in vitro models or in vivo models to measure the synergistic effect, and the results of such studies can also be used to predict the effective dose and plasma concentration ratio ranges, as well as the absolute dose and plasma concentration, required in humans and other species by applying pharmacokinetic / pharmacodynamic methods. Exemplary synergistic effects include, but are not limited to, enhanced therapeutic efficacy, reduced dose at an equal or increased efficacy level, decreased or delayed development of drug resistance, and simultaneous enhancement or equal therapeutic action of at least one therapeutic agent (e.g., having the same therapeutic effect as at least one therapeutic agent) and reduction of the undesired drug actions (e.g., side effects and adverse events) of at least one therapeutic agent.

[0147] As used herein, "inhibit" includes delaying the development of symptoms associated with a disease and / or reducing the severity of such symptoms that would or are expected to accompany the development of the disease. These terms further include ameliorating existing symptoms, preventing additional symptoms, and ameliorating or preventing the underlying cause of such symptoms. Accordingly, these terms indicate that a beneficial result has been conferred upon a vertebrate subject suffering from a disease.

[0148] In some embodiments, an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof exhibits a synergistic effect when administered together with an APRIL-binding antibody or an antigen-binding fragment thereof, as described herein. In some embodiments, an APRIL-binding antibody or an antigen-binding fragment thereof exhibits a synergistic effect when administered together with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof, as described herein.

[0149] As used herein, the term "endothelin receptor antagonist" refers to a compound that inhibits or blocks the binding of endothelin to an endothelin receptor. Endothelin (ET) is a potent vasoconstrictor peptide synthesized and released by vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2, and ET-3, of which only ET-1 and ET-3 are found to be expressed in mammalian systems (unless otherwise specified, "endothelin" as used herein shall mean any or all isoforms of endothelin). There are at least two major known endothelin receptors, ETA and ETB, both of which are G protein-coupled receptors that, upon activation, result in an increase in intracellular free calcium (Davenport (2002) Pharmacol. Rev. 54(2):219-26). Selective ETA receptor antagonists include sitaxentan (CAS No. 184036-34-8, and as described in Barst et al. (2004) American J. Resp. Crit. Care Med. 169(4):441-7); ambrisentan (CAS No. 177036-94-1, and as described in U.S. Patent Nos. 5,703,017, 5,932,730, and 7,109,205); atrasentan (CAS No. 173937-91-2, and as disclosed in U.S. Patent No. 5,767,144); BQ-123 (CAS No. 136553-81-6) and zibotentan (CAS No. 186497-07-4). Dual antagonists of ETA and ETB include bosentan (CAS No. 147536-97-8, and as described in Bien et al. (2007) Cancer Res. 67(21):10428-35), macitentan (CAS No. 441798-33-0), and tezosentan (CAS No. 180384-57-0).

[0150] Atracurium is a selective endothelin A (ETA) receptor antagonist (ETA Ki ~34 pM; ETB Ki ~63 nM, ETA selectivity ~1800x). See, e.g., Wu-Wong et al., Clin. Sci. (Lond.), 103(48), pp. 107s-111s (2002). Selective ETA receptor antagonists block ETA function while minimally affecting the ETB receptor, providing beneficial renal effects, including vasodilation and reduced inflammation, while still being able to clear ET-1. See, e.g., Jandeleit-Dahm and Watson, Curr. Opin. Nephrol. Hypertens., 21(1), pp. 66-71 (2012); see also, Nakamura et al., Nephron, vol. 72, pp. 454-460 (1996). Although ETA receptor antagonists increase renal sodium and water retention, this is typically clinically manageable. See, e.g., Saleh et al., J. Pharm. Exp. Ther., 338(1), pp. 263-270 (2011). Atracurium has been shown to be effective in patients with diabetic kidney disease (DKD), significantly reducing the risk of renal events defined as doubling of serum creatinine or end-stage kidney disease. See, e.g., Heerspink et al., The Lancet, 393, pp. 1937-1947 (2019).

[0151] Exemplary endothelin receptor antagonist formulations for use in the treatment of IgAN are described in PCT / US2020 / 065311, which is hereby incorporated by reference in its entirety.

[0152] The phrase "pharmaceutically acceptable" indicates a substance or composition that must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal being treated therewith.

[0153] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance that facilitates the administration of an active agent to a cell, organism, or subject. A "pharmaceutically acceptable carrier" refers to a carrier or excipient that can be included in the compositions of the present disclosure and that does not cause significant adverse toxicological effects to the subject. Non-limiting examples of pharmaceutically acceptable carriers include water, NaCl, saline solution, lactated Ringer's solution, physiological sucrose, physiological glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, and pigments, liposomes, dispersion media, microcapsules, cationic lipid carriers, isotonic agents, and absorption delaying agents, among others. The carrier can also be a substance for providing stability, sterility, and isotonicity to the formulation (e.g., antimicrobial preservatives, antioxidants, chelating agents, and buffers), a substance for preventing microbial action (e.g., antimicrobial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, etc.), or a substance for providing an edible flavoring agent, etc., to the formulation. In some cases, the carrier is an agent that promotes the delivery of small molecule drugs or antibodies to target cells or tissues. Those skilled in the art will recognize that other pharmaceutical carriers can be used in the present disclosure.

[0154] As used herein, the term "expression" refers to the level of a protein or mRNA in a mammalian cell.

[0155] As used herein, the term "activity" refers to one or more activities of a protein, such as binding activity or enzymatic activity (e.g., one or more of phosphorylation, dephosphorylation, nuclear import, transcriptional activation, transcriptional inhibition, and / or binding activity to a substrate or binding partner).

[0156] As used herein, the term "IL-6 signaling" refers to the expression and / or activity of one or more proteins in a signaling pathway that begins with the activation of the IL-6 receptor and ends with gene expression. Non-limiting examples of proteins in the signaling pathway that begins with the activation of the IL-6 receptor and ends with gene expression include IL-6 receptor, JAK, STAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, and ERK.

[0157] As used herein, the term "NF-kB signaling" refers to the expression and / or activity of one or more of IKKα, IKKβ, IkB, and NF-kB and / or one or more genes (e.g., one or more of TNF-α, IL-1, CAM, COX-2, and iNOS) upregulated by the activity of NF-kB.

[0158] As used herein, the term "PDGF signaling" refers to the expression and / or activity of one or more of PDGF receptor, PKC, PI3K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, and cPLA2.

[0159] As used herein, the term "SGLT-2 inhibitor" refers to a compound that inhibits sodium-glucose cotransporter-2 (SGLT-2). SGLT-2 inhibitors disrupt renal glucose reabsorption, thereby exerting an antihyperglycemic effect. By augmenting glycosuria (independent of insulin), SGLT-2 inhibitors have been shown to treat type 2 diabetes and improve cardiovascular outcomes. See Wright, 2001, Am. J. Physiol. Renal Physiol. 280:F10; and Scheen, 2018, Circ. Res. 122:1439. In some embodiments, the term "SGLT-2 inhibitor" refers to a compound whose primary action is to inhibit SGLT-2, but is not limited to compounds that only inhibit SGLT-2, and thus includes compounds that have other activities (e.g., inhibit SGLT-1) in addition to inhibiting SGLT-2.

[0160] In some embodiments, SGLT-2 inhibitors include compounds of a class of drugs called gliflozins. In some embodiments, SGLT-2 inhibitors include compounds that are approved by a regulatory agency (e.g., FDA or EMA) as SGLT-2 inhibitors. Non-limiting examples of SGLT-2 inhibitors include empagliflozin, canagliflozin dapagliflozin ertugliflozin ipragliflozin (STEGLATRO TM )、ipragliflozin luseogliflozin remogliflozin, sergliflozin, lisigliflozin, sotagliflozin (ZYNQUISTA TM ) and tofogliflozin.

[0161] In some embodiments, the SGLT-2 inhibitors include, but are not limited to, dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, bempagliflozin, luseogliflozin, jagragliflozin (XZP-5695), tofogliflozin, ertugliflozin, henggliflozin (SHR-3824), inagliflozin (DWP-16001), TA-1887 (3-(4-cyclopropylbenzyl)-4-fluoro-1-(β-D-glucopyranosyl)-1H-indole), indole-N-glycoside 18 (3-(4-ethylbenzyl)-1-(β-D-glucopyranosyl)-1H-indole), sotagliflozin, luseogliflozin, sergliflozin etabonate (ethyl carbonate), remogliflozin, remogliflozin etabonate, and T-1095 (((2R,3S,4S,5R,6S)-6-(2-(3-(benzofuran-5-yl)propanoyl)-3-hydroxy-5-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl) etabonate).

[0162] In some embodiments, the SGLT-2 inhibitors include C-glycosides, such as dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, bempagliflozin, luseogliflozin, jagragliflozin (XZP-5695), tofogliflozin, ertugliflozin, henggliflozin (SHR-3824), inagliflozin (DWP-16001). In some embodiments, the SGLT-2 inhibitors include C-glycosides having a bicyclic or spiro pyran group, such as tofogliflozin, ertugliflozin, and henggliflozin (SHR-3824). In some embodiments, the SGLT-2 inhibitors include C-glycosides not having a bicyclic or spiro pyran group, such as dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, bempagliflozin, luseogliflozin, jagragliflozin (XZP-5695), and inagliflozin (DWP-16001).

[0163] In some embodiments, the SGLT-2 inhibitors include N-glycosides, such as TA-1887 (3-(4-cyclopropylbenzyl)-4-fluoro-1-(β-D-glucopyranosyl)-1H-indole) and indole-N-glycoside 18 (3-(4-ethylbenzyl)-1-(β-D-glucopyranosyl)-1H-indole).

[0164] In some embodiments, the SGLT-2 inhibitors include 2-methylthio-C-glycosides, such as sotagliflozin.

[0165] In some embodiments, the SGLT-2 inhibitors include thiopyran-C-glycosides, such as luseogliflozin.

[0166] In some embodiments, the SGLT-2 inhibitors include O-glycosides and O-glycoside prodrugs, such as sergliflozin etabonate (ethyl carbonate), remogliflozin, remogliflozin etabonate, and T-1095 (((2R,3S,4S,5R,6S)-6-(2-(3-(benzofuran-5-yl)propanoyl)-3-hydroxy-5-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl) ethyl carbonate).

[0167] The SGLT-2 inhibitors include pharmaceutically acceptable salts, solvates, complexes, and salts of solvates thereof. For example, "dapagliflozin" includes salts of dapagliflozin (such as hydrochloride) and solvates (such as propylene glycol hydrate); similarly, "canagliflozin" includes solvates (such as canagliflozin hemihydrate) and salts of solvates (such as hydrochloride of the hydrate). Similarly, empagliflozin (SHR-3824) and dapagliflozin include complexes (such as empagliflozin proline complex and dapagliflozin proline complex, respectively).

[0168] In some embodiments, the SGLT-2 inhibitors as defined herein include any compound that exhibits SGLT-2 inhibitory activity. In some embodiments, the SGLT-2 inhibitor has a greater selectivity for SGLT-2 than for SGLT-1. For example, its activity against SGLT-2 is about 2-fold, about 5-fold, about 10-fold, about 20-fold, about 50-fold, about 100-fold, about 200-fold, about 300-fold, about 400-fold, about 500-fold, about 750-fold, about 1,000-fold, about 1,250-fold, about 1,500-fold, about 1,750-fold, about 2,000-fold, about 2,500-fold, or any value therebetween of its activity against SGLT-1. Exemplary SGLT-2 inhibitors may exhibit inhibitory activity (IC 50 ) against SGLT-2 that is less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM as measured in the assays described herein. In some embodiments, the SGLT-2 inhibitor may exhibit inhibitory activity (Icso) against SGLT-2 that is less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured in the assays provided herein. Exemplary assays for determining SGLT-2 inhibitory activity are described in Ryan, et al., Kidney International, Volume 45, pages 48-57 (1994). Briefly, CHO cells are stably transfected with cDNA encoding human SGLT-2 (GenBank accession number M95549). The cells are washed and then incubated with 10 μΜ 14C] α-methylglucopyranoside (AMG) was incubated with 10 μΜ inhibitor. 14 C] The uptake of AMG was quenched with cold buffer containing phlorizin, and the cells were lysed. Then, the uptake of AMG was quantified using appropriate reagents. 14 C] The uptake of AMG.

[0169] SGLT-2 inhibitors include their pharmaceutically acceptable salts, solvates, complexes, and salts of solvates. For example, "dapagliflozin" includes salts of dapagliflozin (such as hydrochloride) and solvates (such as propylene glycol hydrate); similarly, "canagliflozin" includes solvates (such as canagliflozin hemihydrate) and salts of solvates (such as hydrochloride of the hydrate). Similarly, empagliflozin (SHR-3824) and dapagliflozin include complexes (such as empagliflozin proline and dapagliflozin proline, respectively).

[0170] Exemplary SGLT-2 inhibitor formulations for use in the treatment of IgAN are described in PCT / US2008 / 057888, which is hereby incorporated by reference in its entirety.

[0171] As used herein, when a subject is described as having a "controlled serum glucose level", this means that the subject's serum glucose level is within the normal or healthy range. In some embodiments, the fasting serum glucose level of the subject is between about 70 mg / dL and about 130 mg / dL. For example, it has been determined that the fasting serum glucose level of the subject is less than about 130 mg / dL, 125 mg / dL, 120 mg / dL, 115 mg / dL, 110 mg / dL, 105 mg / dL, 100 mg / dL, 95 mg / dL, 90 mg / dL, 85 mg / dL, 80 mg / dL, or 75 mg / dL.

[0172] As used in the methods described herein, the term "decrease" refers to a decrease in the same parameter relative to one or more baseline measurements of the indicated parameter in a subject taken before the administration of the endothelin receptor antagonist or its pharmaceutically acceptable salt and the APRIL-binding antibody or its antigen-binding fragment, or relative to one or more baseline measurements of the indicated parameter in a healthy subject (e.g., a subject without IgA nephropathy). Similarly, the term "increase" as used herein refers to an increase in the same parameter relative to one or more baseline measurements of the indicated parameter in a subject taken before the administration of the endothelin receptor antagonist or its pharmaceutically acceptable salt and the APRIL-binding antibody or its antigen-binding fragment, or relative to one or more baseline measurements of the indicated parameter in a healthy subject (e.g., a subject without IgA nephropathy).

[0173] The term "glomerular filtration rate" (GFR) is defined as the volume of fluid filtered from the renal (kidney) glomerular capillaries into Bowman's capsule per unit time. It indicates overall kidney function. The glomerular filtration rate (GFR) can be calculated by measuring any chemical substance in the blood that has a stable level and is freely filtered but neither reabsorbed nor secreted by the kidneys. Thus, the measured rate is the amount of the substance in the urine that is derived from a calculable volume of blood. GFR is typically recorded in volume units / time (e.g., milliliters per minute) and can be calculated using the following formula: GFR = (urine concentration × urine volume) / plasma concentration. GFR can be determined by injecting inulin into the plasma. Since inulin is neither reabsorbed nor secreted by the kidneys after glomerular filtration, its excretion rate is directly proportional to the filtration rate of water and solutes through the glomerular filter. The normal value is: GFR = 90 - 125 mL / min / 1.73m 2 , particularly GFR = 100 - 125 mL / min / 1.73m 2Other principles for determining GFR include measuring 51Cr-EDTA, [125I] iothalamate, or iohexol. "Estimated glomerular filtration rate (eGFR)" is defined as that derived from serum creatinine values at the time of screening, which are based on, for example, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, the Cockcroft-Gault formula, or the Modification of Diet in Renal Disease (MDRD) formula, all of which are known in the art. As used herein, "stable eGFR" means a decreased rate of decline and / or a blunted rate of decline of eGFR. For example, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the rate of decline of eGFR can be blunted by at least about 20%; at least about 30%; at least about 40%; at least about 50%; at least about 60%; at least about 70%; at least about 80%; at least about 90%; or at least about 95%; or any value in between. This blunting can persist, for example, for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value in between after treatment. In some embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days. In some embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 6 months and about 1 year.

[0174] "ESRD" is an abbreviation for end-stage renal disease. As used herein, the onset of ESRD is defined as the time point when the subject's eGFR is below about 15 mL / min / 1.73 m 2 and / or when the subject has initiated chronic dialysis. When a subject is defined as "at high risk of progressing to ESRD", prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the protein in the subject's urine >1 g / day and / or eGFR <60 has persisted for at least about 3 months.

[0175] As used herein, "onset of IgA nephropathy-related disease" refers to the onset of a disease associated with worsening hematuria, proteinuria, systemic manifestations, and decline in eGFR. Other symptoms associated with the onset of the disease include increased edema, fatigue, increased hematuria, gross hematuria, and other symptoms that generally negatively impact disease progression.

[0176] As used herein, when a subject is described as having a "potassium level maintained within the normal physiological range", the subject's serum potassium level is from about 3.5 mEq / L to about 5.2 mEq / L.

[0177] As used herein, when a subject is described as having a "sodium level maintained within the normal physiological range", the subject's serum sodium level is from about 135 to about 145 mEq / L.

[0178] As used herein, the term "proteinuria" refers to the presence of protein in the urine in excess of normal levels. "Proteinuria" includes "albuminuria" and "microalbuminuria". Protein levels in the urine of a normal person occur in the range of about 0 to 30 mg / L, although for any given urine sample, this level can reach about 80 mg / L. For a 24-hour urine collection, the normal urine protein level in a person is in the range of about 0 to 150 mg. Proteinuria can be indicated by the ratio of total protein / creatinine in the urine (UPCR) or by the ratio of a specific protein (e.g., urine albumin / creatinine ratio (ACR) greater than about 30 mg / g). Typically, the urine UACR value in mg / g is approximately equal to the albumin excretion of the subject in mg / day. Proteinuria (including albuminuria and microalbuminuria) usually results in or indicates a disease, but is not limited to the development of a disease. Proteinuria is intended to cover all forms of proteinuria, including but not limited to physiological proteinuria; functional proteinuria; and exercise proteinuria, which is a form of functional proteinuria that occurs after excessive muscle exertion. Additionally, proteinuria covers benign proteinuria (also known as "primary" proteinuria), which refers to the type or proteinuria that is not caused by pathological changes in the kidney. Proteinuria also covers pathological proteinuria, such as when the protein level in the urine is greater than the normal physiological level.

[0179] As used herein, the term "albuminuria" (also known as "macroalbuminuria") refers to the presence of albumin in the urine in excess of normal levels. Since urinary protein is mainly albumin, the normal urine UACR level in a person is in the range of about 0 to 30 mg / mmol. As used herein, the term "microalbuminuria" refers to the presence of albumin in a person's urine excreted at a rate of about 20 to 200 μg / min or at a level of about 30 to 300 mg / L. When defined by urine ACR, "microalbuminuria" refers to a urine UACR greater than about 30 mg / g, or a urine UACR of about 3.5 mg / mmol or greater for females and about 2.5 mg / mmol or greater for males. Microalbuminuria is usually an early warning sign of kidney disease, but may also be present for other reasons.

[0180] As used herein, the term "hematuria" refers to the presence of blood in the urine. It may present as gross hematuria (visible traces of blood cells) or microscopic hematuria (traces of blood visible under the microscope) in the urine. The confirmation indication for microscopic hematuria is defined as the presence of 3 or more red blood cells per high power field (HPF) of the microscope on at least 3 correctly collected urine samples. Microscopic hematuria can also be clinically detected by urine dipsticks (colorimetric comparison estimate). Hematuria (microscopic or gross) may be asymptomatic (no additional symptoms associated with hematuria), or symptomatic. Additional symptoms include dysuria (painful urination), a feeling of incomplete bladder emptying or increased frequency of urination, or flank pain.

[0181] As used herein, "ALT" refers to alanine aminotransferase. As used herein, "AST" refers to aspartate aminotransferase.

[0182] Unless otherwise specified, any reference in this disclosure to the amount of an endothelin receptor antagonist is based on the free equivalent weight of the endothelin receptor antagonist. For example, 0.75 mg of atrasentan refers to 0.75 mg of atrasentan in free form or an equivalent amount of atrasentan in salt form.

[0183] This disclosure also includes combination therapies using anti-APRIL antibodies or antigen-binding fragments thereof. The antibodies described herein are exemplified using an anti-hAPRIL antibody (also known as VH14_1G.VL15, or also known as BION-1301 as used in clinical trials), the heavy chain of which has the amino acid sequence of SEQ ID NO:28 and the light chain of which has the amino acid sequence of SEQ ID NO:30. In some cases, the anti-APRIL antibody or antigen-binding fragment thereof is VIS649. In some cases, the anti-APRIL antibody or antigen-binding fragment thereof comprises the following: heavy chain complementarity determining region-1 (HC CDR1), which comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:1; heavy chain complementarity determining region-2 (HC CDR2), which comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:2; heavy chain complementarity determining region-3 (HC CDR3), which comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:3; light chain complementarity determining region-1 (LC CDR1), which comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:4; light chain complementarity determining region-2 (LC CDR2), which comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:5; and light chain complementarity determining region-3 (LC CDR3), which comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:6. In some cases, the heavy and light chain CDR sequences are 95% identical to SEQ ID NOs:1-6. In some cases, the heavy and light chain CDR sequences comprise SEQ ID NOs:1-6. In some cases, the heavy and light chain CDR sequences consist of SEQ ID NOs:1-6. In some cases, the APRIL-binding antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:8, 10, 12, 14, 16, 18, 20, 22, or 24. In some cases, the APRIL-binding antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises the amino acid sequence of SEQ ID NO:8, 10, 12, 14, 16, 18, 20, 22, or 24.

[0184] In some cases, the APRIL-binding antibody or an antigen-binding fragment thereof comprises a light chain variable region comprising an amino acid sequence having at least 90%, 95%, or 99% sequence identity to SEQ ID NO:26. In some cases, the APRIL-binding antibody or an antigen-binding fragment thereof comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:26. In some cases, the APRIL-binding antibody or an antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:8, 10, 12, 14, 16, 18, 20, 22, or 24 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:26. In some cases, the APRIL-binding antibody or an antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:24 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:26. In some cases, the APRIL-binding antibody or an antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO:28. In some cases, the APRIL-binding antibody or an antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:28. In some cases, the APRIL-binding antibody or an antigen-binding fragment thereof comprises a light chain comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO:30. In some cases, the APRIL-binding antibody or an antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence of SEQ ID NO:30. In some cases, the APRIL-binding antibody or an antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:28 and a light chain comprising the amino acid sequence of SEQ ID NO:30. In some cases, the APRIL-binding antibody or an antigen-binding fragment thereof comprises a heavy chain secretion leader sequence comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO:32. In some cases, the APRIL-binding antibody or an antigen-binding fragment thereof comprises a heavy chain secretion leader sequence comprising the amino acid sequence of SEQ ID NO:32. In some cases, the APRIL-binding antibody or an antigen-binding fragment thereof comprises a light chain secretion leader sequence comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO:34. In some cases, the APRIL-binding antibody or an antigen-binding fragment thereof comprises a light chain secretion leader sequence comprising the amino acid sequence of SEQ ID NO:34. In some cases, the APRIL-binding antibody or an antigen-binding fragment thereof is generated from a nucleic acid comprising one of SEQ ID NO:7, 9, 11, 13, 15, 17, 19, 21, or 23.In some cases, the APRIL-binding antibody or antigen-binding fragment thereof is generated from a nucleic acid comprising SEQ ID NO: 25, 27, 29, 31, or 33.

[0185] The antibody blocks the binding of human APRIL to human B cell maturation antigen (BCMA) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), and has been shown to significantly reduce IgA levels in healthy volunteers. This reduction in IgA levels is expected to be similar in subjects with IgA nephropathy and is thus expected to have significant therapeutic benefits. Additional features and discussion of antibodies useful in the formulations and methods described herein can be found in PCT Publication No. WO2016 / 110587.

[0186] The anti-APRIL antibody or antigen-binding fragment thereof may be referred to as “BION-1301”, which refers to an IgG4 humanized monoclonal antibody having a CAS Registry Number of 2642175-46-8. The disease-modifying potential of BION-1301 is mediated by blocking the binding of APRIL to its two major receptors, transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), and B cell maturation antigen (BCMA). Elevated APRIL levels are associated with the pathogenesis of IgA nephropathy. Thus, mAb-mediated APRIL neutralization to reduce receptor activation is a promising mechanism for treating IgA nephropathy. BION-1301 does not bind BAFF (required for normal B cell maintenance), in contrast to the approved APRIL antagonist atacicept, which binds APRIL and BAFF.

[0187] BION-1301 has been studied in adults with relapsed or refractory multiple myeloma, as well as in healthy volunteers (HV) and adults with IgAN. Since the initiation of the BION-1301 clinical program, as of July 26, 2022, a total of 153 adults have been enrolled in 5 clinical studies. Interim results from an ongoing Phase 1 / 2 clinical study evaluating IV administration of BION 1301 450 mg Q2W in patients with IgAN indicate that BION-1301 treatment was well tolerated and resulted in sustained decreases in free (unbound) APRIL, Gd-IgA1, and proteinuria (as measured by reduction in UPCR). After IV infusion, serum BION-1301 concentrations appeared comparable to those observed in healthy volunteers at the same dose and regimen. After at least 24 weeks of IV administration, all subjects who switched to SC dosing at 600 mg Q2W maintained similar BION-1301 exposure, biomarker response, and reduction in proteinuria. On average, patients treated with BION-1301 demonstrated a reduction in 24-hour UPCR, which was significant by 3 months and continued to decline over 1 year, providing preliminary clinical evidence of efficacy. The magnitude of proteinuria reduction observed is expected to translate into clinically meaningful preservation of eGFR and significantly improved long-term kidney outcomes.

[0188] Exemplary BION-1301 formulations for use in the treatment of IgAN are described in PCT / US2021 / 035011, which is hereby incorporated by reference in its entirety.

[0189] In the description of this disclosure, at least 90% sequence similarity should be understood to mean at least 95% in some cases, such as at least 99% sequence similarity.

[0190] As used herein, "sequence similarity" refers to the degree to which individual nucleotide or peptide sequences are similar. The degree of similarity between two sequences is based on a combination of the degree of identity and the degree of conservative changes. The percentage of "sequence similarity" is the percentage of identical amino acids or nucleotides or conservatively changed amino acids or nucleotides, i.e., "sequence similarity" = (sequence identity %) + (conservative change %).

[0191] For the purposes of this disclosure, "conservative changes" and "identity" are considered species of the broader term "similarity". Thus, whenever the term sequence "similarity" is used, it encompasses sequence "identity" and "conservative changes". According to certain embodiments, conservative changes are ignored, and the sequence similarity % refers to the sequence identity %.

[0192] The term "sequence identity" is known to those skilled in the art. To determine the degree of sequence identity shared by two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of the first amino acid sequence or nucleic acid sequence for optimal alignment with the second amino acid sequence or nucleic acid sequence). Such alignment can be carried out over the full length of the sequences being compared. Alternatively, the alignment can be carried out over a shorter comparison length, such as over about 20, about 50, about 100 or more nucleic acids / bases or amino acids.

[0193] The amino acid residues or nucleotides at the corresponding amino acid positions or nucleotide positions are then compared. When the position in the first sequence is occupied by the same amino acid residue or nucleotide as at the corresponding position in the second sequence, then the molecules are identical at that position. The degree of identity shared between the sequences is typically expressed as the percent identity between the two sequences and is a function of the number of identical positions shared by the identical residues in the sequences (i.e., % identity = number of identical residues at corresponding positions / total number of positions × 100). In some cases, the two sequences being compared have the same or substantially the same length.

[0194] The percentage of "conservative changes" can be determined similarly to the percentage of sequence identity. However, in this case, changes at specific positions in the amino acid or nucleotide sequence that may retain the functional properties of the original residue (as if no change had occurred) are scored.

[0195] For amino acid sequences, the relevant functional properties are the physicochemical properties of the amino acids. Conservative substitutions of amino acids in the polypeptides of the present disclosure can be selected from other members of the class to which the amino acid belongs. For example, it is well known in the field of protein biochemistry that, without significantly altering the activity of a protein, particularly in regions of the protein not directly related to biological activity, amino acids belonging to an amino acid grouping having a particular size or characteristic (such as charge, hydrophobicity, and hydrophilicity) can be replaced by another amino acid (see, e.g., Watson, et al., Molecular Biology of the Gene, The Benjamin / Cummings Pub. Co., page 224 (4th ed. 1987)). For example, nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and tyrosine. Polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine. Positively charged (basic) amino acids include arginine, lysine, and histidine. Negatively charged (acidic) amino acids include aspartic acid and glutamic acid. Conservative substitutions include, for example, Lys substitution for Arg and vice versa to maintain a positive charge; Glu substitution for Asp and vice versa to maintain a negative charge; Ser substitution for Thr and vice versa to maintain a free - OH; and Gln substitution for Asn and vice versa to maintain a free - NH2.

[0196] For nucleotide sequences, the relevant functional properties are primarily the biological information carried by certain nucleotides within the open reading frame of the sequence that is related to the transcription and / or translation machinery. It is well known that the genetic code is degenerate (or redundant), and in terms of the amino acids it encodes, multiple codons may carry the same information. For example, in certain species, the amino acid leucine is encoded by the codons UUA, UUG, CUU, CUC, CUA, CUG (or for DNA, TTA, TTG, CTT, CTC, CTA, CTG), and the amino acid serine is specified by UCA, UCG, UCC, UCU, AGU, AGC (or for DNA, TCA, TCG, TCC, TCT, AGT, AGC). Nucleotide changes that do not alter the translated information are considered conservative changes.

[0197] For the present disclosure, BLAST (Basic Local Alignment Search Tool) can be used to determine the percent identity and / or similarity between nucleotide or amino acid sequences. Queries using the BLASTn, BLASTp, BLASTx, tBLASTn, and tBLASTx programs of Altschul et al. (1990) can be issued via the online version of BLAST, which is accessible via http: / / www.ncbi.nlm.nih.gov. Alternatively, a stand-alone version of BLAST (e.g., version 2.2.29 (released on January 3, 2014)) can also be used, which can also be downloaded via the NCBI website. BLAST queries are performed using the following parameters. To determine the percent identity and / or similarity between amino acid sequences: algorithm: blastp; word size: 3; scoring matrix: BLOSUM62; gap penalties: existence: 11, extension: 1; compositional adjustment: conditional compositional score matrix adjustment; filter: off; masking: off. To determine the percent identity and / or similarity between nucleotide sequences: algorithm: blastn; word size: 11; maximum matches in query range: 0; match / mismatch scores: 2, -3; gap penalties: existence: 5, extension: 2; filter: low complexity regions; masking: masking only for lookup table.

[0198] With the indicated algorithms and computer programs, the percentage of "conservative changes" can be determined analogously to the percentage of sequence identity. Some computer programs, such as BLASTp, display the number / percentage of positives (= similarity) and the number / percentage of identity. The percentage of conservative changes can be derived by subtracting the percentage of identity from the percentage of positives / similarity (percent conservative change = percent similarity - percent identity).

[0199] According to a further aspect, the present disclosure relates to methods of using isolated polynucleotides encoding VH domains and / or VL domains of an encoded antibody according to the present disclosure, or the heavy and / or light chains of the antibody. The polynucleotide sequence encoding the VH domain is in some cases a polynucleotide sequence having at least 90% sequence similarity with a polynucleotide sequence selected from the group consisting of: SEQ ID NO:7, 9, 11, 13, 15, 17, 19, 21, and 23, in some cases SEQ ID NO:13, 15, or 23, and in some cases SEQ ID NO:23. The polynucleotide sequence encoding the VL domain is in some cases a polynucleotide sequence having at least 90% sequence similarity with the polynucleotide sequence of SEQ ID NO:25. The polynucleotide sequence encoding the heavy chain is in some cases a polynucleotide sequence having at least 90% sequence similarity with the polynucleotide sequence of SEQ ID NO:27. The polynucleotide sequence encoding the light chain is in some cases a polynucleotide sequence having at least 90% sequence similarity with the polynucleotide sequence of SEQ ID NO:29.

[0200] The invention further relates to an expression unit comprising a plurality of expression vectors, the expression vectors comprising a plurality of polynucleotides according to the present disclosure under the control of suitable regulatory sequences, wherein the plurality of polynucleotides encode VH domains or heavy chains and VL domains or light chains of an antibody according to the present disclosure. The expression unit can be designed such that the polynucleotide sequence encoding the VH domain or heavy chain and the polynucleotide sequence encoding the VL domain or light chain are on the same expression vector. Thus, the expression unit can comprise a single vector. Alternatively, the polynucleotide sequence encoding the VH domain or heavy chain and the polynucleotide sequence encoding the VL domain or light chain can be on different expression vectors.

[0201] A further aspect of the present disclosure relates to a host cell comprising a plurality of polynucleotides according to the present disclosure and / or an expression unit according to the present disclosure. The expression unit is in some cases an expression unit comprising an expression vector that comprises a polynucleotide sequence encoding a VH domain or heavy chain and a polynucleotide sequence encoding a VL domain or light chain.

[0202] A humanized APRIL - antagonistic monoclonal antibody (anti - APRIL antibody, as described herein) is under development for the treatment of IgAN and has been tested in clinical trials in healthy volunteers (see clinicaltrials.gov NCT03945318). Blocking APRIL with the anti - APRIL antibody has been shown to significantly reduce IgA and IgM in healthy cynomolgus monkeys and to a lesser extent IgG, and similar results have been shown in healthy human volunteers. In addition, this blocking reduces Gd - IgA1 in healthy human volunteers. Therefore, blocking APRIL in patients with IgAN is expected to result in reduced levels of IgA, IgG, and IgM, as well as a corresponding reduction in gd - IgA1, autoantibodies against gd - IgA1, immune complex deposition, and kidney damage.

[0203] Myette et al. (2019, Kidney International 96(1):104 - 116) demonstrated the efficacy of a murine anti - APRIL antibody in a murine IgA nephropathy model, and the human antibody VIS649 is part of a Phase 2 clinical trial (clinicaltrials.gov NCT04287985).

[0204] The term "antibody" refers to any form of antibody that exhibits the desired biological activity, such as inhibiting the binding of a ligand to its receptor or inhibiting ligand - induced receptor signaling. In the present context, the biological activity includes blocking the binding of APRIL to its receptors BCMA and / or TACI. Thus, "antibody" is used in the broadest sense and specifically encompasses, but is not limited to, monoclonal antibodies (including full - length monoclonal antibodies), and multispecific antibodies (e.g., bispecific antibodies) or antibody fragments based on, for example, technology (Genmab) or technology (Genmab).

[0205] "Antibody fragment" and "antibody-binding fragment" mean antigen-binding fragments and analogs of an antibody, typically including at least a portion of the antigen-binding region or variable region of the parent antibody (e.g., one or more CDRs). Antibody fragments retain at least some of the binding specificity of the parent antibody. Typically, when activity is expressed on a molar basis, antibody fragments retain at least 10% of the binding activity of the parent. In some cases, antibody fragments retain at least 20%, 50%, 70%, 80%, 90%, 95% or 100% or more of the binding affinity of the parent antibody for the target. Examples of antibody fragments include, but are not limited to, Fab, Fab′, F(ab′)2 and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules such as sc-Fv, single-chain monobodies (technology from Genmab); nanobodies (technology from Ablynx); domain antibodies (technology from Domantis); and multispecific antibodies formed from antibody fragments. Engineered antibody variants are reviewed in Holliger and Hudson, 2005, Nat. Biotechnol. 23:1126-1136.

[0206] A "Fab fragment" consists of a light chain and the CH1 and variable regions of a heavy chain. The heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule.

[0207] The "Fc" region contains two heavy chain fragments that include the CH1 and CH2 domains of the antibody. The two heavy chain fragments are held together by two or more disulfide bonds and by hydrophobic interactions of the CH3 domains.

[0208] A "Fab' fragment" contains a light chain and a portion of a heavy chain that contains the VH domain, the CH1 domain, and the region between the CH1 and CH2 domains such that an interchain disulfide bond can be formed between the two heavy chains of two Fab' fragments to form an F(ab')2 molecule.

[0209] An "F(ab’)2 fragment" contains two light chains and two heavy chains that contain a portion of the constant region between the CH1 and CH2 domains such that an interchain disulfide bond is formed between the two heavy chains. An F(ab’)2 fragment thus consists of two Fab' fragments held together by a disulfide bond between the two heavy chains.

[0210] The "Fv region" contains the variable regions from both the heavy and light chains but lacks the constant regions.

[0211] A "single-chain Fv antibody" (or "scFv antibody") refers to an antibody fragment that contains the VH and VL domains of an antibody, where these domains are present in a single polypeptide chain. Generally, the Fv polypeptide further contains a polypeptide linker between the VH and VL domains, and the polypeptide linker enables the scFv to form the desired structure for antigen binding. For a review of scFv, see Pluckthun, 1994, The Pharmacology of Monoclonal Antibodies, Volume 113, edited by Rosenberg and Moore, Springer-Verlag, New York, pp. 269-315. See also International Patent Application Publication No. WO 88 / 01649 and U.S. Patent Nos. 4,946,778 and 5,260,203.

[0212] A "diabody" is a small antibody fragment that has two antigen-binding sites. The fragment contains the heavy-chain variable domain (VH) linked to the light-chain variable domain (VL) in the same polypeptide chain (VH-VL or VL-VH). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domain on the other chain and generate two antigen-binding sites. Diabodies are more fully described, for example, in EP 404,097; WO 93 / 11161; and Holliger et al., 1993, Proc. Natl. Acad. Sci. USA 90:6444-6448.

[0213] "Duobodies" are bispecific antibodies that have a normal IgG structure (Labrijn et al., 2013, Proc. Natl. Acad. Sci. USA 110(13):5145-5150).

[0214] A "hexabody" is an antibody that has enhanced killing ability while retaining the conventional structure and specificity (Diebolder et al., 2014, Science 343(6176):1260-3).

[0215] A "domain antibody fragment" is an immunoglobulin fragment with immunological function that contains only the variable region of the heavy chain or the variable region of the light chain. In some cases, two or more VH regions are covalently linked with a peptide linker to generate a bivalent domain antibody fragment. The two VH regions of the bivalent domain antibody fragment can target the same or different antigens.

[0216] Antibody fragments of the present disclosure may comprise sufficient constant region portions to permit heavy chain dimerization (or multimerization) with reduced disulfide linking capabilities, such as where at least one of the hinge cysteines that are typically involved in inter-heavy chain disulfide linking is altered, as described herein. In another embodiment, an antibody fragment (e.g., an antibody fragment comprising an Fc region) retains at least one of the biological functions that are typically associated with the Fc region when present in a full antibody, such as FcRn binding, antibody half-life modulation, ADCC (antibody-dependent cell cytotoxicity) function, and / or complement binding (e.g., where the antibody has a glycosylation profile necessary for ADCC function or complement binding).

[0217] The term “chimeric” antibody refers to an antibody in which a portion of the heavy and / or light chain is identical or homologous to the corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical or homologous to the corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity. See, e.g., U.S. Patent No. 4,816,567 and Morrison et al., Proc. Natl. Acad. Sci. USA, Vol. 81, pp. 6851-6855 (1984).

[0218] As used herein, the term “humanized antibody” refers to an antibody form that contains sequences from non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies contain minimal sequences derived from non-human immunoglobulins. Typically, a humanized antibody will comprise substantially all of: at least one (typically two) variable domains, wherein all or substantially all of the hypervariable loops correspond to those of the non-human immunoglobulin, and all or substantially all of the FR regions are those of human immunoglobulin sequences. A humanized antibody optionally will also comprise an immunoglobulin constant region (Fc), typically at least a portion of a human immunoglobulin constant region. The humanized form of a rodent antibody substantially comprises the same CDR sequences as the parental rodent antibody, although certain amino acid substitutions may be included to increase affinity, increase the stability of the humanized antibody, or for other reasons.

[0219] The antibodies of the present disclosure also include antibodies having a modified (or blocked) Fc region to provide altered effector functions. See, e.g., U.S. Patent No. 5,624,821; PCT Publication Nos. WO 2003 / 086310, WO 2005 / 120571, and WO 2006 / 0057702; and Presta, Adv. Drug Delivery Rev. [Advanced Drug Delivery Reviews] Vol. 58, pp. 640-656 (2006). Such modifications can be used to enhance or inhibit various responses of the immune system and may have beneficial effects in diagnosis and therapy. Alterations of the Fc region include amino acid alterations (substitutions, deletions, and insertions), glycosylation or deglycosylation, and addition of multiple Fcs. Changes in the Fc also alter the antibody half-life in therapeutic antibodies, and a longer half-life will result in less frequent dosing, while increasing convenience and reducing the use of materials. See Presta, J. Allergy Clin. Immunol. [Journal of Allergy and Clinical Immunology] Vol. 116, No. 731, pp. 734-35 (2005).

[0220] The antibodies of the present disclosure also include antibodies having an intact Fc region that provides intact effector functions, such as antibodies of isotype IgG1, which induce complement-dependent cytotoxicity (CDC) or antibody-dependent cytotoxicity (ADCC) in target cells.

[0221] Antibodies can also be conjugated (e.g., covalently linked) to molecules that improve the stability of the antibody during storage or increase the half-life of the antibody in vivo. Examples of molecules that increase the half-life are albumin (e.g., human serum albumin) and polyethylene glycol (PEG). Albumin-conjugated and pegylated derivatives of antibodies can be prepared using techniques well known in the art. See, e.g., Chapman, 2002, Adv. Drug Deliv. Rev. [Advanced Drug Delivery Reviews] 54:531-545; Anderson and Tomasi, 1988, J. Immunol. Methods [Journal of Immunological Methods] 109:37-42; Suzuki et al., 1984, Biochim. Biophys. Acta [Biochimica et Biophysica Acta] 788:248-255; and Brekke and Sandlie, 2003, Nature Rev. [Nature Reviews] 2:52-62.

[0222] As used herein, the term "hypervariable region" refers to the amino acid residues of an antibody that are responsible for antigen binding. Hypervariable regions contain amino acid residues from "complementary determining regions" or "CDRs" as defined by sequence alignment, such as residues 24-34 (L1), 50-56 (L2), and 89-97 (L3) in the light chain variable domain and residues 31-35 (H1), 50-65 (H2), and 95-102 (H3) in the heavy chain variable domain (see Kabat et al., 1991, Sequences of proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD) and / or those residues from "hypervariable loops" (HVLs) as structurally defined, such as residues 26-32 (L1), 50-52 (L2), and 91-96 (L3) in the light chain variable domain and residues 26-32 (H1), 53-55 (H2), and 96-101 (H3) in the heavy chain variable domain (see Chothia and Lesk, 1987, J. Mol. Biol. 196:901-917).

[0223] "Framework" or "FR" residues or sequences are those variable domain residues or sequences other than the CDR residues as defined herein.

[0224] According to certain embodiments, an antibody of the present disclosure can be an isolated antibody. An "isolated" antibody is one that has been identified, separated, and / or recovered from the components of its natural environment. Contaminant components of its natural environment are materials that would interfere with the diagnostic or therapeutic use of the antibody and can include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, the antibody will be purified to (1) greater than 95% by weight, as determined by the Lowry method, and in some cases greater than 99% by weight, (2) to an extent sufficient to obtain at least 15 residues of the N-terminal or internal amino acid sequence by using a spinning cup sequencer, or (3) to homogeneity by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue or, in some cases, silver staining. Isolated antibodies include in situ antibodies within recombinant cells since at least one component of the antibody's natural environment will not be present. However, typically, isolated antibodies are prepared by at least one purification step.

[0225] A "separated" nucleic acid molecule is a nucleic acid molecule that has been identified and separated from at least one contaminating nucleic acid molecule that is normally associated with it in the natural source of the antibody nucleic acid. The separated nucleic acid molecule is different from its form or environment found in nature. Thus, the separated nucleic acid molecule is distinct from the nucleic acid molecules present in natural cells. However, the separated nucleic acid molecule includes the nucleic acid molecules contained in cells that normally express antibodies. For example, the nucleic acid molecule is located at a chromosomal position different from that of natural cells.

[0226] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., each antibody in the population is identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific for a single antigenic site. In addition, in contrast to conventional (polyclonal) antibody preparations that typically contain different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. The modifier "monoclonal" indicates the characteristic of an antibody obtained from a substantially homogeneous population of antibodies and should not be construed as requiring that the antibody be produced by any particular method. For example, monoclonal antibodies used according to the present disclosure can be prepared by the hybridoma method first described by Kohler et al. 1975 Nature 256:495, or can be prepared by recombinant DNA methods (see, e.g., U.S. Patent No. 4,816,567). For example, "monoclonal antibodies" can also be isolated from phage antibody libraries using the techniques described in Clackson et al. 1991 Nature 352:624-628 and Marks et al. 1991 J. Mol. Biol. 222:581-597. Monoclonal antibodies herein specifically include "chimeric" antibodies.

[0227] As used herein, the term "immune cell" includes cells of hematopoietic origin that play a role in the immune response. Immune cells include lymphocytes such as B cells and T cells, natural killer cells, and myeloid cells such as monocytes, macrophages, eosinophils, mast cells, basophils, and granulocytes.

[0228] As used herein, a sequence “variant” or “variant sequence” refers to a sequence that differs from the disclosed sequence at one or more amino acid residues but retains the biological activity of the parental molecule. This disclosure includes variants of antibodies specifically disclosed by the various sequences. For VH domain CDR1, CDR2, and CDR3 sequences, according to some embodiments, the variant sequence may contain up to 6 amino acid substitutions in total for the CDR1, CDR2, and CDR3 sequences, such as 1, 2, 3, 4, 5, or 6 amino acid substitutions. Similarly, for VL domain CDR1, CDR2, and CDR3 sequences, according to some embodiments, the variant sequence may contain up to 6 amino acid substitutions in total for the CDR1, CDR2, and CDR3 sequences, such as 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[0229] “Conservatively modified variants” or “conservative amino acid substitutions” refer to amino acid substitutions known to those of skill in the art and that can generally be made without altering the biological activity of the resulting molecule. Those of skill in the art recognize that, generally, a single amino acid substitution in a non-essential region of a polypeptide will substantially not alter biological activity (see, e.g., Watson et al., Molecular Biology of the Gene, The Benjamin / Cummings Pub. Co., page 224 (4th ed. 1987)).

[0230] When referring to a ligand / receptor, antibody / antigen, or other binding pair, “specifically binds” indicates a binding reaction that determines the presence of a protein (e.g., APRIL) in a heterogeneous protein population and / or other biological products. Thus, under specified conditions, a defined ligand / antigen binds to a specific receptor / antibody and does not significantly bind to other proteins present in the sample.

[0231] Antibody DNA can also be modified, for example, by replacing the homologous murine sequences with the coding sequences of human heavy and light chain constant domains (U.S. Patent No. 4,816,567; Morrison, et al., 1984, Proc. Natl. Acad. Sci. USA, 81:6851), or by covalently linking all or part of the coding sequence of a non-immunoglobulin substance (e.g., a protein domain) to the immunoglobulin coding sequence. Typically, such non-immunoglobulin substances replace the constant domain of the antibody or replace the variable domain of one antigen-binding site of the antibody to produce a chimeric bivalent antibody that contains one antigen-binding site specific for an antigen and another antigen-binding site specific for a different antigen.

[0232] The amino acid sequence variants of the anti-human APRIL antibody disclosed herein are prepared by introducing appropriate nucleotide changes into the encoding DNA or by peptide synthesis. Such variants include, for example, deletions and / or insertions and / or substitutions of residues in the amino acid sequence shown for the anti-APRIL antibody. Any combination of deletions, insertions, and substitutions can be made to obtain the final construct, provided that the final construct has the desired characteristics. Amino acid changes can also alter the post-translational processes of the anti-APRIL antibody, such as changing the number or location of glycosylation sites.

[0233] Generally, the amino acid sequence variants of the anti-APRIL antibody will have an amino acid sequence that has at least 75% amino acid sequence similarity to the original antibody amino acid sequence of the heavy or light chain, more in some cases at least 80%, more in some cases at least 85%, in some cases at least 90%, and in some cases at least 95%, 98%, or 99%. The similarity or homology of the sequence is as defined above.

[0234] Antibodies with the desired characteristics identified herein can be screened for improved in vitro biological activity or suitable binding affinity. To screen for antibodies that bind to the same epitope on human APRIL as hAPRIL.01A, conventional cross-blocking assays can be performed, such as the assays described in Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1988). Antibodies that bind to the same epitope are likely to cross-block in such assays, but not all cross-blocking antibodies necessarily bind to exactly the same epitope, as cross-blocking can be caused by steric hindrance of antibody binding through binding to overlapping epitopes or even adjacent non-overlapping epitopes.

[0235] Alternatively, epitope mapping can be performed (e.g., as described in Champe et al., 1995, J. Biol. Chem. 270:1388-1394) to determine whether an antibody binds to an epitope of interest. "Alanine-scanning mutagenesis" (as described by Cunningham and Wells, 1989, Science 244:1081-1085) or some other form of point mutagenesis of the amino acid residues in human APRIL can also be used to determine the functional epitopes of the anti-APRIL antibodies of the present disclosure. Another method of antibody epitope mapping is to study the binding of the antibody to synthetic linear peptides and CLIPS peptides, which can be screened using a credit card format mini-PEPSCAN card, as described by Slootstra et al. (Slootstra et al., 1996, Mol. Diversity 1:87-96) and Timmerman et al. (Timmerman et al., 2007, J. Mol. Recognit. 20:283-299). The binding of the antibody to each peptide is determined by a PEPSCAN-based enzyme-linked immunosorbent assay (ELISA).

[0236] Additional antibodies that bind the same epitope as hAPRIL.01A can be obtained, for example, by screening for the binding of antibodies raised against APRIL to the epitope, or by immunizing an animal with a peptide comprising a human APRIL fragment containing the epitope sequence. Antibodies that bind the same functional epitope would be expected to exhibit similar biological activities, such as similar APRIL binding and BCMA and TACI blocking activities, and these activities can be confirmed by functional assays of the antibody.

[0237] The antibody can be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA, and IgE. In some cases, the antibody is an IgG antibody. Any isotype of IgG can be used, including IgG1, IgG2, IgG3, and IgG4. Variants of the IgG isotypes are also contemplated. The antibody can comprise sequences from more than one class or isotype. By screening the antibody using bioassays known in the art or as described herein, it is readily achievable to optimize the constant region sequence required to generate the desired biological activity.

[0238] Likewise, either class of light chain can be used in the compositions and methods herein. Specifically, κ, λ, or variants thereof can be used in the compositions and methods of the invention.

[0239] The antibodies and antibody fragments of the present disclosure may also be conjugated to cytotoxic payloads such as cytotoxic agents or radio nucleotides, such as the radio nucleotides 99Tc, 90Y, 111In, 32P, 14C, 125I, 3H, 131I, 11C, 15O, 13N, 18F, 35S, 51Cr, 57To, 226Ra, 60Co, 59Fe, 57Se, 152Eu, 67Cu, 217Ci, 211At, 212Pb, 47Sc, 109Pd, 234 Th and 40K, 157Gd, 55Mn, 52Tr and 56Fe. Such antibody conjugates can be used in immunotherapy to selectively target and kill cells that express the target (the antigen of the antibody) on their surface. Exemplary cytotoxic agents include ricin, vinca alkaloids, methotrexate, Pseudomonas exotoxin, saporin, diphtheria toxin, cisplatin, doxorubicin, abrin, gelonin and pokeweed antiviral protein.

[0240] The antibodies and antibody fragments of the present disclosure may also be conjugated to: fluorescent or chemiluminescent labels, including fluorophores (such as rare earth chelates), fluorescein and its derivatives, rhodamine and its derivatives, isothiocyanates, phycoerythrin, phycocyanin, allophycocyanin, o-phthalaldehyde, fluorescamine, 152Eu, dansyl, umbelliferone, luciferin, luminallabel, isoluminallabel, aromatic acridinium ester label, imidazole label, acridinium salt label, oxalate label, aequorin label, 2,3-dihydrophthalazine dione, biotin / avidin, spin labels and stable free radicals.

[0241] Any method known in the art for conjugating the antibody molecules or protein molecules of the present disclosure to various moieties can be employed, including those described by the following references: Hunter et al., 1962, Nature 144:945; David et al. 1974, Biochemistry 13:1014; Pain et al. 1981, J. Immunol. Meth. 40:219; and Nygren, J., 1982, Histochem. And Cytochem. 30:407. Methods for conjugating antibodies and proteins are conventional and well known in the art.

[0242] The various aspects of the present disclosure are described in more detail in the following subsections.

[0243] B. Treatment methods

[0244] In normal healthy human kidneys, ET-1 and ET-RA are more strongly expressed in vascular tissue and less strongly in glomerular structures. In contrast, subjects with IgAN show increased expression of ET-1 and ET-RA in the kidney. In this population, ET-1 expression is positively correlated with proteinuria, which is at least partially improved by administration of an ACE inhibitor. Indeed, current therapies for IgAN are to optimize antihypertensive and antiproteinuric agents (e.g., angiotensin-converting enzyme inhibitors and / or angiotensin II receptor blockers) and corticosteroid regimens to inhibit disease progression. See, e.g., Penfold et al., Int. J. Nephrol. And Renovascular Dis. 11, pp. 137-148 (2017). However, the combination of these agents may exhibit significant dose-limiting side effects, such as hyperkalemia, and may require further immunosuppression in more severe cases.

[0245] Clinically, IgAN is diagnosed by renal biopsy, indicating the presence of mesangial cell proliferation and / or matrix expansion (or advanced focal segmental glomerulosclerosis), where immunofluorescence shows predominant mesangial granular deposition of IgA (2+ or more). This pathology is different from other progressive kidney diseases, such as diabetic nephropathy, which typically presents with diffuse capillary basement membrane thickening, with peripheral hyaline PAS-positive nodules, with advanced segmental or global glomerulosclerosis, and thickened arterioles with hyaline deposits. See, e.g., Zanatta, et al., Renal Failure, 34(3), pp. 308-315 (2012).

[0246] Accordingly, some embodiments provide a method of treating IgA nephropathy, the method comprising administering an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. In some embodiments, the administration of the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and the APRIL-binding antibody or an antigen-binding fragment thereof provides a synergistic effect, such as those described herein.

[0247] Some embodiments provide a combination therapy (an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof) for treating IgA nephropathy in a subject in need thereof.

[0248] In some cases, the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is selected from the group consisting of tezosentan, sparsentan, bosentan, spironolactone, macitentan, ambrisentan, sitaxentan, atrial natriuretic peptide, atrasentan, and a pharmaceutically acceptable salt of any of the foregoing, and combinations thereof. In some cases, the endothelin receptor is atrasentan or a pharmaceutically acceptable salt thereof. In some cases, the endothelin receptor is sparsentan or a pharmaceutically acceptable salt thereof.

[0249] Some embodiments provide a method of treating IgA nephropathy in a subject in need thereof, the method comprising administering to the subject atrasentan or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. Some embodiments provide a method of treating IgA nephropathy in a subject in need thereof, the method comprising administering to the subject sparsentan or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0250] Some embodiments provide a method of treating IgA nephropathy in a subject in need thereof, the method comprising administering to the subject atrasentan or a pharmaceutically acceptable salt thereof, and BION-1301. Some embodiments provide a method of treating IgA nephropathy in a subject in need thereof, the method comprising administering to the subject sparsentan or a pharmaceutically acceptable salt thereof, and BION-1301.

[0251] In some cases, the sequences shown in the sequence listing are related to the amino acid sequences and the coding DNA sequences of the VH and VL domains of an anti-APRIL antibody for use in the formulations and methods described herein, and the amino acid sequences and the coding DNA sequences of the heavy and light chains, including the amino acid sequences and the coding DNA sequences of the heavy and light chains of the antibodies described herein. In addition, the amino acid sequences of the CDRs of both the heavy and light chains of the antibodies described herein are presented. Table 1 below correlates the sequence IDs with their respective sequences.

[0252] Table 1: Sequences of anti-APRIL antibodies

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262] Anti - APRIL antibodies have been previously described in US Application Publication No. 2021 / 0379183.

[0263] Various dosing regimens can be employed as described below. In certain embodiments, the method comprises repeating infusions or subcutaneous administrations for multiple cycles (e.g., 4 weeks, 6 weeks, 8 weeks, etc.) on a once - weekly (“QW”) schedule. In other embodiments, the method comprises repeating infusions or subcutaneous administrations for multiple cycles (e.g., 4 weeks, 6 weeks, 8 weeks, etc.) on a schedule of at least every two weeks (as used herein, “biweekly” or “Q2W”). Alternatively, the method comprises repeating infusions or subcutaneous administrations for multiple cycles (e.g., 8 weeks, 12 weeks, 16 weeks, etc.) on a schedule of at least every 4 weeks (“Q4W”) or once a month (“QMT”). In certain embodiments, a pre - load dosing regimen is employed. When referring to the administration of an active agent, the term “pre - load” refers to an initial loading dose followed by a maintenance dose. The initial loading dose (single or multiple) is intended to more rapidly increase the serum concentration of the active agent in an animal or human patient to an effective target serum concentration. In various embodiments, the pre - load is achieved by delivering the initial dose over 3 weeks or less to bring the antibody to the target serum concentration. Preferably, the loading dose or series of doses is administered over 2 weeks or less, more preferably 1 week or less, e.g., 1 day or less. Most preferably, the loading dose is a single administration, with no maintenance dose required for at least one week thereafter, and the loading dose is administered within 1 day or less. To avoid adverse immune reactions to the antibody active agent, it may be preferred to administer the loading dose of the antibody by intravenous injection. This disclosure includes the loading dose and maintenance dose of the pre - load active agent delivered by intravenous or subcutaneous administration.

[0264] The administration of a loading dose can be, for example, one or more administrations at time intervals of at least about 1, 2, 3, 4, 5, 6, 7, or 8 weeks. In some embodiments, at least one loading dose is administered by one or more intravenous injections, and then at least one maintenance dose is administered by one or more intravenous or subcutaneous administrations. In other embodiments, the instructions can be used to administer at least one loading dose by, for example, one or more intravenous or subcutaneous administrations, and to administer at least one maintenance dose by one or more intravenous or subcutaneous administrations. In certain embodiments, at least one loading dose and at least one maintenance dose are administered subcutaneously. In other embodiments, at least one loading dose is administered by intravenous infusion, followed by subcutaneous administration of at least one maintenance dose. For example, the treatment method can include administering a loading dose of 150 - 1350 mg of an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., BION-1301) by intravenous infusion or subcutaneous injection. After the loading dose (e.g., 1 week, 2 weeks, 3 weeks, or 4 weeks after the loading dose), a maintenance dose of 600 mg or less of an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., BION-1301) can be administered by subcutaneous injection every 4 weeks or less, preferably every 3 weeks or less, more preferably every 2 weeks or less, and in embodiments every 1 week or less.

[0265] The loading dose of the active agent can be greater than the subsequent maintenance dose (e.g., about 1.5, 2, 3, 4, or 5 times greater than the subsequent maintenance dose). One or more therapeutically effective maintenance doses can be any therapeutically effective amount described herein. The loading dose can be about 2 or 3 times greater than the maintenance dose. The active agent can be administered in two (or more) loading doses before the maintenance dose. The first loading dose of the antibody or its fragment can be administered on day 1, the second loading dose can be administered, for example, about 1 or 2 weeks later, and the maintenance dose can be administered, for example, once a week or once every 2 weeks thereafter for the duration of the treatment. The first loading dose can be about 3 or 4 times greater than the maintenance dose, and the second loading dose can be about 2, 3, 4, 5, or more times greater than the maintenance dose.

[0266] In one instance, the loading dosing regimen includes administration by intravenous infusion or subcutaneous administration, repeated at least every two weeks for at least 4 weeks, followed by a maintenance dosing regimen that includes administration by intravenous infusion or subcutaneous administration, where the maintenance dosing regimen results in administration of a lesser amount of anti-APRIL antibody, either by including a lesser amount of anti-APRIL antibody per administration, or by administering at longer intervals than during the loading dosing regimen. In another instance, the loading dosing regimen includes administration by intravenous infusion or subcutaneous administration, repeated at least daily, and more preferably twice daily, for at least 4 days, followed by a maintenance dosing regimen that includes administration by intravenous infusion or subcutaneous administration, such as in a QW, Q2W, Q4W, QM, etc. regimen. In one embodiment, the loading dosing regimen includes administration of the antibody by intravenous infusion and the maintenance dosing regimen includes administration of the antibody by subcutaneous injection. In another embodiment, both the loading dosing regimen and the maintenance dosing regimen include administration of the antibody by subcutaneous injection. In another embodiment, both the loading dosing regimen and the maintenance dosing regimen include administration of the antibody by intravenous infusion. This is not an exhaustive list of dosing regimens.

[0267] By way of example only, subcutaneous injection of the method includes administering approximately 2 mL of the antibody formulation to a preferred injection site of the patient (e.g., thigh, abdomen, upper arm, etc.). In a preferred embodiment, the concentration of the anti-APRIL antibody in the formulation is approximately 150 mg / mL, resulting in administration of approximately 300 mg of anti-APRIL antibody in a single injection. In certain embodiments, subcutaneous injection of the method includes administering an antibody formulation of anti-APRIL antibody at a concentration of approximately 150 mg / mL at approximately 4 mL (as a single injection or as 2 x 2 mL injections), resulting in administration of approximately 600 mg of anti-APRIL antibody. The volume of administration and the number of injections required as part of a single administration can be adjusted as needed to achieve a total desired dose of anti-APRIL antibody between approximately 10 mg and approximately 1350 mg.

[0268] In certain other embodiments, intravenous infusion of the method includes: (a) diluting the formulation of the first aspect of the present disclosure and its examples in 0.9% saline to a concentration between approximately 0.1 mg / mL and approximately 10 mg / mL; and (b) administering to an individual a total dose of anti-APRIL antibody between approximately 10 mg and approximately 1350 mg as a single intravenous dose of the diluted formulation over a period of approximately 2 hours. Again, by way of example only, approximately 15 mL of a formulation with an anti-APRIL antibody concentration of approximately 20 mg / mL is added to approximately 235 mL of 0.9% saline to provide an intravenous dose with a concentration of approximately 1.2 mg / mL.

[0269] In certain embodiments, a method of administering an anti-APRIL antibody to an individual in need thereof comprises administering a formulation as described herein by a loading / maintenance administration regimen. Such a regimen may comprise a loading component of the regimen that includes: administering the anti-APRIL antibody one or more times at a concentration higher than the concentration of the anti-APRIL antibody in the maintenance component of the loading / maintenance administration regimen; administering the anti-APRIL antibody one or more times at a frequency higher than the frequency of administration of the anti-APRIL antibody in the maintenance component of the loading / maintenance administration regimen; and / or administering the anti-APRIL antibody one or more times by a route different from the route of administration of the anti-APRIL antibody in the maintenance component of the loading / maintenance administration regimen.

[0270] By way of example only, the loading component of the loading / maintenance administration regimen may include one or more intravenous administrations of the anti-APRIL antibody, and the maintenance component of the loading / maintenance administration regimen includes one or more subcutaneous administrations of the anti-APRIL antibody. In such examples, the concentration of the one or more loading administrations may be higher than the concentration used in the one or more maintenance administrations, and / or the frequency of administration may be greater than the frequency of administration used in the one or more maintenance administrations.

[0271] In another example, the loading component of the loading / maintenance administration regimen may include one or more subcutaneous administrations of the anti-APRIL antibody, and the maintenance component of the loading / maintenance administration regimen includes one or more intravenous administrations of the anti-APRIL antibody. In such examples, the concentration of the one or more loading administrations may be higher than the concentration used in the one or more maintenance administrations, and / or the frequency of administration may be greater than the frequency of administration used in the one or more maintenance administrations.

[0272] In another example, the loading component of the loading / maintenance administration regimen may include one or more subcutaneous administrations of the anti-APRIL antibody, and the maintenance component of the loading / maintenance administration regimen includes one or more subcutaneous administrations of the anti-APRIL antibody. In such examples, the concentration of the one or more loading administrations may be higher than the concentration used in the one or more maintenance administrations, and / or the frequency of administration may be greater than the frequency of administration used in the one or more maintenance administrations.

[0273] In one embodiment, the loading dose comprises an intravenous infusion of 150 to 1350 mg of an anti-APRIL antibody and at least one subsequent infusion of that amount at a first time interval, and the maintenance dose comprises administering i) a lower amount of the anti-APRIL antibody at the first time interval after the last loading dose infusion and at least one subsequent administration of that lower amount and at the same time interval for at least 12 weeks, ii) the same amount of the anti-APRIL antibody at a second time interval after the last loading dose infusion and at least one subsequent administration of that same amount and at the second time interval for at least 12 weeks, wherein the second time interval is longer than the first time interval, or iii) a lower amount of the anti-APRIL antibody at the second time interval after the last loading dose infusion and at least one subsequent administration of that same amount at the second time interval for at least 12 weeks, wherein the maintenance administration can be by intravenous infusion or by subcutaneous injection, preferably subcutaneous injection. In one embodiment, the loading dose comprises a subcutaneous infusion of 150 to 1350 mg of an anti-APRIL antibody and at least one subsequent subcutaneous infusion of that amount at a first time interval, and the maintenance dose comprises administering i) a lower amount of the anti-APRIL antibody at the first time interval after the last loading dose infusion and at least one subsequent administration of that lower amount and at the same time interval for at least 12 weeks, ii) the same amount of the anti-APRIL antibody at a second time interval after the last loading dose infusion and at least one subsequent administration of that same amount and at the second time interval for at least 12 weeks, wherein the second time interval is longer than the first time interval, or iii) a lower amount of the anti-APRIL antibody at the second time interval after the last loading dose infusion and at least one subsequent administration of that same amount at the second time interval for at least 12 weeks, wherein the maintenance administration can be by intravenous infusion or by subcutaneous injection.

[0274] In certain embodiments, it has been determined that the subject has a controlled serum glucose level. In some embodiments, a subject having a controlled serum glucose level is not receiving treatment for diabetes. In some embodiments, a subject having a controlled serum glucose level is receiving treatment for diabetes. In some embodiments, a subject having a controlled serum glucose level is not receiving treatment for type 2 diabetes. In some embodiments, a subject having a controlled serum glucose level is receiving treatment for type 2 diabetes. In some embodiments, it has been determined that the subject has a controlled serum glucose level. For example, it has been determined that the fasting serum glucose level of the subject is less than about 130 mg / dL, about 125 mg / dL, about 120 mg / dL, about 115 mg / dL, about 110 mg / dL, about 105 mg / dL, about 100 mg / dL, about 95 mg / dL, about 90 mg / dL, about 85 mg / dL, about 80 mg / dL, or about 75 mg / dL or any value therebetween.

[0275] In another aspect, the present disclosure provides a method for inhibiting mesangial cell activation in a subject having IgA nephropathy, the method comprising administering to the subject an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. In some instances, inhibition of mesangial cell activation comprises reducing mesangial cell inflammation and / or the activity of one or more biomarkers indicative of mesangial cell proliferation. Reducing mesangial cell inflammation comprises decreasing the expression and / or activity of one or more of IL6, MCP1, or other biomarkers indicative of mesangial cell inflammation. In some instances, inhibition of mesangial cell activation comprises reducing the profibrotic response in mesangial cells. In some instances, mesangial cell activation is induced by IgA immune complexes. In some instances, mesangial cell activation is associated with the presence of IgA immune complexes.

[0276] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks or any value therebetween), renal inflammation in a subject having IgA nephropathy is reduced by at least about 10%. In certain embodiments, renal inflammation in the subject is reduced by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% or any value therebetween. In certain of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days.

[0277] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks or any value therebetween), renal fibrosis in a subject with IgA nephropathy is reduced by at least about 10%. In certain embodiments, renal fibrosis in the subject is reduced by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% or any value therebetween. In some of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days.

[0278] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks or any value therebetween), renal fibrosis in a subject with IgA nephropathy is reduced to less than about 50% of the cortical area of one or both affected kidneys. In certain embodiments, renal fibrosis in the subject is reduced to less than about 40% of the cortical area. For example, in some embodiments, renal fibrosis in the subject is reduced to less than about 35%, about 30%, about 25%, about 20%, about 15%, or about 10% of the cortical area or any value therebetween. In some of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days.

[0279] In another aspect, provided herein is a method of reducing the occurrence of renal hematuria in a subject with IgA nephropathy, the method comprising administering an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, each as described herein.

[0280] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or any value therebetween), the number of urinary red blood cells / high power (microscopic) field (rbc / hpf) in a subject with IgA nephropathy is reduced by at least about 10%. In certain embodiments, the urinary rbc / hpf in the subject is reduced by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 95% or any value therebetween. In some of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days.

[0281] In another aspect, the present disclosure provides a method of stabilizing eGFR in a subject with IgA nephropathy, the method comprising administering an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0282] In some embodiments, provided herein is a method of reducing the rate of decline of eGFR in a subject with IgA nephropathy, the method comprising administering an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or any value therebetween), the rate of decline of eGFR in the subject is reduced by at least about 10%. In some embodiments, the rate of decline of eGFR in the subject is reduced by at least about 20%; at least about 30%; at least about 40%; at least about 50%; at least about 60%; at least about 70%; at least about 80%; at least about 90%; or at least about 95%; or any value therebetween. In certain of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days. In certain of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 6 months and about 1 year.

[0283] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the rate of decline of eGFR in a subject with IgA nephropathy is reduced to less than about 10 mL / min / 1.73m 2 . For example, after 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or any value therebetween. In certain embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 6 months and about 1 year, the rate of decline of eGFR in the subject is reduced to less than about 9 mL / min / 1.73m 2 , about 8 mL / min / 1.73m 2 , about 7 mL / min / 1.73m 2, approximately 6 mL / min / 1.73 m 2 , approximately 5 mL / min / 1.73 m 2 , approximately 4 mL / min / 1.73 m 2 , approximately 3 mL / min / 1.73 m 2 , approximately 2 mL / min / 1.73 m 2 , approximately 1 mL / min / 1.73 m 2 or approximately 0.75 mL / min / 1.73 m 2 or any value therebetween. For example, in subjects from about 20 to about 30 years of age, the typical decline in eGFR with age is about 1 mL / min / 1.73 m 2 / year.

[0284] On the other hand, provided herein is a method for reducing the number of disease flares associated with IgA nephropathy in a subject having IgA nephropathy, the method comprising administering to a subject in need thereof an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. In some embodiments, the method reduces disease flares associated with hematuria. In some embodiments, the method reduces disease flares associated with proteinuria. In some embodiments, the method reduces IgA nephropathy-associated disease flares associated with systemic manifestations. In some embodiments, the method reduces the decline in eGFR as described anywhere herein. In some embodiments, the method reduces one or more of edema, fatigue, hematuria, or gross hematuria. In some embodiments, the method has a positive effect on disease progression.

[0285] On the other hand, provided herein is a method for delaying the onset of ESRD in a subject having IgA nephropathy, the method comprising administering to a subject in need thereof an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0286] In some embodiments, the method increases the time between diagnosis of IgA nephropathy in the subject and the subject's eGFR dropping below 15 mL / min / 1.73 m 2 In certain embodiments, the method increases the time between diagnosis of IgA nephropathy in the subject and the subject's eGFR dropping below 15 mL / min / 1.73 m 2 by at least about 10%. For example, in some embodiments, the method increases the time between diagnosis of IgA nephropathy in the subject and the subject's eGFR dropping below 15 mL / min / 1.73 m 2The time between the times increases by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, or about 500% or any value therebetween.

[0287] In certain embodiments, the method diagnoses IgA nephropathy in a subject and reduces the subject's eGFR to below 15 mL / min / 1.73m 2 The time between the times increases by at least about 1 year. For example, the method can reduce the subject's eGFR to below 15 mL / min / 1.73m 2 The time is delayed by at least about 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, 5 years, 5.5 years, 6 years, 6.5 years, 7 years, 7.5 years, 8 years, 8.5 years, 9 years, 9.5 years, 10 years, 11 years, 12 years, 13 years, 15 years, 15 years, 16 years, 17 years, 18 years, 19 years, or 20 years.

[0288] In another aspect, provided herein is a method of reducing proteinuria in a subject having IgA nephropathy, the method comprising administering to a subject in need thereof an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0289] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks or any value therebetween), the amount of protein (e.g., albumin) in the urine of a subject having IgA nephropathy is reduced by at least about 10%. In some embodiments, the amount of protein in the urine of the subject is reduced by at least about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% or any value therebetween. In certain of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days.

[0290] In certain embodiments, between about 2 days and about 30 days after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the amount of protein (e.g., albumin) in the urine of a subject with IgA nephropathy is reduced by about 20% to about 80%. In certain embodiments, between about 15 days and about 30 days after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the amount of protein (e.g., albumin) in the urine of a subject with IgA nephropathy is reduced by about 20% to about 80%. In some of these embodiments, the amount of protein in the urine of the subject is reduced by about 25% to about 80%. In some of these embodiments, the amount of protein in the urine of the subject is reduced by about 30% to about 80%. In some of these embodiments, the amount of protein in the urine of the subject is reduced by about 35% to about 80%. In some of these embodiments, the amount of protein in the urine of the subject is reduced by about 40% to about 80%. In some of these embodiments, the amount of protein in the urine of the subject is reduced by about 45% to about 80%. In some of these embodiments, the amount of protein in the urine of the subject is reduced by about 50% to about 80%. In the foregoing embodiments, the reduction in the amount of protein (e.g., albumin) in the urine of a subject with IgA nephropathy is relative to the amount of protein (e.g., albumin) in the urine before starting treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0291] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween), the amount of protein (e.g., albumin) in the urine of a subject with IgA nephropathy is reduced by about 100 mg / dL to about 3,000 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 100 mg / dL to about 2,500 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 100 mg / dL to about 2,000 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 100 mg / dL to about 1,500 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 100 mg / dL to about 1,000 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 100 mg / dL to about 500 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 100 mg / dL to about 400 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 100 mg / dL to about 300 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 100 mg / dL to about 200 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 500 mg / dL to about 2,500 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 500 mg / dL to about 2,000 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 500 mg / dL to about 1,500 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 500 mg / dL to about 1,000 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 500 mg / dL to about 900 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 500 mg / dL to about 800 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 600 mg / dL to about 900 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 700 mg / dL to about 900 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 1,000 mg / dL to about 2,000 mg / dL.In some of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days. In the foregoing embodiments, the reduction in the amount of protein (e.g., albumin) in the urine of a subject with IgA nephropathy is relative to the amount of protein (e.g., albumin) in the urine prior to the initiation of treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0292] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days, the amount of protein (e.g., albumin) in the urine of a subject with IgA nephropathy is reduced by about 100 mg / dL to about 500 mg / dL. In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days, the amount of protein in the urine of the subject is reduced by about 200 mg / dL to about 500 mg / dL. In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days, the amount of protein in the urine of the subject is reduced by about 300 mg / dL to about 500 mg / dL. In the foregoing embodiments, the reduction in the amount of protein (e.g., albumin) in the urine of a subject with IgA nephropathy is relative to the amount of protein (e.g., albumin) in the urine prior to the initiation of treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0293] In certain embodiments, between about 15 days and about 30 days after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the amount of protein (e.g., albumin) in the urine of a subject with IgA nephropathy is reduced by about 500 mg / dL to about 900 mg / dL. In certain embodiments, between about 15 days and about 30 days after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the amount of protein in the urine of a subject is reduced by about 600 mg / dL to about 900 mg / dL. In certain embodiments, between about 15 days and about 30 days after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the amount of protein in the urine of a subject is reduced by about 700 mg / dL to about 900 mg / dL. In the foregoing embodiments, the reduction in the amount of protein (e.g., albumin) in the urine of a subject with IgA nephropathy is relative to the amount of protein (e.g., albumin) in the urine prior to initiation of treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0294] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, 50 weeks, 60 weeks, 70 weeks, 80 weeks, 90 weeks, 100 weeks, 110 weeks, 120 weeks, 130 weeks, 140 weeks, 150 weeks, 160 weeks, 170 weeks, 180 weeks, 190 weeks, or 200 weeks of treatment), the level of protein (e.g., albumin) in the urine of a subject with IgA nephropathy is reduced to less than about 1.0 gram per day. In certain embodiments, the level of protein in the urine of the subject is reduced to less than about 0.9 gram per day. In certain embodiments, the level of protein in the urine of the subject is reduced to less than about 0.8 gram per day. In certain embodiments, the level of protein in the urine of the subject is reduced to less than about 0.7 gram per day. In certain embodiments, the level of protein in the urine of the subject is reduced to less than about 0.6 gram per day. In certain embodiments, the level of protein in the urine of the subject is reduced to less than about 0.5 gram per day. In certain embodiments, the level of protein in the urine of the subject is reduced to less than about 0.4 gram per day. In certain embodiments, the level of protein in the urine of the subject is reduced to less than about 0.3 gram per day. In certain embodiments, the level of protein in the urine of the subject is reduced to less than about 0.2 gram per day. In some of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days. In the foregoing embodiments, the reduction in the amount of protein (e.g., albumin) in the urine of a subject with IgA nephropathy is relative to the amount of protein (e.g., albumin) in the urine prior to initiation of treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0295] In another aspect, provided herein is a method of reducing fatigue in a subject with IgA nephropathy, the method comprising administering to a subject in need thereof an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0296] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween), fatigue in subjects with IgA nephropathy is reduced by about 5% to about 80%. In certain embodiments, fatigue is reduced by about 10% to about 75%. In certain embodiments, fatigue is reduced by about 10% to about 70%. In certain embodiments, fatigue is reduced by about 10% to about 65%. In certain embodiments, fatigue is reduced by about 10% to about 60%. In certain embodiments, fatigue is reduced by about 10% to about 55%. In certain embodiments, fatigue is reduced by about 10% to about 50%. In certain embodiments, fatigue is reduced by about 10% to about 45%. In certain embodiments, fatigue is reduced by about 10% to about 40%. In certain embodiments, fatigue is reduced by about 10% to about 35%. In certain embodiments, fatigue is reduced by about 10% to about 30%. In certain embodiments, fatigue is reduced by about 10% to about 25%. In certain embodiments, fatigue is reduced by about 10% to about 20%. In certain embodiments, fatigue is reduced by about 10% to about 15%. In certain embodiments, fatigue is reduced by about 20% to about 75%. In certain embodiments, fatigue is reduced by about 20% to about 70%. In certain embodiments, fatigue is reduced by about 20% to about 65%. In certain embodiments, fatigue is reduced by about 20% to about 60%. In certain embodiments, fatigue is reduced by about 20% to about 55%. In certain embodiments, fatigue is reduced by about 20% to about 50%. In certain embodiments, fatigue is reduced by about 20% to about 45%. In certain embodiments, fatigue is reduced by about 20% to about 40%. In certain embodiments, fatigue is reduced by about 20% to about 35%. In certain embodiments, fatigue is reduced by about 20% to about 30%. In certain embodiments, fatigue is reduced by about 30% to about 75%. In certain embodiments, fatigue is reduced by about 30% to about 70%. In certain embodiments, fatigue is reduced by about 30% to about 65%. In certain embodiments, fatigue is reduced by about 30% to about 60%. In certain embodiments, fatigue is reduced by about 30% to about 55%. In certain embodiments, fatigue is reduced by about 30% to about 50%. In certain embodiments, fatigue is reduced by about 30% to about 45%. In certain embodiments, fatigue is reduced by about 30% to about 40%. In certain embodiments, fatigue is reduced by about 40% to about 75%. In certain embodiments, fatigue is reduced by about 40% to about 70%. In certain embodiments, fatigue is reduced by about 40% to about 65%.In certain embodiments, fatigue is reduced by about 40% to about 60%. In certain embodiments, fatigue is reduced by about 40% to about 55%. In certain embodiments, fatigue is reduced by about 40% to about 50%. In certain embodiments, fatigue is reduced by about 50% to about 75%. In certain embodiments, fatigue is reduced by about 50% to about 70%. In certain embodiments, fatigue is reduced by about 50% to about 65%. In certain embodiments, fatigue is reduced by about 50% to about 60%. In some of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days. In certain embodiments, the reduction in fatigue comprises a decrease in the score of one or more of the following: Fatigue Severity Scale, Chalder Fatigue Scale, FACIT Fatigue Scale, Brief Fatigue Inventory, FACT-F subscale, General Vitality and Impact, May and Kline Adjective Checklist, Pearson-Byars Fatigue Sensation Checklist, Rhoten Fatigue Scale, Fatigue and Weakness Schedule, Visual Analogue Scale, or Personal Fatigue Intensity Scale. In the foregoing embodiments, the reduction in fatigue experienced by a subject with IgA nephropathy is relative to the fatigue experienced by the subject prior to starting treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. In some embodiments, the reduction in fatigue comprises a decrease in the score on the Brief Fatigue Inventory.

[0297] Subject selection

[0298] One or more methods known in the art can be used to diagnose a subject with IgA nephropathy as described anywhere herein. Non-limiting examples include: kidney biopsy, detection of galactose-deficient IgA (e.g., Gd-IgA1), detection of antiglycan antibodies, detection of deposition of IgA immune complexes in the kidney, or a combination of any of the foregoing. In some embodiments, the diagnosis of IgA nephropathy comprises detection of deposition of IgA immune complexes in the kidney. In certain embodiments, the diagnosis of IgA nephropathy comprises kidney biopsy. In certain embodiments, the diagnosis of IgA nephropathy comprises detection of galactose-deficient IgA. In certain embodiments, the diagnosis of IgA nephropathy comprises detection of antiglycan antibodies (e.g., KM55). In certain embodiments, the diagnosis of IgA nephropathy comprises kidney biopsy followed by detection of deposition of IgA immune complexes in the kidney (e.g., by light microscopy and / or immunofluorescence microscopy).

[0299] In some embodiments, the presence and / or level of a specific protein in a subject is determined prior to administering an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. For example, the level of Gd-IgA1 in serum, the level of Gd-IgA1-specific autoantibodies in serum, and / or the level of IgA1-containing immune complexes in serum and / or urine. See, e.g., Knoppova, et al., Front. Immunol. [Frontiers in Immunology], Vol. 17, Article 117 (2016). In some embodiments, prior to administering an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the Gd-IgA level of the subject is at or above the 90th percentile. In some embodiments, prior to administering an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the Gd-IgA level of the subject is at or above the 95th percentile. In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for about 6 months to 1 year, the Gd-IgA level of the subject drops to below the 90th percentile.

[0300] In certain embodiments, the subject has mesangial cellularity in approximately ≥50% (e.g., approximately ≥60%, approximately ≥70%, or approximately ≥80%) of the glomeruli, where mesangial cellularity is defined as more than four mesangial cells in any mesangial region of the glomerulus. In certain embodiments, there is intraglomerular hypercellularity in the subject, where intraglomerular hypercellularity is defined as hypercellularity resulting from an increased number of cells in the glomerular capillary lumen. In certain embodiments, there is segmental sclerosis in the subject, where segmental sclerosis is defined as adhesion or sclerosis (occlusion of the capillary lumen by matrix) of part but not the entire glomerular tuft. In certain embodiments, the subject has tubulointerstitial atrophy / fibrosis in approximately ≥50% (e.g., approximately ≥60%, approximately ≥65%, approximately ≥70%, approximately ≥75%, or approximately ≥80%) of the cortical area, where tubulointerstitial atrophy / fibrosis is defined as the estimated percentage of the cortical area showing tubulointerstitial atrophy or fibrosis. In certain embodiments, there are crescents on the glomeruli of the subject. In some of these embodiments, the subject has crescents on less than approximately 25% (e.g., less than approximately 20%, approximately 15%, approximately 10%, or approximately 5%) of the glomeruli. In certain embodiments, according to the Oxford MEST-C classification system, the subject's MEST-C score is M1; E1; S1; T1 or T2; and / or C0 or C1. The Oxford MEST-C classification system is defined in: Kidney International (2009) 76,546–556 and Nature Reviews Nephrology (2017) 13,385-386 (see also: Kidney Research and Clinical Practice (2016) 35,197-203; and IgA Nephropathy in Medscape (accessed November 4, 2019)).

[0301] In some embodiments, the subject is at high risk of progressing to ESRD. In some of these embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the subject excretes an average of approximately 1 gram or more of protein in the urine per day for at least approximately 3 months. In certain embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the subject has an average eGFR ≤60 mL / min / 1.73m 2(e.g., about ≤55, about ≤50, about ≤45, about ≤40, about ≤35) for at least about 3 months. In some of these embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the subject has an eGFR > 30 mL / min / 1.73m 2 .

[0302] In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the subject excretes an average of about 1 gram or more of protein in the urine per day for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years). For example, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the subject excretes an average of about 1.1 grams, 1.2 grams, 1.3 grams, 1.4 grams, 1.5 grams, 1.6 grams, 1.7 grams, 1.8 grams, 1.9 grams, 2.0 grams, 2.1 grams, 2.2 grams, 2.3 grams, 2.4 grams, 2.5 grams, 2.6 grams, 2.7 grams, 2.8 grams, 2.9 grams, 3.0 grams, 3.1 grams, 3.2 grams, 3.3 grams, 3.4 grams, 3.5 grams, 5 grams, or 7.5 grams, or 10 grams, or any value therebetween of protein in the urine per day for at least about 3 months.

[0303] In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the subject excretes an average of about 0.3 grams to about 2 grams of protein in the urine per day for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years). For example, the subject can excrete about 0.3 grams to 0.5 grams, 0.5 grams to 1 gram, about 0.5 grams to 1.5 grams, about 1 gram to 1.5 grams, or about 1.5 grams to 2 grams of protein in the urine per day for at least 3 months.

[0304] In some embodiments, for at least two out of three consecutive measurements, a subject excretes at least about 1 gram of protein in the urine per day for one year prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. For example, for at least two out of three consecutive measurements, a subject excretes about 1.1 grams, 1.2 grams, 1.3 grams, 1.4 grams, 1.5 grams, 1.6 grams, 1.7 grams, 1.8 grams, 1.9 grams, 2.0 grams, 2.1 grams, 2.2 grams, 2.3 grams, 2.4 grams, 2.5 grams, 2.6 grams, 2.7 grams, 2.8 grams, 2.9 grams, 3.0 grams, 3.1 grams, 3.2 grams, 3.3 grams, 3.4 grams, 3.5 grams, 5 grams, or 7.5 grams, or 10 grams of protein in the urine per day for one year prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, or any value therebetween.

[0305] In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the UACR value of the subject is at least about 300 mg / g, for example, from 300 mg / g to about 5,000 mg / g for at least three months. In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the UACR value of the subject is about 800 mg / g, for example, from 800 mg / g to about 5,000 mg / g for at least three months. In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the UACR value of the subject is at least about 500 mg / g, about 600 mg / g, about 700 mg / g, about 800 mg / g, about 900 mg / g, about 1,000 mg / g, about 1,500 mg / g, about 2,000 mg / g, about 2,500 mg / g, about 3,000 mg / g, about 3,500 mg / g, about 4,000 mg / g, about 4,500 mg / g or about 5,000 mg / g or any value therebetween for at least three months.

[0306] In some embodiments, the UACR value of the subject is reduced by at least about 30% relative to the average UACR value of the subject for at least three months prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. For example, the UACR value of the subject is reduced by about 30% to about 100% relative to the average UACR value of the subject for at least three months prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. In some embodiments, the UACR value of the subject is reduced by at least about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% or any value therebetween relative to the average UACR value of the subject for at least three months prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. In some embodiments, the subject with a reduced UACR value also does not experience significant sodium retention and / or significant fluid retention. In some embodiments, the significant fluid retention can be about 1 kg to about 4 kg within 6 weeks. For example, about 4 kg, about 3.5 kg, about 3 kg, about 2.5 kg, about 2 kg, about 1.5 kg, or about 1 kg or any value therebetween within six weeks. In some embodiments, the subject with significant fluid retention exhibits clinical symptoms of edema.

[0307] In certain embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the average eGFR of the subject is about 20 to about 90 mL / min / 1.73m 2 for at least about 3 months (e.g., about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 1.5 years, or about 2 years). For example, about 20 to about 50 mL / min / 1.73m 2 ; about 30 to about 60 mL / min / 1.73m 2 ; about 40 to about 70 mL / min / 1.73m 2 ; about 50 to about 80 mL / min / 1.73m 2 ; or about 60 to about 90 mL / min / 1.73m 2 for at least about 3 months. In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the average eGFR of the subject is ≤ 60 mL / min / 1.73m 2Last for at least about 3 months. In certain embodiments, the average eGFR of the subject is ≤55 mL / min / 1.73m 2 and last for at least about 3 months. In certain embodiments, the average eGFR of the subject is ≤50 mL / min / 1.73m 2 and last for at least about 3 months. In certain embodiments, the average eGFR of the subject is ≤45 mL / min / 1.73m 2 and last for at least about 3 months. In certain embodiments, the average eGFR of the subject is ≤40 mL / min / 1.73m 2 and last for at least about 3 months. In certain embodiments, the average eGFR of the subject is ≤35 mL / min / 1.73m 2 and last for at least about 3 months. In certain embodiments, the average eGFR of the subject is ≤25 mL / min / 1.73m 2 and last for at least about 3 months. In certain embodiments, the average eGFR of the subject is ≤20 mL / min / 1.73m 2 and last for at least about 3 months. In some of the foregoing embodiments, prior to administering an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the average eGFR of the subject is about 30 mL / min / 1.73m 2 and about 60 mL / min / 1.73m 2 for at least 3 months. For example, the average eGFR of the subject can be between about 30 mL / min / 1.73m 2 and about 55 mL / min / 1.73m 2 between, between about 30 mL / min / 1.73m 2 and about 50 mL / min / 1.73m 2 between, between about 30 mL / min / 1.73m 2 and about 45 mL / min / 1.73m 2 between, or between about 30 mL / min / 1.73m 2 and about 40 mL / min / 1.73m 2 between.

[0308] In certain embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the average eGFR of the subject is about 30 mL / min / 1.73m 2 to about 45 mL / min / 1.73m 2, for example, about ≤45, about ≤40, about ≤35, or about ≤30 for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years). In some embodiments, before the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the mean eGFR of the subject is about 25 mL / min / 1.73m 2 to about 75 mL / min / 1.73m 2 for at least about 3 months. For example, before the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, it is about 25 mL / min / 1.73m 2 , about 30 mL / min / 1.73m 2 , about 35 mL / min / 1.73m 2 , about 40 mL / min / 1.73m 2 , about 45 mL / min / 1.73m 2 , about 50 mL / min / 1.73m 2 , about 55 mL / min / 1.73m 2 , about 60 mL / min / 1.73m 2 , about 65 mL / min / 1.73m 2 , about 70 mL / min / 1.73m 2 , about 75 mL / min / 1.73m 2 or any value therebetween for at least about 3 months.

[0309] In some embodiments, before the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the mean HbA1c of the subject is about 4% to about 6% for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years). For example, the mean HbA1c of the subject can be about 4.2%, about 4.4%, about 4.6%, about 4.8%, about 5.0%, about 5.2%, about 5.4%, about 5.6%, about 5.8%, or about 6% or any value therebetween.

[0310] In some embodiments, before the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the mean fasting blood glucose level of the subject is about 125 mg / dL or lower for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years). For example, the mean fasting blood glucose level of the subject can be about 120 mg / dL, about 115 mg / dL, about 110 mg / dL, about 105 mg / dL, about 100 mg / dL, about 95 mg / dL, about 90 mg / dL, about 85 mg / dL, about 80 mg / dL, or about 75 mg / dL or any value therebetween.

[0311] In some embodiments, the potassium level of the subject is maintained within the normal physiological range. In certain embodiments, before the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the potassium level of the subject is maintained within the normal physiological range for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years). In certain embodiments, the potassium level of the subject is maintained within 3.5 to 5.2 mEq / L. For example, the mean potassium level of the subject is maintained at about 3.5 mEq / L, about 3.6 mEq / L, about 3.7 mEq / L, about 3.8 mEq / L, about 3.9 mEq / L, about 4.0 mEq / L, about 4.1 mEq / L, about 4.2 mEq / L, about 4.3 mEq / L, about 4.4 mEq / L, about 4.5 mEq / L, about 4.6 mEq / L, about 4.7 mEq / L, about 4.8 mEq / L, about 4.9 mEq / L, about 5.0 mEq / L, about 5.1 mEq / L, or about 5.2 mEq / L or any value therebetween.

[0312] In some embodiments, the sodium level of the subject is maintained within the normal physiological range. In certain embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the potassium level of the subject is maintained within the normal physiological range for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years, or at least about 2 years). In certain embodiments, the sodium level of the subject is maintained within 135 to 145 mEq / L. For example, the average sodium level of the subject is maintained at about 135 mEq / L, about 136 mEq / L, about 137 mEq / L, about 138 mEq / L, about 139 mEq / L, about 140 mEq / L, about 141 mEq / L, about 142 mEq / L, about 143 mEq / L, about 144 mEq / L, or about 145 mEq / L or any value therebetween.

[0313] In some embodiments, the ALT / AST level of the subject during the administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof is substantially the same as the ALT / AST level prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. For example, the ALT / AST level of the subject during the administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof is within about 25%, about 20%, about 15%, about 10%, about 5%, or about 2.5% or any value therebetween of the level prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0314] In some embodiments, the bilirubin level of the subject during the administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof is substantially the same as the bilirubin level prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. For example, the bilirubin level of the subject during the administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof is within about 25%, about 20%, about 15%, about 10%, about 5%, or about 2.5% or any value therebetween of the level prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0315] In some embodiments, fluid retention in a subject can be managed with a diuretic (e.g., during and / or prior to administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof). For example, fluid retention can be less than about 3 kilograms (kg) of weight gain within 6 weeks. In some embodiments, fluid retention is less than about 4 kg, about 3.5 kg, about 3 kg, about 2.5 kg, about 2 kg, about 1.5 kg, or about 1 kg or any value therebetween within 6 weeks.

[0316] In some embodiments, prior to, substantially simultaneously with, or following administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof as described herein, a subject undergoes surgery and / or another protocol. In some embodiments, prior to, substantially simultaneously with, or following administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof as described herein, a subject receives other chemotherapeutic and / or biotherapeutic agents.

[0317] In some embodiments, prior to first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, a subject has received one or more renin-angiotensin system inhibitors for at least about 60 weeks. For example, in some embodiments, prior to first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, a subject has received one or more renin-angiotensin system inhibitors for at least about 12 weeks, about 24 weeks, about 48 weeks, or about 60 weeks or any value therebetween.

[0318] In some embodiments, the subject has been receiving a maximum tolerated stable dose of one or more renin-angiotensin system inhibitors. For example, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the subject may have been receiving a maximum tolerated stable dose of one or more renin-angiotensin system inhibitors for at least about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 25 weeks, about 30 weeks, about 35 weeks, about 40 weeks, about 45 weeks, or about 50 weeks or any value therebetween. In some embodiments, the one or more renin-angiotensin system inhibitors are selected from the group consisting of: angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), renin inhibitors, and aldosterone antagonists. For example, the one or more renin-angiotensin system inhibitors can be an ACE inhibitor, an ARB, or a combination thereof, wherein the ACE inhibitor or ARB can be described anywhere herein. For example, the ACE inhibitor can be selected from the group consisting of: quinapril, fosinopril, perindopril, captopril, enalapril, enalaprilat, ramipril, cilazapril, delapril, fosampril, zofenopril, indolapril, benazepril, lisinopril, spirapril, trandolapril, perindopril, pentopril, moexipril, resinamyl, and pivopril. For example, the ARB can be selected from the group consisting of: candesartan, candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan, olmesartan medoxomil, telmisartan, valsartan, azilsartan medoxomil, and BRA-657.

[0319] In some embodiments, the subject is also receiving one or more additional agents. In some embodiments, the one or more additional agents are selected from the group consisting of: calcineurin inhibitors, proteasome inhibitors, aminoquinolines, complement inhibitors, B-cell inhibitors, cytotoxic agents, mTOR inhibitors, and steroids. In some embodiments, the dose of one or more additional agents is reduced between about 15 days and about 30 days after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. In some embodiments, the one or more additional agents are immunosuppressive agents.

[0320] In some embodiments, the subject is not currently receiving one or more additional agents. In certain embodiments, the subject has not used one or more additional agents for two or more weeks within 6 months prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0321] In some embodiments, the one or more additional agents are selected from the group consisting of: calcineurin inhibitors, proteasome inhibitors, aminoquinolines, complement inhibitors, B-cell inhibitors, cytotoxic agents, mTOR inhibitors, and steroids.

[0322] In certain embodiments, the one or more additional agents are steroids. For example, the one or more additional agents can be selected from the group consisting of: prednisone, dexamethasone, hydrocortisone, cyclosporine, and any combination of the foregoing.

[0323] In certain embodiments, the one or more additional agents are aminoquinolines. For example, the one or more additional agents can be hydroxychloroquine.

[0324] In some embodiments, a subject is receiving one or more additional agents while being treated with atrasentan. In certain embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, 50 weeks, 60 weeks, 70 weeks, 80 weeks, 90 weeks, 100 weeks, 110 weeks, 120 weeks, 130 weeks, 140 weeks, 150 weeks, 160 weeks, 170 weeks, 180 weeks, 190 weeks, or 200 weeks of treatment), the dose of one or more additional agents is reduced. In some of these embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days, the dose of one or more additional agents is reduced. In some of the foregoing embodiments, the dose of the additional agent is reduced by about 10% to about 100%. In certain embodiments, the dose of the additional agent is reduced by about 15% to about 100%. In certain embodiments, the dose of the additional agent is reduced by about 20% to about 100%. In certain embodiments, the dose of the additional agent is reduced by about 25% to about 100%. In certain embodiments, the dose of the additional agent is reduced by about 30% to about 100%. In certain embodiments, the dose of the additional agent is reduced by about 35% to about 100%. In certain embodiments, the dose of the additional agent is reduced by about 40% to about 100%. In certain embodiments, the dose of the additional agent is reduced by about 45% to about 100%. In certain embodiments, the dose of the additional agent is reduced by about 50% to about 100%. In certain embodiments, the dose of the additional agent is reduced by about 55% to about 100%. In certain embodiments, the dose of the additional agent is reduced by about 60% to about 100%. In certain embodiments, the dose of the additional agent is reduced by about 65% to about 100%. In certain embodiments, the dose of the additional agent is reduced by about 70% to about 100%. In certain embodiments, the dose of the additional agent is reduced by about 75% to about 100%. In certain embodiments, the dose of the additional agent is reduced by about 80% to about 100%. In certain embodiments, the dose of the additional agent is reduced by about 85% to about 100%. In certain embodiments, the dose of the additional agent is reduced by about 90% to about 100%. In some of the foregoing embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for about 15 days to about 30 days (e.g., about 15 days, about 20 days, about 25 days, or about 30 days), the dose of one or more additional agents is reduced. When the dose of the additional agent as described herein is reduced by 100%, the subject no longer requires the additional agent.

[0325] In certain embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, for example, between about 15 days and about 30 days after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the dose of one or more steroids is reduced. In some embodiments, the steroid dose is reduced by about 10% to about 100%, as described herein. In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the dose of prednisone, dexamethasone, hydrocortisone, cyclosporine, or any combination of the foregoing is reduced by about 10% to about 100%.

[0326] In certain embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, for example, between about 15 days and about 30 days after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the dose of one or more aminoquinolines is reduced. In some embodiments, the aminoquinoline dose is reduced by about 10% to about 100%, as described herein. In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the dose of hydroxychloroquine is reduced by about 10% to about 100%.

[0327] In some embodiments, the subject is concurrently receiving one or more additional therapeutic agents. The one or more additional therapeutic agents are described herein. For example, the subject is concurrently receiving an inhibitor of one or more elements of the renin-angiotensin-aldosterone system. In certain embodiments, the subject is concurrently receiving an SGLT-2 inhibitor, an ACE inhibitor, an ARB, a statin, a diuretic, a calcium channel blocker, a β-blocker, an aldosterone antagonist, fish oil, hydroxychloroquine, or a combination of any of the foregoing. In some of these embodiments, the subject is concurrently receiving an SGLT-2 inhibitor. In some of these embodiments, the subject is concurrently receiving an ACE inhibitor, an ARB, or a combination thereof. In certain embodiments, the subject is concurrently receiving one or more statins, such as atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin. In certain embodiments, the subject is concurrently receiving one or more diuretics, such as hydrochlorothiazide, trichlormethiazide, hydroflumethiazide, chlorthalidone, metolazone, chlorothiazide, polythiazide, indapamide, methyclothiazide, bumetanide, torsemide, piretanide, ethacrynic acid, furosemide, triamterene, spironolactone, eplerenone, and amiloride. In certain embodiments, the subject is concurrently receiving an SGLT-2 inhibitor, such as canagliflozin, dapagliflozin, empagliflozin, or ipragliflozin. In certain embodiments, the subject is concurrently receiving one or more ACE inhibitors, such as quinapril, fosinopril, perindopril, captopril, enalapril, enalaprilat, ramipril, cilazapril, delapril, fosinopril, zofenopril, indolapril, benazepril, lisinopril, spirapril, trandolapril, perindopril, pentopril, moexipril, resinamyl, and pivopril. In certain embodiments, the subject is concurrently receiving an ARB, such as candesartan, candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan, olmesartan medoxomil, telmisartan, valsartan, azilsartan medoxomil, and BRA-657. In certain embodiments, the subject is concurrently receiving a diuretic and an ACE inhibitor or an ARB. In certain embodiments, the subject is concurrently receiving a diuretic, an ACE inhibitor, and an ARB. In certain embodiments, the subject is concurrently receiving a diuretic and an SGLT-2 inhibitor, and an ACE inhibitor or an ARB. In certain embodiments, the subject is concurrently receiving a diuretic, an SGLT-2 inhibitor, an ACE inhibitor, and an ARB. In certain embodiments, a subject concurrently receiving one or more additional therapeutic agents has not previously received one or more therapeutic agents. For example, a subject concurrently receiving an SGLT-2 inhibitor has not previously received an SGLT-2 inhibitor.

[0328] In some embodiments, the subject has previously received but is not concurrently receiving one or more additional therapeutic agents, such as those described herein. For example, the subject has previously received but is not concurrently receiving an SGLT-2 inhibitor, an ACE inhibitor, an ARB, a statin, a diuretic, a calcium channel blocker, a β-blocker, an aldosterone antagonist, fish oil, hydroxychloroquine, or any combination of the foregoing, as described herein. In certain of these embodiments, the subject has previously received but is not concurrently receiving an SGLT-2 inhibitor.

[0329] In some embodiments, within 6 months prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the subject has cellular glomerular crescents in approximately ≤ 25% of glomeruli. For example, the subject may have cellular glomerular crescents in approximately 25%, approximately 20%, approximately 15%, approximately 10%, approximately 5%, or approximately 1% of glomeruli, or any value therebetween. In some embodiments, the subject does not have cellular glomerular crescents in the glomeruli. In certain embodiments, the subject is not clinically suspected of having rapidly progressive glomerulonephritis (RPGN).

[0330] In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the subject has not undergone an organ transplant.

[0331] In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the systolic blood pressure of the subject is less than about 160 mmHg. For example, the systolic blood pressure of the subject may be less than about 155 mmHg, less than about 150 mmHg, less than about 145 mmHg, or less than about 140 mmHg. In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the diastolic blood pressure of the subject is less than about 100 mmHg. For example, the diastolic blood pressure of the subject may be less than about 100 mmHg, less than about 95 mmHg, or less than about 90 mmHg. In some embodiments, the systolic blood pressure of the subject is between about 100 mmHg and about 130 mmHg, and the diastolic blood pressure is from about 70 mmHg to about 90 mmHg.

[0332] In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the subject has not been diagnosed with heart failure. In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the subject has not been previously hospitalized for a condition related to fluid overload. Non-limiting examples of the condition include uncontrolled peripheral edema, pleural effusion, or ascites. In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the subject has not been diagnosed with clinically significant liver disease. In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the subject's transaminase or bilirubin values do not exceed twice the upper limit of normal. For example, the subject's ALT level is less than about 110 U / L (e.g., less than about 100 U / L, less than 90 U / L, less than about 80 U / L, less than about 70 U / L, less than about 60 U / L, less than about 50 U / L, or less than about 40 U / L or any value therebetween). As another example, the subject's AST level is less than 100 U / L (e.g., less than 90 U / L, less than about 80 U / L, less than about 70 U / L, less than about 60 U / L, less than about 50 U / L, or less than about 40 U / L or any value therebetween). As yet another example, the subject's bilirubin level is less than about 2.5 mg / dL (e.g., less than about 2 mg / dL, less than about 1.5 mg / dL, less than about 1.4 mg / dL, less than about 1.3 mg / dL, less than about 1.2 mg / dL, less than about 1.1 mg / dL, less than about 1.0 mg / dL, or less than about 0.9 mg / dL or any value therebetween).

[0333] In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the hemoglobin level of the subject is higher than about 9 g / dL (e.g., higher than about 10 g / dL, about 11 g / dL, about 12 g / dL, or about 13 g / dL or any value therebetween). In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the subject has not received a blood transfusion for anemia for at least about 3 months (e.g., at least about 4 months, about 5 months, about 6 months, or about one year). In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the subject has not been diagnosed with cancer for at least 5 years. In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the subject has not been diagnosed with cancer (e.g., lung cancer or prostate cancer) for at least 5 years. In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the subject has not been diagnosed with cancer for at least 5 years, unless the cancer is non-melanoma skin cancer that does not require ongoing treatment. In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the subject does not have cancer, unless the cancer is non-melanoma skin cancer that does not require ongoing treatment. In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the subject has not developed cancer, unless the cancer is non-melanoma skin cancer that does not require ongoing treatment. In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the subject has not been undergoing cancer treatment for at least 5 years, unless the cancer is non-melanoma skin cancer that does not require ongoing treatment.

[0334] In some embodiments, it has been determined that the subject has a controlled serum glucose level. In certain embodiments, it has been determined that the subject has a controlled serum glucose level. For example, it has been determined that the fasting serum glucose level of the subject is lower than about 130 mg / dL, about 125 mg / dL, about 120 mg / dL, about 115 mg / dL, about 110 mg / dL, about 105 mg / dL, about 100 mg / dL, about 95 mg / dL, about 90 mg / dL, about 85 mg / dL, about 80 mg / dL, or about 75 mg / dL or any value therebetween.

[0335] In some embodiments, the subject has not been previously diagnosed with a chronic kidney disease other than IgA nephropathy. Non-limiting examples include diabetic kidney disease, hypertensive kidney disease, or primary glomerulopathy determined to be unrelated to IgA nephropathy. In certain embodiments, the subject has not been previously diagnosed with diabetic kidney disease. In certain embodiments, the subject has not been previously diagnosed with hypertensive kidney disease. In certain embodiments, the subject has not been diagnosed with primary glomerulopathy determined to be unrelated to IgA nephropathy.

[0336] In some embodiments, the subject does not have a chronic kidney disease other than IgA nephropathy. Non-limiting examples include diabetic kidney disease, hypertensive kidney disease, or primary glomerulopathy determined to be unrelated to IgA nephropathy. In certain embodiments, the subject does not have diabetic kidney disease. In certain embodiments, the subject does not have hypertensive kidney disease. In certain embodiments, the subject does not have primary glomerulopathy determined to be unrelated to IgA nephropathy.

[0337] In some embodiments, the subject does not suffer from a chronic kidney disease other than IgA nephropathy. Non-limiting examples include diabetic kidney disease, hypertensive kidney disease, or primary glomerulopathy determined to be unrelated to IgA nephropathy. In certain embodiments, the subject does not suffer from diabetic kidney disease. In certain embodiments, the subject does not suffer from hypertensive kidney disease. In certain embodiments, the subject does not suffer from primary glomerulopathy determined to be unrelated to IgA nephropathy.

[0338] In some embodiments, the subject is not being treated for a chronic kidney disease other than IgA nephropathy. Non-limiting examples include diabetic kidney disease, hypertensive kidney disease, or primary glomerulopathy determined to be unrelated to IgA nephropathy. In certain embodiments, the subject is not being treated for diabetic kidney disease. In certain embodiments, the subject is not being treated for hypertensive kidney disease. In certain embodiments, the subject is not being treated for primary glomerulopathy determined to be unrelated to IgA nephropathy.

[0339] Treatment outcome

[0340] In some embodiments of the methods, uses, or products used herein, renal inflammation is reduced after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. In some embodiments, renal inflammation in a subject is reduced by at least about 10% after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In some embodiments, renal inflammation in the subject is reduced by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%, or any value therebetween. In certain of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days.

[0341] In some embodiments, renal fibrosis is reduced after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. In some embodiments, renal fibrosis in a subject is reduced by at least about 10% after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween). In certain embodiments, renal fibrosis in the subject is reduced by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%, or any value therebetween. In certain of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days.

[0342] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or any value therebetween), renal fibrosis in the subject is reduced to less than about 50% of the cortical area. In certain embodiments, renal fibrosis in the subject is reduced to less than about 40% of the cortical area. For example, in some embodiments, renal fibrosis in the subject is reduced to less than about 35%, about 30%, about 25%, about 20%, about 15% or about 10% of the cortical area or any value therebetween. In some of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days.

[0343] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the occurrence of hematuria in the subject is reduced. In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks), the number of urinary red blood cells / high power (microscopic) field (rbc / hpf) in the subject is reduced by at least about 10%. In certain embodiments, the urinary rbc / hpf in the subject is reduced by at least about 20%. For example, in some embodiments, the urinary rbc / hpf in the subject is reduced by at least about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 95% or any value therebetween. In some of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days.

[0344] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for 1 week, 2 weeks, 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks or any value therebetween), the rate of decline of the eGFR of the subject is reduced by at least about 10%. In certain embodiments, the rate of decline of the eGFR of the subject is reduced by at least about 20%. For example, in some embodiments, the rate of decline of the eGFR of the subject is reduced by at least about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% or any value therebetween. In some of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days. In some of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 6 months and about 1 year.

[0345] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or any value therebetween), the rate of decline of eGFR in the subject is reduced to less than about 10 mL / min / year. In some embodiments, the rate of decline of eGFR in the subject is reduced to less than about 9 mL / min / year. For example, in some embodiments, the rate of decline of eGFR in the subject is reduced to less than about 8 mL / min / year, about 7 mL / min / year, about 6 mL / min / year, about 5 mL / min / year, about 4 mL / min / year, about 3 mL / min / year, about 2 mL / min / year or about 1 mL / min / year or any value therebetween. In certain of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days. In certain of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 6 months and about 1 year.

[0346] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween), the risk of a subject developing ESRD is reduced by about 20% to about 99%. For example, the risk of a subject developing ESRD can be reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 99%, or any value therebetween. In certain of the foregoing embodiments, the subject has received treatment for about 90 days to about 180 days. In certain embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 90 and about 180 days, the risk of a subject developing ESRD is reduced by about 20% to about 99%. In certain of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 6 months and about 1 year.

[0347] In some embodiments, the method increases the time between diagnosing IgA nephropathy in a subject and the subject's eGFR dropping below about 15 mL / min / 1.73m 2 In certain embodiments, the method increases the time between diagnosing IgA nephropathy in a subject and the subject's eGFR dropping below 15 mL / min / 1.73m 2 by at least about 10%. For example, in some embodiments, the method increases the time between diagnosing IgA nephropathy in a subject and the subject's eGFR dropping below about 15 mL / min / 1.73m 2 by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, or about 500%, or any value therebetween.

[0348] In some embodiments, the method increases the time between diagnosing IgA nephropathy in a subject and the subject's eGFR dropping below 15 mL / min / 1.73m 2The time between increases the time by at least about 1 year. For example, the method can reduce the subject's eGFR to less than 15 mL / min / 1.73m 2 The time delay is at least about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about 5 years, about 5.5 years, about 6 years, about 6.5 years, about 7 years, about 7.5 years, about 8 years, about 8.5 years, about 9 years, about 9.5 years, about 10 years, about 11 years, about 12 years, about 13 years, about 15 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years or about 20 years or any value therebetween.

[0349] In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the method reduces the average rate of decline of eGFR by about 0.75 mL / min / year to about 6 mL / min / year for at least about 3 months (e.g., at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 1.5 years or at least about 2 years). For example, the method reduces the average rate of decline of eGFR by about 0.75 mL / min / year, about 1 mL / min / year, about 1.5 mL / min / year, about 2 mL / min / year, about 2.5 mL / min / year, about 3 mL / min / year, about 3.5 mL / min / year, about 4 mL / min / year, about 4.5 mL / min / year, about 5 mL / min / year, about 5.5 mL / min / year or about 6 mL / min / year. In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the method reduces the average rate of decline of eGFR by about 4 mL / min / year to about 5 mL / min / year for at least about 3 months. In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the method reduces the average rate of decline of eGFR by about 3 mL / min / year to about 6 mL / min / year for at least about 3 months. In some embodiments, prior to the first administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the method reduces the average rate of decline of eGFR by about 4 mL / min / year to about 5 mL / min / year for at least about 3 months. In some embodiments, the decline in eGFR in units of mL / min / year refers to per 1.73m 2 of units.

[0350] In some embodiments, between about 6 months and about 24 months after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the method reduces the average rate of decline of eGFR by about 15% to about 30%. In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for about 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months, the average rate of decline of eGFR can be reduced by about 15%. In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for about 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months, the average rate of decline of eGFR can be reduced by about 20%. In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for about 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months, the average rate of decline of eGFR can be reduced by about 25%. In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for about 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months, the average rate of decline of eGFR can be reduced by about 30%.

[0351] In another aspect, provided herein is a method of reducing proteinuria, the method comprising administering to a subject in need thereof an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0352] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or any value therebetween), the amount of protein (e.g., albumin) in the urine of the subject is reduced by at least about 10%. In some embodiments, the amount of protein in the urine of the subject is reduced by at least about 15%. For example, in some embodiments, the amount of protein in the urine of the subject is reduced by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 95% or any value therebetween. In some of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days.

[0353] In certain embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days, the amount of protein (e.g., albumin) in the urine of the subject is reduced by about 20% to about 80%. In some of these embodiments, the amount of protein in the urine of the subject is reduced by about 25% to about 80%. In some of these embodiments, the amount of protein in the urine of the subject is reduced by about 30% to about 80%. In some of these embodiments, the amount of protein in the urine of the subject is reduced by about 35% to about 80%. In some of these embodiments, the amount of protein in the urine of the subject is reduced by about 40% to about 80%. In some of these embodiments, the amount of protein in the urine of the subject is reduced by about 45% to about 80%. In some of these embodiments, the amount of protein in the urine of the subject is reduced by about 50% to about 80%.

[0354] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or any value therebetween), the amount of protein (e.g., albumin) in the urine of the subject is reduced by about 100 mg / dL to about 3,000 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 100 mg / dL to about 2,500 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 100 mg / dL to about 2,000 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 100 mg / dL to about 1,500 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 100 mg / dL to about 1,000 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 100 mg / dL to about 500 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 100 mg / dL to about 400 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 100 mg / dL to about 300 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 100 mg / dL to about 200 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 500 mg / dL to about 2,500 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 500 mg / dL to about 2,000 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 500 mg / dL to about 1,500 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 500 mg / dL to about 1,000 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 500 mg / dL to about 900 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 500 mg / dL to about 800 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 600 mg / dL to about 900 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 700 mg / dL to about 900 mg / dL. In certain embodiments, the amount of protein in the urine of the subject is reduced by about 1,000 mg / dL to about 2,000 mg / dL.In some of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days.

[0355] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days, the amount of protein (e.g., albumin) in the urine of the subject is reduced by about 100 mg / dL to about 500 mg / dL. In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days, the amount of protein in the urine of the subject is reduced by about 200 mg / dL to about 500 mg / dL. In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days, the amount of protein in the urine of the subject is reduced by about 300 mg / dL to about 500 mg / dL.

[0356] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days, the amount of protein (e.g., albumin) in the urine of the subject is reduced by about 500 mg / dL to about 900 mg / dL. In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days, the amount of protein in the urine of the subject is reduced by about 600 mg / dL to about 900 mg / dL. In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days, the amount of protein in the urine of the subject is reduced by about 700 mg / dL to about 900 mg / dL.

[0357] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks), the level of protein (e.g., albumin) in the urine of the subject is reduced to less than about 1.0 gram per day. In some embodiments, the level of protein in the urine of the subject is reduced to less than about 0.9 gram per day. For example, in some embodiments, the level of protein in the urine of the subject is reduced to less than about 0.8 gram per day, about 0.7 gram per day, about 0.6 gram per day, 0.5 gram per day, about 0.4 gram per day, about 0.3 gram per day or about 0.2 gram per day or any value therebetween. In certain of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days.

[0358] In some embodiments, the subject is between about 15 and about 40 years of age. In some embodiments, the subject is between about 15 to about 25 years of age, about 20 to about 30 years of age, about 25 to about 35 years of age, about 30 to about 40 years of age or any age therebetween. In some embodiments, the subject is between about 20 to about 30 years of age or any age therebetween. In some embodiments, the subject is about 20 years old, about 21 years old, about 22 years old, about 23 years old, about 24 years old, about 25 years old, about 26 years old, about 27 years old, about 28 years old, about 29 years old or about 30 years old.

[0359] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the fatigue level of a patient is reduced. In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or any value therebetween), the fatigue is reduced by about 5% to about 80%. In certain embodiments, the fatigue is reduced by about 10% to about 75%. In certain embodiments, the fatigue is reduced by about 10% to about 70%. In certain embodiments, the fatigue is reduced by about 10% to about 65%. In certain embodiments, the fatigue is reduced by about 10% to about 60%. In certain embodiments, the fatigue is reduced by about 10% to about 55%. In certain embodiments, the fatigue is reduced by about 10% to about 50%. In certain embodiments, the fatigue is reduced by about 10% to about 45%. In certain embodiments, the fatigue is reduced by about 10% to about 40%. In certain embodiments, the fatigue is reduced by about 10% to about 35%. In certain embodiments, the fatigue is reduced by about 10% to about 30%. In certain embodiments, the fatigue is reduced by about 10% to about 25%. In certain embodiments, the fatigue is reduced by about 10% to about 20%. In certain embodiments, the fatigue is reduced by about 10% to about 15%. In certain of the foregoing embodiments, the subject has been treated with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof for between about 15 days and about 30 days. In certain embodiments, the reduction in fatigue comprises a decrease in scores on one or more of the following: Fatigue Severity Scale, Chalder Fatigue Scale, FACIT Fatigue Scale, Brief Fatigue Scale, FACT-F subscale, General Vitality and Impact, May and Kline Adjective Checklist, Pearson-Byars Fatigue Sensation Checklist, Rhoten Fatigue Scale, Fatigue and Weakness Schedule, or Personal Fatigue Intensity Scale.

[0360] Some embodiments provide a method of inhibiting mesangial cell activation in a subject having IgA nephropathy, the method comprising administering to the subject an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0361] Some embodiments provide a method of inhibiting PDGF signaling activity (e.g., reducing the expression and / or activity of one or more of PIK3R1, PDGFRA, NFKBIA, PIK3CG, PLA2G4A, TIAM1, PDGFB, NFKB1, and MAP3K1) in mesangial cells in a subject having IgA nephropathy, the method comprising administering to the subject an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0362] Some embodiments provide a method of inhibiting mesangial cell activation, the method comprising contacting mesangial cells with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0363] In some embodiments, mesangial cell activation is induced by IgA immune complexes. In some embodiments, mesangial cell activation is associated with the presence of IgA immune complexes. The presence and / or amount of IgA immune complexes can be detected by a variety of methods. For example, the complexes can be detected in serum or urine and can also be detected in kidney biopsy samples.

[0364] In some embodiments, inhibition of mesangial cell activation includes reducing the expression and / or activity of one or more biomarkers indicative of mesangial cell proliferation. In some embodiments, inhibition of mesangial cell activation includes reducing mesangial cell inflammation. In some embodiments, reducing mesangial cell inflammation includes reducing the expression and / or activity of one or more of IL6, MCP1, or other biomarkers indicative of mesangial cell inflammation. In some embodiments, reducing mesangial cell inflammation includes reducing the expression and / or activity of IL-6. In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks or any value therebetween), the expression and / or activity of one or more biomarkers indicative of mesangial cell inflammation is reduced by about 25% to about 99%. In some embodiments, the expression and / or activity of one or more biomarkers indicative of mesangial cell inflammation is reduced by about 25% to about 50%, about 40% to about 60%, about 50% to about 75%, about 60% to about 80%, about 75% to about 90%, about 85% to about 99%, or any value therebetween. For example, in some such embodiments, one or more biomarkers can be IL-6.

[0365] In some embodiments, inhibition of mesangial cell activation includes reducing mesangial cell inflammation. In some embodiments, reducing mesangial cell inflammation includes reducing IL-6 signaling (e.g., reducing the expression and / or activity of one or more proteins involved in the IL-6 signaling pathway, e.g., reducing the expression and / or activity of one or more of Cntfr, Il1b, Csf1, Il2ra, Map3k8, and Il1r1). In some embodiments, reducing mesangial cell inflammation includes reducing the expression and / or activity of one or more (e.g., 1, 2, 3, 4, or 5) of the following: Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1.

[0366] In some embodiments, inhibition of mesangial cell activation includes reducing the profibrotic response in mesangial cells. In some embodiments, reducing the profibrotic response in mesangial cells includes decreasing the expression and / or activity of one or more of NF-κB, TGF, PDGF, CTGF, MMP, TIMPS, or other biomarkers indicative of mesangial cell fibrosis. In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks or any value therebetween), the expression and / or activity of one or more of NF-κB, TGF, PDGF, CTGF, MMP, and TIMPS is reduced by about 25% to about 99% relative to the expression and / or activity before administration of the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and the APRIL-binding antibody or an antigen-binding fragment thereof. In some embodiments, the expression and / or activity of one or more of NF-κB, TGF, PDGF, CTGF, MMP, and TIMPS is reduced by about 25% to about 50%, about 40% to about 60%, about 50% to about 75%, about 60% to about 80%, about 75% to about 90%, about 85% to about 99%, or any value therebetween.

[0367] In some embodiments, inhibition of mesangial cell activation includes reducing the profibrotic response in mesangial cells. In some embodiments, reducing the profibrotic response includes reducing NF-κB signaling. In some embodiments, reducing the profibrotic response includes decreasing the expression and / or activity of one or more (e.g., 1, 2, 3, 4, or 5) of the following: Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, and / or increasing the expression and / or activity of one or more (e.g., 1, 2, 3, 4, or 5) of the following: Ehd1, Snn, Tnfaip8, Ackr3, Id2, Ccn1, Efna1, Ccnd1, Cdkn1a, Pnrc1 (in the case where the component inhibits NF-κB signaling).

[0368] In some embodiments, reducing the profibrotic response includes reducing PDGF signaling. In some embodiments, reducing the profibrotic response includes decreasing the expression and / or activity of one or more (e.g., 1, 2, 3, 4, or 5) of the following: Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1, Pdgfb, Nfkb1, and / or increasing the expression and / or activity of one or more (e.g., 1, 2, 3, 4, or 5) of the following: Hras (in the case where the component inhibits PDGF signaling).

[0369] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks or any value therebetween), the expression and / or activity of NF-κB and / or the expression and / or activity of PDGF is reduced by about 25% to about 99% relative to the expression and / or activity before administration of the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and the APRIL-binding antibody or an antigen-binding fragment thereof. In some embodiments, the expression and / or activity of NF-κB and / or PDGF is reduced by about 25% to about 50%, about 40% to about 60%, about 50% to about 75%, about 60% to about 80%, about 75% to about 90%, about 85% to about 99% or any value therebetween.

[0370] In some embodiments, reducing the profibrotic response in mesangial cells includes reducing matrix secretion by mesangial cells. In some embodiments, reducing matrix secretion by mesangial cells includes decreasing the expression and / or activity of one or more overexpressed matrix secretions in mesangial cells.

[0371] Some embodiments provide a method of reducing the activation of mesangial cells in contact with IgA immune complexes, the method comprising contacting the mesangial cells with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. In some embodiments, reducing the activation of mesangial cells includes decreasing the expression and / or activity of one or more biomarkers indicative of mesangial cell proliferation.

[0372] In some embodiments, reducing the activation of mesangial cells includes reducing mesangial cell inflammation. In some embodiments, reducing mesangial cell inflammation includes decreasing the expression and / or activity of one or more of IL-6, MCP1 or other biomarkers indicative of mesangial cell inflammation.

[0373] In some embodiments, reducing the activation of mesangial cells includes reducing the profibrotic response in mesangial cells. In some embodiments, reducing the profibrotic response in mesangial cells includes decreasing the expression and / or activity of one or more of TGF, PDGF, CTGF, MMP, TIMPS or other biomarkers indicative of mesangial cell fibrosis.

[0374] In some embodiments, reducing the profibrotic response in mesangial cells includes reducing matrix secretion by mesangial cells. In some embodiments, reducing matrix secretion by mesangial cells includes decreasing the expression and / or activity of one or more biomarkers indicative of excessive matrix secretion by mesangial cells.

[0375] In some embodiments, reducing the activation of mesangial cells includes reducing unwanted mesangial cell migration. In some embodiments, the reduction of unwanted mesangial cell migration occurs about 15 days to about 30 days after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. In some embodiments, the reduction of unwanted mesangial cell migration occurs about 3 months to about 6 months after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0376] In some embodiments, reducing the activation of mesangial cells includes reducing unwanted mesangial cell proliferation. In some embodiments, the reduction of unwanted mesangial cell proliferation occurs about 15 days to about 30 days after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. In some embodiments, the reduction of unwanted mesangial cell proliferation occurs about 3 months to about 6 months after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0377] In some embodiments, after treatment with an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, or about 200 weeks, or any value therebetween), the unwanted mesangial cell proliferation is reduced by about 25% to about 99%. In some embodiments, the unwanted mesangial cell proliferation is reduced by about 25% to about 50%, about 40% to about 60%, about 50% to about 75%, about 60% to about 80%, about 75% to about 90%, about 85% to about 99%, or any value therebetween.

[0378] In some embodiments, mesangial cell activation can be evaluated by one or more of serum analysis, urine analysis, and microscopy of kidney biopsy samples (e.g., light microscopy and / or immunofluorescence microscopy).

[0379] In some embodiments, the contacting is performed in vitro. In some embodiments, the contacting is performed in vivo.

[0380] Some embodiments provide a method of treating IgA nephropathy in a subject in need thereof, the method comprising: a) determining an elevated serum Gd-IgA1 level in the subject; and b) administering to the subject an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0381] Some embodiments provide a method of treating IgA nephropathy in a subject in need thereof, the method comprising: a) determining an elevated level of mesangial cell activation in the subject; and b) administering to the subject an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0382] In some embodiments, determining an elevated level of mesangial cell activation comprises obtaining a sample from the subject and assessing the level of mesangial cell activation in the sample. In some embodiments, the sample is a kidney biopsy sample. In some embodiments, the sample is selected from a blood sample, a urine sample, a kidney biopsy sample, or a combination of two or three of the foregoing.

[0383] In some embodiments, the sample exhibits an elevated level of one or more of the following: matrix secretion by mesangial cells, IgA immune complex deposition, mesangial cell proliferation, and intraglomerular cell proliferation. In some embodiments, the sample exhibits an elevated level of IgA immune complex deposition.

[0384] In some embodiments, in the year prior to administering the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and the APRIL-binding antibody or an antigen-binding fragment thereof, the subject has been determined to have proteinuria of at least about 1 g / day in at least two of three consecutive readings. For example, about 1 g / day, about 1.2 g / day, about 1.4 g / day, about 1.6 g / day, about 1.8 g / day, or about at least 2 g / day.

[0385] In some embodiments, prior to administering the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and the APRIL-binding antibody or an antigen-binding fragment thereof, the subject has been administered a maximally tolerated stable dose of an RAS inhibitor for at least 12 weeks. In some embodiments, the subject is co-administered a maximally tolerated stable dose of an RAS inhibitor and an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. In some embodiments, the RAS inhibitor is an angiotensin-converting enzyme inhibitor. In some embodiments, the RAS inhibitor is an angiotensin receptor blocker (ARB).

[0386] In some embodiments, it has been determined that the subject has hematuria prior to administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. In some embodiments, the hematuria is microscopic hematuria. In some embodiments, the hematuria is gross hematuria.

[0387] In some embodiments, it has been determined that the subject has an eGFR of at least 30 mL / min / 1.73m 2 prior to administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. In some embodiments, it has been determined that the subject has an eGFR of about 30 mL / min / 1.73m 2 to about 60 mL / min / 1.73m 2 prior to administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0388] Some embodiments provide a method of treating IgA nephropathy in a subject in need thereof, the method comprising: a) determining an elevated level of IgA immune complexes in the kidneys of the subject; and b) administering to the subject an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0389] In some embodiments, determining an elevated level of IgA immune complexes in the kidneys comprises obtaining a sample from the subject and assessing the level of IgA immune complexes in the sample. In some embodiments, the sample is a kidney biopsy sample. In some embodiments, the sample is selected from a blood sample, a urine sample, a kidney biopsy sample, or a combination of two or three of the foregoing. In some embodiments, IgA immune complexes are deposited in the glomerular mesangium.

[0390] In some embodiments, the level of IgA immune complexes can be assessed by one or more of serum analysis, urine analysis, and microscopy of a kidney biopsy sample (e.g., light microscopy and / or immunofluorescence microscopy).

[0391] In some embodiments, the sample exhibits an elevated level of one or more of: matrix secretion by mesangial cells, IgA immune complex deposition in the glomerular mesangium, mesangial cell activation, mesangial cell proliferation, and intraglomerular cell proliferation.

[0392] In some embodiments, during the year prior to administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, it has been determined that the subject has proteinuria of at least about 1 g / day in at least two of three consecutive readings. For example, about 1 g / day, about 1.2 g / day, about 1.4 g / day, about 1.6 g / day, about 1.8 g / day, or about at least 2 g / day.

[0393] In some embodiments, prior to administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, the subject has been administered a maximally tolerated stable dose of an RAS inhibitor for at least 12 weeks. In some embodiments, the subject is administered a maximally tolerated stable dose of an RAS inhibitor and an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof concurrently. In some embodiments, the RAS inhibitor is an angiotensin-converting enzyme inhibitor. In some embodiments, the RAS inhibitor is an angiotensin receptor blocker (ARB).

[0394] In some embodiments, prior to administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, it has been determined that the subject has hematuria. In some embodiments, the hematuria is microscopic hematuria. In some embodiments, the hematuria is gross hematuria.

[0395] In some embodiments, prior to administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, it has been determined that the subject has an eGFR of at least 30 mL / min / 1.73m 2 In some embodiments, prior to administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, it has been determined that the subject has an eGFR of about 30 mL / min / 1.73m 2 to about 60 mL / min / 1.73m 2 of eGFR.

[0396] In some embodiments, the method includes determining the expression and / or activity of one or more of ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, and NF-kB in the subject. In some embodiments, the expression and / or activity is determined prior to administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. In some embodiments, the expression and / or activity is determined after administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0397] In some embodiments, the determination of expression and / or activity is performed prior to administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof. In some embodiments, the determination of expression and / or activity is performed after administration of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof (e.g., after treatment for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks or about 200 weeks or any value therebetween).

[0398] In some embodiments, it has been determined that the subject has increased expression and / or activity of one or more of the following: ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA2, TNF-α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK, MCP1, Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1 and Pdgfb. In some embodiments, it has been determined that the subject has increased expression and / or activity of one or more of the following: ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA2, TNF-α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK and MCP1.In some embodiments, it has been determined that the subject has increased expression and / or activity of one or more of the following: Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1, and Pdgfb. In some embodiments, it has been determined that the subject has increased expression and / or activity of one or more of the following: ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, and NF-kB. In some embodiments, it has been determined that the subject has increased expression and / or activity of one or more of the following: ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, and SLC6A19.

[0399] Some embodiments provide a method of treating IgA nephropathy in a subject, the method comprising: (a) determining that the subject has elevated expression and / or activity of one or more of the following: ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA2, TNF-α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK, MCP1, Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1 and Pdgfb; and (b) administering to the subject an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0400] Some embodiments provide a method of treating IgA in a subject determined to have elevated expression and / or activity of one or more of the following: ET1, TGF, PDGF, CTGF, MMP, TIMPS, IGF1, DPEP1, ASL, AMN, ALPL, SLC6A19, IL-6, NF-kB, PKC, PI3K, Src, Ras, ERK1 / 2, Rho, Rac, Akt, mTOR, NAPDH oxidase, MAPK, cPLA2, TNF-α, IL-1, CAM, COX-2, iNOS, JAK, STAT3, PI3K, Akt / PKB, IKKs, IkBs, NF-kB, MAPK, Ras, Raf, MEK, ERK, MCP1, Cntfr, Il1b, Csf1, Il2ra, Map3k8, Il1r1, Pfkfb3, Nr4a1, Gem, Fosl2, Klf4, F3, Nfkbia, Ifit2, Nr4a2, Klf2, Jag1, Dnajb4, Il1b, Spsb1, Btg2, Atf3, Csf1, Trib1, Zbtb10, Btg1, Rhob, Nfat5, Edn1, Rel, Nr4a3, Nfkb1, Serpine1, Ccl20, Per1, Cxcl2, Map3k8, Traf1, Pik3r1, Pdgfra, Nfkbia, Pik3cg, Pla2g4a, Tiam1, and Pdgfb, the method comprising administering to the subject an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof.

[0401] In any of the embodiments described herein, various combinations of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof that produces an effect and an APRIL-binding antibody or an antigen-binding fragment thereof are contemplated. In some embodiments, the effect (e.g., any of the beneficial or desired outcomes described herein) is greater than the sum of the effects observed when the same amounts of the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and the APRIL-binding antibody or an antigen-binding fragment thereof (when co-administered) are administered as monotherapies. In some embodiments, co-administration of the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and the APRIL-binding antibody or an antigen-binding fragment thereof produces an effect, e.g., a therapeutic effect, using a lower dose of one or both of these compounds as monotherapies. For example, a lower dose of the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and the APRIL-binding antibody or an antigen-binding fragment thereof is used to produce a therapeutic effect as compared to the amounts used in monotherapy. For example, in some embodiments, the dose of the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof co-administered with the APRIL-binding antibody or an antigen-binding fragment thereof can be about 50% to about 90% of the dose of the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof that produces the same therapeutic effect (e.g., including any of the beneficial or desired outcomes described herein) when administered as a monotherapy. In some embodiments, the dose of the APRIL-binding antibody or an antigen-binding fragment thereof co-administered with the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof can be about 50% to about 90% of the dose of the APRIL-binding antibody or an antigen-binding fragment thereof that produces the same therapeutic effect (e.g., including any of the beneficial or desired outcomes described herein) when administered as a monotherapy. For example, treating IgA nephropathy, reducing renal inflammation and / or fibrosis, reducing hematuria, reducing proteinuria, stabilizing eGFR, reducing the number of IgA nephropathy-related disease episodes, delaying the onset of ESRD, reducing fatigue, and reducing the activation of mesangial cells.

[0402] C. Atrasentan

[0403] Atrasentan, also known as (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid, ABT-627, A-147627, or A-127722, is a small molecule having the following chemical structure:

[0404]

[0405] Atrasentan and methods for its preparation are described in U.S. Patent No. 7,208,517 and PCT Publication No. WO 1997 / 030045 (see, e.g., Example 501).

[0406] In some embodiments, atrasentan is administered as the free base. In some other embodiments, atrasentan is administered as a pharmaceutically acceptable salt as described anywhere herein.

[0407] Atrasentan is an ET A inhibitor that is approximately 1,860-fold selective for ET A over ET B As used herein, "ET A " is an abbreviation for endothelin receptor A; and "ET B " is an abbreviation for endothelin receptor B. See, e.g., Ann Rheum Dis. [Annals of the Rheumatic Diseases], 66(11), pp. 1467–1472 (2007); Eur. Resp. J. [European Respiratory Journal], 37, pp. 475-476 (2011); Plos One [PLoS ONE], 9, e87548 (2014); J. Clin. Oncol. [Journal of Clinical Oncology], 10, 31(14), pp. 1740-7 (2013); Pharmacol. Rev. [Pharmacological Reviews], 68(2) pp. 357-418 (2016); and Nephrol. Dial. Transplant. [Nephrology Dialysis Transplantation], 29, pp. i69–i73 (2014).

[0408] salt

[0409] In some embodiments, atrasentan is in the form of a pharmaceutically acceptable salt. As used herein, the phrase "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the present disclosure (e.g., atrasentan). Exemplary salts include acid addition salts formed by the reaction of atrasentan with an acid (e.g., an organic acid or an inorganic acid). Non-limiting examples include: sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, mandelate (e.g., (S)-mandelate or (R)-mandelate), gentisate, fumarate, gluconate, glucuronate, galacturonate, formate, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate, and p-toluenesulfonate, pamoate (i.e., 4,4'-methylene-b–s-(2-hydroxy-3-naphthoate)). Exemplary salts also include base addition salts formed by the reaction of atrasentan with a base. Non-limiting examples include alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule, such as an acetate ion, a succinate ion, or other counterion. The counterion can be any organic or inorganic moiety that stabilizes the charge on the parent compound. In addition, a pharmaceutically acceptable salt can have more than one charged atom in its structure. The situation where multiple charged atoms are part of a pharmaceutically acceptable salt can have multiple counterions. Thus, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterions. When referring to atrasentan, the term "one or more salts" should be understood to mean salts of atrasentan, which can exist alone or in admixture with free atrasentan.

[0410] In some embodiments, atrasentan is in the form of a hydrochloride salt. In some embodiments, atrasentan hydrochloride has a molar ratio of atrasentan to HCl of 1:1.

[0411] In some embodiments, atrasentan is in the form of a mandelate salt. In certain embodiments, atrasentan is in the form of (S)-mandelate salt. In certain embodiments, atrasentan is in the form of (R)-mandelate salt. In certain embodiments, in atrasentan mandelate, the molar ratio of atrasentan to mandelate is 1:1. In certain embodiments, in atrasentan mandelate, the molar ratio of atrasentan to mandelate is 2:1. Atrasentan mandelate and its preparation method are further described in U.S. Patent Nos. 8,962,675 and 9,637,476.

[0412] In some embodiments, atrasentan is in the form of a hemisulfate. The hemisulfate and its preparation method are further described in U.S. Patent Nos. 8,962,675 and 9,637,476.

[0413] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is in the anhydrous form. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is in the hydrate form. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is in the solvate form.

[0414] In some embodiments, the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is present in a substantially amorphous form (e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99% or >99.5% amorphous). For example, in some embodiments, the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is amorphous atrasentan hydrochloride (described in PCT Publication No. WO 2006 / 034085).

[0415] In some embodiments, the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is present in one or more crystalline forms ("polymorphs", e.g., >75%, >80%, >85%, >90%, >95%, >98%, >99% or >99.5% crystalline). For example, in some embodiments, the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is atrasentan hydrochloride Form 1 (described in PCT Publication No. WO 2006 / 034094). In some embodiments, the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is atrasentan hydrochloride Form 2 (described in PCT Publication No. WO 2006 / 034084). In some embodiments, the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is atrasentan hydrochloride Form 3 (described in PCT Publication No. WO2006 / 034234 and U.S. Patent No. 9,051,301).

[0416] In certain embodiments, crystalline atrasentan mandelate is crystalline atrasentan (S)-mandelate. In certain embodiments, atrasentan (S)-mandelate is an anhydrous salt. In certain embodiments, atrasentan (S)-mandelate is a solvated salt. In certain embodiments, atrasentan (S)-mandelate is a solvated salt selected from the group consisting of: acetonitrile solvate, ethanol solvate, and pyridine solvate. In certain embodiments, atrasentan (S)-mandelate is a hydrated salt.

[0417] In certain embodiments, crystalline atrasentan (S)-mandelate is crystalline atrasentan (S)-mandelate, wherein the molar ratio of atrasentan to (S)-mandelate is about 1:1. In certain embodiments, atrasentan (S)-mandelate is an anhydrous salt. In certain embodiments, atrasentan (S)-mandelate is a solvated salt. In certain embodiments, atrasentan (S)-mandelate is a solvated salt selected from the group consisting of an acetonitrile solvate, an ethanol solvate, and a pyridine solvate. In certain embodiments, atrasentan (S)-mandelate is a hydrated salt. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is substantially crystalline atrasentan (S)-mandelate, wherein the molar ratio of atrasentan to (S)-mandelate is about 1:1.

[0418] In certain embodiments, when measured with monochromatic Kα1 radiation at about 25 °C, crystalline (S)-mandelate has an X-ray powder diffraction pattern comprising peaks at 5.5 ± 0.2, 9.7 ± 0.2, and 19.4 ± 0.2 degrees 2θ. In certain embodiments, when measured with monochromatic Kα1 radiation at about 25 °C, crystalline (S)-mandelate has an X-ray powder diffraction pattern comprising peaks at 5.5 ± 0.2, 9.7 ± 0.2, 12.1 ± 0.2, and 19.4 ± 0.2 degrees 2θ. In certain embodiments, when measured with monochromatic Kα1 radiation at about 25 °C, crystalline (S)-mandelate has an X-ray powder diffraction pattern comprising peaks at 5.5 ± 0.2, 9.7 ± 0.2, 12.1 ± 0.2, 18.0 ± 0.2, 18.4 ± 0.2, and 19.4 ± 0.2 degrees 2θ. In certain embodiments, the experimental error associated with the X-ray powder diffraction peak values recited in the various embodiments above is ±0.1 degree 2θ. In certain embodiments, crystalline (S)-mandelate is an anhydrous salt. In certain embodiments, the molar ratio of atrasentan to (S)-mandelate is about 1:1.

[0419] In certain embodiments, crystalline (S)-mandelate has an orthorhombic lattice type. In certain embodiments, crystalline (S)-mandelate has a P212121 space group. In certain embodiments, the unit cell a, b, and c values of crystalline (S)-mandelate are respectively about about and about In certain embodiments, the unit cell α, β, and γ values of crystalline (S)-mandelate are respectively about 90°, about 90°, and about 90°. In certain embodiments, crystalline (S)-mandelate has at least three or more of the following properties: (a) an orthorhombic lattice type, (b) a P212121 space group, (c) unit cell a, b, and c values respectively about about and about and / or (d) the α, β, and γ values of the unit cell are approximately 90°, approximately 90°, and approximately 90°, respectively. In certain embodiments, crystalline (S)-mandelate has: (a) an orthorhombic lattice type, (b) a P212121 space group, (c) unit cell a, b, and c values of approximately approximately and approximately and (d) the α, β, and γ values of the unit cell are approximately 90°, approximately 90°, and approximately 90°, respectively. In certain embodiments, crystalline (S)-mandelate is an anhydrous salt. In certain embodiments, the molar ratio of atrasentan to (S)-mandelate is approximately 1:1.

[0420] In certain embodiments, crystalline (S)-mandelate is crystalline atrasentan (S)-mandelate, wherein the molar ratio of atrasentan to (S)-mandelate is approximately 2:1. In certain embodiments, crystalline atrasentan (S)-mandelate is an anhydrous salt. In certain embodiments, crystalline atrasentan (S)-mandelate is a solvated salt. In certain embodiments, crystalline atrasentan (S)-mandelate is a hydrated salt. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is substantially crystalline atrasentan (S)-mandelate, wherein the molar ratio of atrasentan to (S)-mandelate is approximately 2:1.

[0421] In certain embodiments, when measured with monochromatic Kα1 radiation at approximately 25°C, crystalline (S)-mandelate has an X-ray powder diffraction pattern comprising peaks at 4.5 ± 0.2, 8.6 ± 0.2, and 18.1 ± 0.2 degrees 2θ. In certain embodiments, when measured with monochromatic Kα1 radiation at approximately 25°C, crystalline (S)-mandelate has an X-ray powder diffraction pattern comprising peaks at 4.5 ± 0.2, 8.6 ± 0.2, 18.1 ± 0.2, and 18.7 ± 0.2 degrees 2θ. In certain embodiments, when measured with monochromatic Kα1 radiation at approximately 25°C, crystalline (S)-mandelate has an X-ray powder diffraction pattern comprising peaks at 4.5 ± 0.2, 8.6 ± 0.2, 9.1 ± 0.2, 18.1 ± 0.2, and 18.7 ± 0.2 degrees 2θ. In certain embodiments, the experimental error associated with the X-ray powder diffraction peak values listed in the various embodiments above is ±0.1 degree 2θ. In certain embodiments, crystalline (S)-mandelate is an anhydrous salt. In certain embodiments, crystalline (S)-mandelate is a hydrated salt.

[0422] In certain embodiments, crystalline atrasentan mandelate is crystalline atrasentan (R)-mandelate. In certain embodiments, crystalline atrasentan (R)-mandelate is an anhydrous salt. In certain embodiments, crystalline atrasentan (R)-mandelate is a solvated salt. In certain embodiments, crystalline atrasentan (R)-mandelate is a hydrated salt.

[0423] In certain embodiments, crystalline atrasentan (R)-mandelate is crystalline atrasentan (R)-mandelate, wherein the molar ratio of atrasentan to (R)-mandelate is about 1:1. In certain embodiments, crystalline atrasentan (R)-mandelate is an anhydrous salt. In certain embodiments, crystalline atrasentan (R)-mandelate is a solvated salt. In certain embodiments, crystalline atrasentan (R)-mandelate is a hydrated salt. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is substantially crystalline atrasentan (R)-mandelate, wherein the molar ratio of atrasentan to (R)-mandelate is about 1:1.

[0424] In certain embodiments, when measured with monochromatic Kα1 radiation at about 25 °C, crystalline atrasentan (R)-mandelate has an X-ray powder diffraction pattern comprising peaks at 5.7 ± 0.2, 11.8 ± 0.2, and 20.9 ± 0.2 degrees 2θ. In certain embodiments, when measured with monochromatic Kα1 radiation at about 25 °C, crystalline atrasentan (R)-mandelate has an X-ray powder diffraction pattern comprising peaks at 5.7 ± 0.2, 8.2 ± 0.2, 11.8 ± 0.2, and 20.9 ± 0.2 degrees 2θ. In certain embodiments, when measured with monochromatic Kα1 radiation at about 25 °C, crystalline atrasentan (R)-mandelate has an X-ray powder diffraction pattern comprising peaks at 5.7 ± 0.2, 8.2 ± 0.2, 8.6 ± 0.2, 11.8 ± 0.2, and 20.9 ± 0.2 degrees 2θ. In certain embodiments, the experimental error associated with the X-ray powder diffraction peak values recited in the various embodiments above is ±0.1 degree 2θ. In certain embodiments, crystalline atrasentan (R)-mandelate is an anhydrous salt.

[0425] In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof comprises amorphous atrasentan mandelate. In certain embodiments, atrasentan or a pharmaceutically acceptable salt thereof is substantially amorphous atrasentan mandelate.

[0426] In certain embodiments, amorphous atrasentan mandelate is amorphous atrasentan (S)-mandelate. In certain embodiments, amorphous atrasentan (S)-mandelate is an anhydrous salt. In certain embodiments, amorphous atrasentan (S)-mandelate is a solvated salt. In certain embodiments, amorphous atrasentan (S)-mandelate is a solvated salt selected from the group consisting of an acetonitrile solvate, an ethanol solvate, and a pyridine solvate. In certain embodiments, amorphous atrasentan (S)-mandelate is a hydrate salt. In certain embodiments, in amorphous atrasentan (S)-mandelate, the molar ratio of atrasentan to (S)-mandelate is about 1:1. In certain embodiments, in amorphous atrasentan (S)-mandelate, the molar ratio of atrasentan to (S)-mandelate is about 2:1.

[0427] In certain embodiments, amorphous atrasentan mandelate is amorphous atrasentan (R)-mandelate. In certain embodiments, amorphous atrasentan (R)-mandelate is an anhydrous salt. In certain embodiments, amorphous atrasentan (R)-mandelate is a solvated salt. In certain embodiments, amorphous atrasentan (R)-mandelate is a solvated salt selected from the group consisting of an acetonitrile solvate, an ethanol solvate, and a pyridine solvate. In certain embodiments, amorphous atrasentan (R)-mandelate is a hydrate salt. In certain embodiments, in amorphous atrasentan (R)-mandelate, the molar ratio of atrasentan to (R)-mandelate is about 1:1. In certain embodiments, in amorphous atrasentan (R)-mandelate, the molar ratio of atrasentan to (R)-mandelate is about 2:1.

[0428] Crystalline and amorphous atrasentan mandelate are further described in U.S. Patent Nos. 8,962,675 and 9,637,476.

[0429] D. Formulations and Kits

[0430] As used herein, the term "pharmaceutical composition" is intended to cover products containing an active ingredient and inert ingredients that make up a carrier, as well as any product directly or indirectly produced by the combination, compounding, or aggregation of any two or more of these ingredients, or by the dissociation of one or more of these ingredients, or by other types of reactions or interactions of one or more of these ingredients. Accordingly, the pharmaceutical compositions of the present disclosure cover any composition made by mixing a compound of the present disclosure or a pharmaceutically acceptable salt or solvate or solvate of a salt thereof with a pharmaceutically acceptable carrier.

[0431] For the preparation of pharmaceutical or sterile compositions, the active agent is typically admixed with a pharmaceutically acceptable carrier or excipient, see, e.g., Remington's Pharmaceutical Sciences and U.S. Pharmacopeia: National Formulary, Mack Publishing Company, Easton, Pa. (1984). Formulations of one or more active agents can be prepared by admixing with a physiologically acceptable carrier, excipient or stabilizer in the form of, for example, lyophilized powder, slurry, aqueous solution or suspension (see, e.g., Hardman, et al., 2001, Goodman and Gilman’s The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, N.Y.; Gennaro, 2000, Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, N.Y.; Avis et al. (eds.), 1993, Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, N.Y.; Lieberman et al. (eds.), 1990, Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, N.Y.; Lieberman et al. (eds.), 1990, Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, N.Y.; Weiner and Kotkoskie, 2000, Excipient Toxicity and Safety, Marcel Dekker, New York, N.Y.).

[0432] Some embodiments provide a kit comprising: an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or an antigen-binding fragment thereof, wherein the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and the APRIL-binding antibody or an antigen-binding fragment thereof can be in the same dosage form and / or in separate dosage forms. In some embodiments, the kit may further comprise an SGLT-2 inhibitor.

[0433] Some embodiments provide a kit comprising: an SGLT-2 inhibitor and an APRIL-binding antibody or an antigen-binding fragment thereof, wherein the SGLT-2 inhibitor and the APRIL-binding antibody or an antigen-binding fragment thereof can be in the same dosage form and / or in separate dosage forms.

[0434] Exemplary dosage forms of APRIL-binding antibodies or antigen-binding fragments thereof

[0435] Some embodiments provide a sterile liquid formulation of an APRIL-binding antibody or an antigen-binding fragment thereof.

[0436] Exemplary formulations of an APRIL-binding antibody or an antigen-binding fragment thereof and methods for their preparation are further described in U.S. Patent Nos. 9,364,458 and 10,016,393.

[0437] Exemplary dosage forms of endothelin receptor antagonists

[0438] In some embodiments, provided herein are stable solid pharmaceutical dosage forms comprising an endothelin receptor antagonist and a pharmaceutically acceptable diluent.

[0439] Suitable diluents for use in the described dosage forms include, but are not limited to, lactose (e.g., lactose monohydrate, anhydrous lactose, and DCL21), sucrose, glucose, mannitol, sorbitol, isomalt, microcrystalline cellulose (e.g., PH101 and PH102), siliconized microcrystalline cellulose (e.g., SMCC 50 and SMCC 90), dibasic calcium phosphate, starch, and combinations thereof. In some embodiments, the diluent is selected from the group consisting of lactose, mannitol, isomalt, microcrystalline cellulose, dibasic calcium phosphate, and combinations thereof. In some embodiments, the diluent is lactose.

[0440] In some embodiments, the weight percentage of the diluent in the dosage form is from about 70 weight percent to about 99 weight percent. In some embodiments, the weight percentage of the diluent in the dosage form is from about 80 weight percent to about 99 weight percent. In some embodiments, the weight percentage of the diluent in the dosage form is from about 85 weight percent to about 99 weight percent. In certain of the foregoing embodiments, the diluent is selected from the group consisting of lactose, mannitol, isomaltitol, and combinations thereof. As a non-limiting example, the diluent can be lactose.

[0441] In some embodiments, the endothelin receptor antagonist is atrasentan or a pharmaceutically acceptable salt thereof. In some embodiments, the endothelin receptor antagonist is sparsentan or a pharmaceutically acceptable salt thereof.

[0442] In some embodiments, provided herein is a stable solid pharmaceutical dosage form comprising from about 200 mg to about 1,000 mg of sparsentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0443] In some embodiments, provided herein is a stable solid pharmaceutical dosage form comprising: (a) from about 0.25 mg to about 1.25 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof; wherein the weight percentage of atrasentan or a pharmaceutically acceptable salt thereof in the dosage form is from about 0.05 weight percent to about 2.0 weight percent based on the equivalent weight of atrasentan free base; and (b) a pharmaceutically acceptable diluent.

[0444] In some embodiments, provided herein is a stable solid pharmaceutical dosage form comprising: (a) from about 0.25 mg to about 1.25 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof; wherein the weight percentage of atrasentan or a pharmaceutically acceptable salt thereof in the dosage form is from about 0.05 weight percent to about 2.0 weight percent based on the equivalent weight of atrasentan free base; (b) a pharmaceutically acceptable antioxidant; wherein the molar ratio of the antioxidant to atrasentan or a pharmaceutically acceptable salt thereof is from about 10:1 to about 1:10; and (c) a pharmaceutically acceptable diluent.

[0445] The dosage form may comprise the free base of atrasentan, a pharmaceutically acceptable salt of atrasentan, or a combination thereof. In some embodiments, the dosage form comprises the free base of atrasentan. In some embodiments, the dosage form comprises a pharmaceutically acceptable salt of atrasentan. In some embodiments, the dosage form comprises atrasentan hydrochloride. In some embodiments, the dosage form comprises atrasentan hydrochloride having a polymorphic form selected from the group consisting of atrasentan hydrochloride Form 1, atrasentan hydrochloride Form 2, and atrasentan hydrochloride Form 3. In some embodiments, the dosage form comprises amorphous atrasentan hydrochloride. In some embodiments, the dosage form comprises atrasentan hydrochloride Form 1. In some embodiments, the dosage form comprises atrasentan hydrochloride Form 2. In some embodiments, the dosage form comprises atrasentan hydrochloride Form 3. In some embodiments, the dosage form comprises atrasentan mandelate. In certain embodiments, the dosage form comprises crystalline atrasentan mandelate (e.g., crystalline atrasentan (S)-mandelate and / or crystalline atrasentan (R)-mandelate). In certain embodiments, the dosage form comprises amorphous atrasentan mandelate (e.g., amorphous atrasentan (S)-mandelate and / or amorphous atrasentan (R)-mandelate). In certain of the foregoing embodiments (when the dosage form comprises crystalline and / or amorphous atrasentan (S)- and / or (R)-mandelate), the molar ratio of atrasentan to mandelate is 1:1. In certain other embodiments, the molar ratio of atrasentan to mandelate is 2:1.

[0446] In some embodiments, the dosage form comprises from about 0.25 mg to about 1.25 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises from about 0.40 mg to about 1.00 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises from about 0.40 mg to about 0.85 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 0.50 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 0.75 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0447] In some embodiments, the dosage form comprises from about 0.25 mg to about 1.25 mg of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises from about 0.40 mg to about 1.00 mg of atrasentan or an equivalent amount of atrasentan hydrochloride. In some embodiments, the dosage form comprises from about 0.40 mg to about 0.85 mg of atrasentan or an equivalent amount of atrasentan hydrochloride. In some embodiments, the dosage form comprises about 0.50 mg of atrasentan or an equivalent amount of atrasentan hydrochloride. In some embodiments, the dosage form comprises about 0.75 mg of atrasentan or an equivalent amount of atrasentan hydrochloride.

[0448] In some embodiments, the dosage form further comprises a pharmaceutically acceptable disintegrant, and the weight ratio of the disintegrant to an antioxidant (e.g., L-cysteine) or a pharmaceutically acceptable salt or ester thereof is from about 60:1 to about 3:1. In some embodiments, the weight ratio of the disintegrant to an antioxidant (e.g., L-cysteine) or a pharmaceutically acceptable salt or ester thereof is from about 50:1 to about 4:1. In some embodiments, the weight ratio of the disintegrant to an antioxidant (e.g., L-cysteine) or a pharmaceutically acceptable salt or ester thereof is from about 35:1 to about 5:1.

[0449] Suitable antioxidants for use in the described dosage forms include antioxidants that act as reducing agents and are oxidized to pharmaceutically acceptable reduction products in the dosage form. In some embodiments, the redox potential of the antioxidant is less than the redox potential of atrasentan (i.e., the redox potential is less than about 900 mV) and greater than about 550 mV. In some embodiments, the redox potential of the antioxidant is less than about 550 mV. In some embodiments, the redox potential of the antioxidant is from about 1 mV to about 550 mV. In some embodiments, the solubility of the antioxidant in water at about 25 °C is greater than about 24 mg / mL. In some embodiments, the antioxidant is an amino acid or a pharmaceutically acceptable salt or ester thereof. In some embodiments, the antioxidant is cysteine. In some embodiments, the antioxidant is L-cysteine or a pharmaceutically acceptable salt or ester thereof. In some embodiments, the antioxidant is selected from the group consisting of L-cysteine hydrochloride monohydrate, L-cysteine hydrochloride anhydrous, and L-cysteine ethyl ester. In some embodiments, the dosage form comprises L-cysteine hydrochloride monohydrate.

[0450] In some embodiments, the weight percentage of the antioxidant in the dosage form is from about 0.05 weight percent to about 1.0 weight percent. In some embodiments, the weight percentage of the antioxidant in the dosage form is from about 0.07 weight percent to about 0.7 weight percent. In some embodiments, the weight percentage of the antioxidant in the dosage form is from about 0.09 weight percent to about 0.5 weight percent.

[0451] In some embodiments, the molar ratio of the antioxidant to atrasentan or a pharmaceutically acceptable salt thereof is from about 10:1 to about 1:10. In some embodiments, the molar ratio of the antioxidant to atrasentan or a pharmaceutically acceptable salt thereof in the dosage form is from about 5:1 to about 1:5. In some embodiments, the molar ratio of the antioxidant to atrasentan or a pharmaceutically acceptable salt thereof is from about 2:1 to about 1:2. In some embodiments, the molar ratio of the antioxidant to atrasentan or a pharmaceutically acceptable salt thereof is about 1:1.

[0452] In some embodiments, the antioxidant is L-cysteine or a pharmaceutically acceptable salt thereof. In certain embodiments, the weight percentage of L-cysteine or a pharmaceutically acceptable salt or ester thereof in the dosage form is from about 0.05 weight percent to about 1.0 weight percent. In certain embodiments, the weight percentage of L-cysteine or a pharmaceutically acceptable salt or ester thereof in the dosage form is from about 0.07 weight percent to about 0.7 weight percent. In certain embodiments, the weight percentage of L-cysteine or a pharmaceutically acceptable salt or ester thereof in the dosage form is from about 0.09 weight percent to about 0.5 weight percent.

[0453] In some embodiments, the dosage form is a solid pharmaceutical dosage form that comprises from about 0.25 mg to about 1.25 mg of atrasentan or a pharmaceutically acceptable salt thereof (e.g., atrasentan hydrochloride) on the basis of the equivalent weight of atrasentan parent. In some embodiments, the dosage form is a solid pharmaceutical dosage form that comprises from about 0.40 mg to about 1.00 mg of atrasentan or a pharmaceutically acceptable salt thereof (e.g., atrasentan hydrochloride) on the basis of the equivalent weight of atrasentan parent. In some embodiments, the dosage form is a solid pharmaceutical dosage form that comprises about 0.50 mg of atrasentan or a pharmaceutically acceptable salt thereof (e.g., atrasentan hydrochloride) on the basis of the equivalent weight of atrasentan parent. In some embodiments, the dosage form is a solid pharmaceutical dosage form that comprises about 0.75 mg of atrasentan or a pharmaceutically acceptable salt thereof (e.g., atrasentan hydrochloride) on the basis of the equivalent weight of atrasentan parent.

[0454] In certain of the foregoing embodiments, the dosage form is a tablet.

[0455] Some embodiments provide a kit that comprises (a) a pharmaceutical composition comprising an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof; (b) an APRIL-binding antibody or an antigen-binding fragment thereof; and (c) instructions for use.

[0456] E. Dosage and Administration

[0457] In some embodiments, the dose of the APRIL-binding antibody or antigen-binding fragment thereof is from about 4 mg / kg to about 15 mg / kg, such as about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 5.5 mg / kg, about 6 mg / kg, about 6.5 mg / kg, about 7 mg / kg, about 7.5 mg / kg, about 8 mg / kg, about 8.5 mg / kg, about 9 mg / kg, about 9.5 mg / kg, about 10 mg / kg, about 10.5 mg / kg, about 11 mg / kg, about 11.5 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 13.5 mg / kg, about 14 mg / kg, about 14.5 mg / kg or about 15 mg / kg. In some embodiments, the dose of the APRIL-binding antibody or antigen-binding fragment thereof is from about 4 mg / kg to about 10 mg / kg. In some embodiments, the dose of the APRIL-binding antibody or antigen-binding fragment thereof is from about 8 mg / kg to about 12 mg / kg. In some embodiments, the dose of the APRIL-binding antibody or antigen-binding fragment thereof is from about 10 mg / kg to about 15 mg / kg.

[0458] In some embodiments, the total dose of the APRIL-binding antibody or antigen-binding fragment thereof is from about 450 mg to about 600 mg. In some embodiments, the total dose of the APRIL-binding antibody or antigen-binding fragment thereof is 450 mg or 600 mg.

[0459] In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof is administered parenterally. Parenteral administration refers to a mode of administration other than enteral and topical administration, typically by injection, and includes epidermal, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, intratracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural and intrasternal injection and infusion. In some embodiments, the route of administration of the APRIL-binding antibody or antigen-binding fragment thereof is intravenous injection or infusion. In some embodiments, the route of administration of the APRIL-binding antibody or antigen-binding fragment thereof is intravenous infusion. In some embodiments, the route of administration of the APRIL-binding antibody or antigen-binding fragment thereof is intravenous injection. In some embodiments, the route of administration of the APRIL-binding antibody or antigen-binding fragment thereof is subcutaneous injection.

[0460] In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof is administered once a week. In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof is administered once every other week (i.e., once every two weeks). In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof is administered once every three weeks. In some embodiments, the APRIL-binding antibody or antigen-binding fragment thereof is administered once a month.

[0461] In some embodiments, the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is administered at the approved dose of the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof.

[0462] In some embodiments, the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is sparsentan or a pharmaceutically acceptable salt thereof, and the sparsentan is administered at a dose of about 200 mg to about 1,000 mg, or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the sparsentan is administered at a dose of about 200 mg to about 600 mg, or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the sparsentan is administered at a dose of about 400 mg to about 800 mg, or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the sparsentan is administered at a dose of 200 mg, 400 mg or 600 mg, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0463] In some embodiments, the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is atrasentan or a pharmaceutically acceptable salt thereof, and the atrasentan is administered at a dose of about 0.10 mg to about 1.50 mg (e.g., about 0.10, about 0.20, about 0.30, about 0.40, about 0.50, about 0.60, about 0.70, about 0.75, about 0.80, about 0.90, about 1.00, about 1.10, about 1.20, about 1.30, about 1.40, about 1.50 or any value therebetween) of atrasentan or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, the dose of atrasentan is about 0.75 mg, or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, the dose of atrasentan is about 0.25 mg, or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, the dose of atrasentan is about 0.35 mg, or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, the dose of atrasentan is about 1.00 mg, or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, the dose of atrasentan is about 1.25 mg, or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, the dose of atrasentan is about 1.50 mg, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0464] In some embodiments, the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is administered orally (e.g., as a tablet or capsule).

[0465] In some embodiments, the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is administered every other day.

[0466] In some embodiments, the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is administered more than once daily, e.g., in divided doses. In some embodiments, the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is administered once daily. For example, in some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is administered once daily to a subject. In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is administered once daily to a subject at a dose of about 0.75 mg of atrasentan free base. In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is administered once daily to a subject at a dose of 0.75 mg of atrasentan free base. In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is administered once daily to a subject at a dose of about 0.25 mg of atrasentan free base. In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is administered once daily to a subject at a dose of 0.25 mg of atrasentan free base. In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is administered once daily to a subject at a dose of about 0.35 mg of atrasentan free base. In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is administered once daily to a subject at a dose of 0.35 mg of atrasentan free base. In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is administered once daily to a subject at a dose of about 1.00 mg of atrasentan free base. In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is administered once daily to a subject at a dose of 1.00 mg of atrasentan free base. In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is administered once daily to a subject at a dose of about 1.50 mg of atrasentan free base. In some embodiments, atrasentan or a pharmaceutically acceptable salt thereof is administered once daily to a subject at a dose of 1.50 mg of atrasentan free base.

[0467] In some embodiments, the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount. In some embodiments, the APRIL-binding antibody or an antigen-binding fragment thereof is administered in a therapeutically effective amount. In some embodiments, when administered together, the endothelin...

Claims

1. A method for treating IgA nephropathy, the method comprising administering to a subject an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof, and an APRIL-binding antibody or an antigen-binding fragment thereof.

2. A method for reducing renal inflammation and / or fibrosis in a subject having IgA nephropathy, the method comprising administering to the subject an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof, and an APRIL-binding antibody or an antigen-binding fragment thereof.

3. A method for reducing the occurrence of renal hematuria in a subject having IgA nephropathy, the method comprising administering to the subject an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof, and an APRIL-binding antibody or an antigen-binding fragment thereof.

4. A method for stabilizing eGFR in a subject having IgA nephropathy, the method comprising administering to the subject an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof, and an APRIL-binding antibody or an antigen-binding fragment thereof.

5. The method according to any one of claims 1 to 4, wherein the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is selected from the group consisting of tezosentan, selexipag, bosentan, sparsentan, macitentan, ambrisentan, sitaxentan, atrial natriuretic peptide, atrasentan, and pharmaceutically acceptable salts of any one of the foregoing, and combinations thereof.

6. The method according to any one of claims 1 to 5, wherein the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is sparsentan or a pharmaceutically acceptable salt thereof.

7. The method according to any one of claims 1 to 5, wherein the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof is atrasentan or a pharmaceutically acceptable salt thereof.

8. The method according to claim 5 or claim 7, wherein atrasentan is administered as a pharmaceutically acceptable salt.

9. The method according to any one of claims 1 to 5, 7, and 8, wherein atrasentan or a pharmaceutically acceptable salt thereof is administered to the subject in an amount equivalent to about 0.20 mg to about 1.50 mg of atrasentan free base.

10. The method according to claim 9, wherein atrasentan or a pharmaceutically acceptable salt thereof is administered to the subject in an amount equivalent to about 0.75 mg of atrasentan free base.

11. The method according to claim 8, wherein the pharmaceutically acceptable salt of atrasentan is atrasentan hydrochloride or atrasentan mandelate.

12. The method according to claim 11, wherein the pharmaceutically acceptable salt of atrasentan is atrasentan hydrochloride.

13. The method according to claim 11, wherein the pharmaceutically acceptable salt of atrasentan is atrasentan mandelate.

14. The method according to any one of claims 1 to 5, 7, 9, and 10, wherein atrasentan is administered as a free base.

15. The method according to any one of claims 1 to 14, wherein the APRIL-binding antibody or an antigen-binding fragment thereof comprises: (a) heavy chain complementarity determining region-1 (HC CDR1) which comprises the amino acid sequence of SEQ ID NO:1; (b) Heavy chain complementarity determining region-2 (HC CDR2), which comprises the amino acid sequence of SEQ ID NO:2; (c) Heavy chain complementarity determining region-3 (HC CDR3), which comprises the amino acid sequence of SEQ ID NO:3; (d) Light chain complementarity determining region-1 (LC CDR1), which comprises the amino acid sequence of SEQ ID NO:4; (e) Light chain complementarity determining region-2 (LC CDR2), which comprises the amino acid sequence of SEQ ID NO:5; and (f) Light chain complementarity determining region-3 (LC CDR3), which comprises the amino acid sequence of SEQ ID NO:

6.

16. The method according to any one of claims 1 to 15, wherein the APRIL-binding antibody or antigen-binding fragment thereof comprises a heavy chain variable region, and the heavy chain variable region comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:8, 10, 12, 14, 16, 18, 20, 22 or 24.

17. The method according to any one of claims 1 to 16, wherein the APRIL-binding antibody or antigen-binding fragment thereof comprises a light chain variable region, and the light chain variable region comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:

26.

18. The method according to any one of claims 1 to 17, wherein the APRIL-binding antibody or antigen-binding fragment thereof comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO:24 and a light chain variable region containing the amino acid sequence of SEQ ID NO:

26.

19. The method according to any one of claims 1 to 18, wherein the APRIL-binding antibody or antigen-binding fragment thereof comprises a heavy chain, and the heavy chain comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:

28.

20. The method according to any one of claims 1 to 19, wherein the APRIL-binding antibody or antigen-binding fragment thereof comprises a light chain, and the light chain comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:

30.

21. The method according to any one of claims 1 to 20, wherein the APRIL-binding antibody or antigen-binding fragment thereof comprises a heavy chain containing the amino acid sequence of SEQ ID NO:28 and a light chain containing the amino acid sequence of SEQ ID NO:

30.

22. The method according to any one of claims 1 to 21, wherein the APRIL-binding antibody or antigen-binding fragment thereof is generated from a nucleic acid comprising one of SEQ ID NO:7, 9, 11, 13, 15, 17, 19, 21 or 23.

23. The method according to any one of claims 1 to 22, wherein the APRIL-binding antibody or antigen-binding fragment thereof is generated from a nucleic acid comprising SEQ ID NO:25, 27, 29, 31 or 33.

24. The method according to any one of claims 1 to 23, wherein the APRIL-binding antibody or antigen-binding fragment thereof is administered once a day, once every 2 days, once every 3 days, twice a week, once a week, once every 2 weeks, once every 3 weeks, once a month, once every 6 weeks, once every 2 months, or once every 3 months, optionally for a period of at least about 1 week, 2 weeks, 1 month (4 weeks), 6 weeks, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years or longer.

25. The method according to any one of claims 1 to 24, wherein about 0.05 mg / kg to about 8 mg / kg of the APRIL-binding antibody or antigen-binding fragment thereof is administered to the subject.

26. The method according to any one of claims 1 to 25, wherein the method comprises repeated administration of the APRIL-binding antibody or antigen-binding fragment thereof at a schedule of at least once a week (QW) for at least 2 dosing cycles; or wherein the method comprises repeated administration of the APRIL-binding antibody or antigen-binding fragment thereof at a schedule of at least once every two weeks (Q2W) for at least 2 dosing cycles; or wherein the method comprises repeated administration of the APRIL-binding antibody or antigen-binding fragment thereof at a schedule of at least once every 4 weeks (Q4W) or once a month (QMT) for at least 2 dosing cycles.

27. The method according to any one of claims 24 to 26, which comprises administering the APRIL-binding antibody or antigen-binding fragment thereof by a loading / maintenance dosing regimen.

28. The method according to any one of claims 1 to 28, wherein the subject is concurrently receiving an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), or a combination thereof.

29. The method according to any one of claims 1 to 29, which further comprises administering a therapeutically effective amount of a sodium-glucose cotransporter-2 (SGLT-2) inhibitor.

30. A kit comprising: an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and an APRIL-binding antibody or antigen-binding fragment thereof, wherein the endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and the APRIL-binding antibody or antigen-binding fragment thereof may be in the same dosage form and / or in separate dosage forms.

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