Methods for treating IGA nephropathy (IGAN) and monitoring responsiveness to treatment

Abstract

Provided herein are methods for treating immunoglobulin A nephropathy (IgAN) in a human patient using an anti‑C5 antibody, such as ravulizumab (ULTOMIRIS®), as well as methods of monitoring responsiveness of a patient having IgAN to treatment with an anti-C5 antibody

Description

[0001] ALXN-1004-PCT01-NP (PCT)

[0002] METHODS FOR TREATING IGA NEPHROPATHY (IGAN) AND MONITORING RESPONSIVENESS TO TREATMENT

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No.

[0004] 63 / 779,708, filed March 28, 2025, which is incorporated herein by reference in its entirety.

[0005] BACKGROUND

[0006] Chronic kidney disease (CKD) has become a worldwide public health issue due to its high incidence, poor prognosis, and substantial economic burden. When not properly diagnosed and managed, CKD can lead to many adverse outcomes, such as end-stage renal disease (ESRD). Despite advances in immunosuppressive treatments, immunoglobulin A nephropathy (IgAN) continues to respond poorly to treatment, resulting over time in CKD. No disease-specific therapies are currently available, therefore effective treatments for IgAN, represent a high unmet medical need. Accordingly, it is an object of the present disclosure to provide improved methods for treating patients with IgAN.

[0007] SUMMARY

[0008] Provided herein are methods for treating immunoglobulin A nephropathy (IgAN) in a human patient, as well as methods of monitoring responsiveness of a patient having IgAN to treatment with an anti-C5 antibody.

[0009] In one aspect, provided herein is method for treating a patient with immunoglobulin A nephropathy (IgAN) who has been determined to have a 24 hour urine protein (UP) measurement > 1 g / day, the method comprising administering to the patient an anti-C5 antibody in an amount and with a frequency sufficient to decrease albumin to creatinine ratio in a urine sample from the patient compared to Baseline, wherein the decrease is assessed by a spot urine albumin-creatinine ratio (UACR), thereby treating IgAN in the patient.

[0010] In another aspect, provided herein is a method for treating a patient with IgAN comprising:

[0011] (1) determining or having determined that the patient has a 24 hour UP measurement > 1 g / day, and

[0012] (2) administering to the patient an anti-C5 antibody in an amount and with a frequency sufficient to decrease albumin to creatinine ratio in a urine sample from the patient comparedALXN-1004-PCT01-NP (PCT) to Baseline, wherein the decrease is assessed by a UACR, thereby treating IgAN in the patient.

[0013] In another aspect, provided herein is a method for monitoring responsiveness of a patient having IgAN to treatment with an anti-C5 antibody, the method comprising: determining a UACR in urine samples from the patient obtained during and after treatment, wherein: a decrease in albumin to creatinine ratio in a urine sample from the patient after treatment compared to Baseline, indicates that the patient is responsive to treatment with the anti -C 5 antibody.

[0014] In some embodiments, the method further comprising determining a Urine Protein-to-Creatinine Ratio (UPCR) in urine samples from the patient obtained during and after treatment, wherein: a decrease in albumin to creatinine ratio in a urine sample from the patient after treatment compared to Baseline as assessed by UACR and UPCR, indicates that the patient is responsive to treatment with the anti-C5 antibody.

[0015] In some embodiments, the patient has an estimated glomerular filtration rate (eGFR) > 30 mL / min / 1.73m2 prior to treatment. In some embodiments, the patient is an IgAN patient who has previously been treated with a renin-angiotensin system (RAS) inhibiting medication, such as an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB).

[0016] In some embodiments, a UACR of less than 30 mg / g is considered normal for a healthy patient (e.g., 29 mg / g, 28 mg / g, 27 mg / g, 26 mg / g, 25 mg / g, 24 mg / g, 23 mg / g, 22 mg / g, 21 mg / g, 20 mg / g, 19 mg / g, 18 mg / g, 17 mg / g, 16 mg / g, 15 mg / g, 14 mg / g, 13 mg / g, 12 mg / g, 11 mg / g, 10 mg / g, 9 mg / g, 8 mg / g, 7 mg / g, 6 mg / g, 5 mg / g, 4 mg / g, 3 mg / g, 2 mg / g, 1 mg / g, or 0 mg / g. In some embodiments, the treatment results in a UACR of less than 10 mg / g (e.g., 10 mg / g, 9 mg / g, 8 mg / g, 7 mg / g, 6 mg / g, 5 mg / g, 4 mg / g, 3 mg / g, 2 mg / g, 1 mg / g, or 0 mg / g). In some embodiments, the treatment results in a UACR of less than 5 mg / g (e.g., 5 mg / g, 4 mg / g, 3 mg / g, 2 mg / g, 1 mg / g, or 0 mg / g). In some embodiments, the treatment results in a UACR of less than 3 mg / g (e.g., 3 mg / g, 2 mg / g, 1 mg / g, or 0 mg / g). In some embodiments, the treatment results in a UACR of about 0 mg / g.

[0017] In some embodiments, the treatment results in a 20% or more decrease in albumin to creatinine ratio in a urine sample from the patient compared to Baseline, as assessed by a UACR. For example, in some embodiments, the treatment results in a 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%,ALXN-1004-PCT01-NP (PCT) 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% decrease in albumin to creatinine ratio in a urine sample from the patient compared to Baseline, as assessed by a UACR. In some embodiments, the treatment results a UACR of about 0 mg / g.

[0018] In some embodiments, a UPCR of less than 0.2 mg / mg is considered normal for a healthy patient. In some embodiments, the treatment results in a 20% or more decrease in albumin to creatinine ratio in a urine sample from the patient compared to Baseline, as assessed by a UPCR. For example, in some embodiments, the treatment results in a 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% decrease in albumin to creatinine ratio in a urine sample from the patient compared to Baseline, as assessed by a UPCR.

[0019] In some embodiments, the treatment results in a decrease in albumin to creatinine ratio in a urine sample from the patient at 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, or 30 weeks after treatment compared to baseline, as assessed by a UACR. In some embodiments, the treatment results in a decrease in albumin to creatinine ratio in a urine sample from the patient at 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, or 30 weeks after treatment after treatment compared to baseline, as assessed by a UACR and UPCR.

[0020] In some embodiments, the anti-C5 antibody is a human antibody, a humanized antibody, a bispecific antibody, a chimeric antibody, a Fab, a Fab’2, a ScFv, a SMIP, an Affibody®, a nanobody, or a domain antibody which inhibits C5.

[0021] An exemplary anti-C5 antibody is ravulizumab (UUTOMIRIS®) comprising the heavy and light chains having the sequences shown in SEQ ID NOs: 14 and 11, respectively, or antigen binding fragments and variants thereof. In other embodiments, the antibody comprises the heavy and light chain complementarity determining regions (CDRs) or variable regions (VRs) of ravulizumab. Accordingly, in one embodiment, the antibody comprises theALXN-1004-PCT01-NP (PCT) CDR1, CDR2 and CDR3 domains of the heavy chain variable (VH) region of ravulizumab having the sequence shown in SEQ ID NO: 12, and the CDR1, CDR2 and CDR3 domains of the light chain variable (VL) region of ravulizumab having the sequence shown in SEQ ID NO:8. In another embodiment, the antibody comprises CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs:19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO:8, respectively. In another embodiment, the antibody comprises a heavy chain constant region as set forth in SEQ ID NO: 13.

[0022] In another embodiment, the antibody comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgGFc constant region, each according to the EU numbering convention.

[0023] In another embodiment, the antibody comprises CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs:19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively and a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each according to the EU numbering convention.

[0024] In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the BNJ421 antibody (described in WO2015134894 and US Patent No. 9,079,949). In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the 7086 antibody (see US Patent Nos. 8,241,628 and 8,883,158). In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the 8110 antibody (see US Patent Nos. 8,241,628 and 8,883,158). In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the 305LO5 antibody (see US Patent No. 9,765,135). In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the SKY59 antibody. In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the REGN3918 antibody.ALXN-1004-PCT01-NP (PCT) In another embodiment, the antibody competes for binding with, and / or binds to the same epitope on C5 as any of the above-mentioned antibodies. In another embodiment, the antibody has at least about 90% variable region amino acid sequence identity to any of the above-mentioned antibodies (e.g., at least about 90%, 95% or 99% variable region identity with SEQ ID NO: 12 or SEQ ID NO: 8).

[0025] In another embodiment, the antibody binds to human C5 at pH 7.4 and 25°C with an affinity dissociation constant (KD) that is in the range 0.1 nM < KD < 1 nM. In another embodiment, the antibody binds to human C5 at pH 7.4 and 25°C with an affinity dissociation constant (KD) of about 0.5 nM. In another embodiment, the antibody binds to human C5 at pH 6.0 and 25°C with a KD > 10 nM. In another embodiment, the antibody binds to human C5 at pH 6.0 and 25°C with a KD of about 22 nM. In yet another embodiment, the [(KD of the antibody or antigen-binding fragment thereof for human C5 at pH 6.0 and at 25°C) / (KD of the antibody or antigen-binding fragment thereof for human C5 at pH 7.4 and at 25°C)] of the antibody is greater than 25.

[0026] In some embodiments, the methods comprise administering to the patient an anti-C5 antibody according to a particular clinical dosage regimen (e.g., at a particular dose amount and according to a specific dosing schedule). In some embodiments, the dose of the anti-C5 antibody, or antigen binding fragment thereof, is based on the weight of the patient. In certain embodiments, dosage regimens are adjusted to provide the optimum desired response e.g., an effective response).

[0027] In some embodiments, the anti-C5 antibody is administered:

[0028] (a) once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 40 to < 60 kg;

[0029] (b) once on Day 1 at a dose of 2700 mg, followed by a dose of 3900 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 60 to < 100 kg; or

[0030] (c) once on Day 1 at a dose of 3000 mg, followed by a dose of 5400 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 100 kg.

[0031] In some embodiments, the anti-C5 antibody is administered:

[0032] (a) once on Day 1 at a dose of 1200 mg, followed by a dose of 2700 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 30 to < 40 kg;

[0033] (b) once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 40 to < 60 kg;ALXN-1004-PCT01-NP (PCT) (c) once on Day 1 at a dose of 2700 mg, followed by a dose of 3300 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 60 to < 100 kg; or

[0034] (d) once on Day 1 at a dose of 3000 mg, followed by a dose of 3600 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 100 kg.

[0035] In some embodiments, the patient is an adult patient. In some embodiments, the patient is a pediatric patient. In some embodiments, the pediatric patient is treated according to the dosing regimen described in U.S. Provisional Application No. 63 / 746,039 (filed January 16, 2025), the contents of which are expressly incorporated herein by reference.

[0036] In some embodiments, the treatment results in a reduction or cessation in one or more of the following symptoms compared to baseline: foamy urine, proteinuria, edema, high blood pressure, kidney inflammation, kidney impairmentjoint pain,joint swelling, muscle pain, fever with no known cause, high levels of creatinine in the blood, and / or a red rash.

[0037] In some embodiments, the treatment results in a Partial Renal Response (PRR). In some embodiments, the treatment results in a Complete Renal Response (CRR).

[0038] Further provided herein are kits for treating IgAN in a human patient. In some embodiments, the kit comprises:

[0039] (a) a dose of an anti-C5 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:8; and

[0040] (b) instructions for using the anti-C5 antibody in any of the methods described herein.

[0041] In another aspect, provided herein is an anti-C5 antibody, for use in treatment of a patient having IgAN who has been determined to have a 24 hour urine protein (UP) measurement > 1 g / day, wherein the anti-C5 antibody is administered to the patient in an amount and with a frequency sufficient to decrease albumin to creatinine ratio in a urine sample from the patient compared to Baseline, wherein the decrease is assessed by a spot urine albumin-creatinine ratio (UACR).

[0042] In another aspect, provided herein is an anti-C5 antibody, for use in monitoring responsiveness of a patient having IgAN to treatment with the anti-C5 antibody, comprising: determining a UACR in urine samples from the patient obtained during and after treatment, wherein a decrease in albumin to creatinine ratio in a urine sample from the patient afterALXN-1004-PCT01-NP (PCT) treatment compared to Baseline, indicates that the patient is responsive to treatment with the anti -C 5 antibody.

[0043] In another aspect, provided herein is the use of an anti-C5 for treatment of a patient having IgAN who has been determined to have a 24 hour urine protein (UP) measurement > 1 g / day, wherein the anti-C5 antibody is administered to the patient in an amount and with a frequency sufficient to decrease albumin to creatinine ratio in a urine sample from the patient compared to Baseline, wherein the decrease is assessed by a spot urine albumin-creatinine ratio (UACR).

[0044] In another aspect, provided herein is the use of an anti-C5 antibody in monitoring responsiveness of a patient having IgAN to treatment with the anti-C5 antibody, comprising: determining a UACR in urine samples from the patient obtained during and after treatment, wherein a decrease in albumin to creatinine ratio in a urine sample from the patient after treatment compared to Baseline, indicates that the patient is responsive to treatment with the anti -C 5 antibody.

[0045] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic of the study.

[0046] FIGs. 2A-2D show the correlation between spot and 24 assessments from Baseline to Week 50. Specifically, FIG. 2A shows the spot UPCR and 24 hour UPCR Spearman correlation coefficient. FIG. 2B shows the spot UPCR and spot UACR Spearman correlation coefficient. Note: The ‘n’ values represent the number of patient assessments where both clinical measures were collected and used to calculate the Spearman Correlation.

[0047] FIG. 2C shows the spot UPCR and 24 hour UP Spearman correlation coefficient. FIG. 2D shows the spot UACR and 24 hour UACR Spearman correlation coefficient.

[0048] FIGs. 3A-3C are Bland- Altman plots for difference versus average of spot UPCR and 24h UPCR. Specifically, FIG. 3A shows ravulizumab and placebo initial evaluation at baseline. FIG. 3B shows ravulizumab at Week 26. FIG. 3C shows placebo at Week 26. Note: only patients with both assessments are displayed. Difference is defined as spot UPCR (g / g) minus 24h UPCR (g / g).

[0049] DETAILED DESCRIPTION

[0050] As described herein and exemplified in the working Example, it has been discovered that urinary albumin creatinine ration (UACR) is a reliable test for use in IgAN treatments,ALXN-1004-PCT01-NP (PCT) including treatments with an anti-C5 antibody, such as ravulizumab (ULTOMIRIS®).

[0051] Specifically, UACR can be used as either a substitute for, or in addition to, urinary protein creatinine ratio (UPCR) in methods of treating an IgAN patient with an anti-C5 antibody, as well as monitoring responsiveness of the patient to the treatment.

[0052] I. Definitions

[0053] As used herein, the term “subject” or “patient” is a human patient (e.g., a patient having IgAN).

[0054] As used herein, the term “pediatric” patient is a human patient that has been classified by a physician or caretaker as belonging to a non-adult category and can include, e.g., newborn (both preterm and of term), infants, children, and adolescents. Typically, pediatric patients are patients under 18 years of age (<18 years of age).

[0055] As used herein, the term “adult” patient is a human patient that has been classified by a physician or caretaker as such, e.g., one who is not a newborn, infant, child or adolescent, e.g., based on age, developmental status, physiological features, etc. Typically, adult patients are patients who are 18 years of age or older (>18 years of age).

[0056] As used herein, “urine albumin-creatinine ratio” (UACR) refers to a test that measures the amount of albumin (a protein) in the urine relative to the amount of creatinine (a waste product). It is used to assess kidney function and detect early signs of kidney damage. To obtain a UACR, a urine sample is collected and analyzed for albumin and creatinine. The ratio of albumin to creatinine is then calculated and expressed in milligrams per gram (mg / g). A normal UACR is generally less than 30 mg / g. Preferably, a normal UACR is about 0 mg / g. A UACR between 30 and 300 mg / g may indicate microalbuminuria, which is an early sign of kidney damage. A UACR over 300 mg / g may indicate macroalbuminuria, which is a more severe form of kidney damage.

[0057] As used herein, “urine protein to creatinine ratio” (UPCR) refers to a test that measures the amount of protein in the urine relative to the amount of creatinine. The purpose of the UPCR test is to detect proteinuria (excess protein in the urine), which can be a sign of kidney damage or other underlying medical conditions. To obtain a UPCR, a urine sample is collected and analyzed for protein and creatinine levels. The UPCR is calculated by dividing the protein concentration by the creatinine concentration. The normal UPCR range varies depending on age, sex, and other factors. Generally, a UPCR of less than 0.2 mg / mg is considered normal. A high UPCR result may indicate proteinuria.ALXN-1004-PCT01-NP (PCT) As used herein, IgA nephropathy (IgAN), also known as Berger’s disease, refers to the most common global primary glomerulonephropathy that can progress to renal failure (see, e.g., Lai etal., FlOOOResearch. 2016;5 : 161). Symptoms of IgAN include, but are not limited to, hematuria (blood in the urine that can sometimes make it pink, dark brown or cola colored), edema (e.g., in the hands, ankles or feet), pain on the side of the back (flank pain), high blood pressure (hypertension), and / or foamy urine (due to proteinuria, excess protein in urine).

[0058] Immunoglobulin A (IgA) nephropathy is a lifelong disease leading to CKD and progresses to ESRD in 30% to 40% of patients over the course of 20 to 30 years (Lai, 2016). Patients initially present with hematuria and hypertension and proteinuria develops as the disease progresses. Diagnosis of IgAN is made by renal biopsy demonstrating IgA immunofluorescence in the glomeruli usually co-dominant with complement 3 (C3) according to the Oxford Classification nomenclature (see, e.g., KDIGO Clinical practice guideline for glomerulonephritis. Kidney International Supplements. 2012;2(2):140, Rizk eta!.. Front Immunol. 2019; 10:504; and Trimarchi et al., Kidney Int. 2017;91(5): 1014-1021).

[0059] The pathophysiology of IgAN is related to the overproduction of under-glycosylated immunoglobulin Al (IgAl) which accumulates in the kidney glomeruli. However, aberrant galactosylation alone is insufficient to induce renal injury; glycan-specific immunoglobulin A (IgA) and immunoglobulin G (IgG) autoantibodies that recognize the under-galactosylated IgAl molecule likely also contribute. This process leads to the local inflammation and complement activation in the kidney (see, e.g., Oortwijn et al., Semin Nephrol. 2008;28(l):58-65). Both the alternative and lectin complement pathways may be activated, leading to generation of anaphylatoxins, and the membrane attack complex terminal complement (C5b-9), with subsequent promotion of inflammatory mediators (see, e.g., Maillard et al., J Am Soc Nephrol. 2015;26(7): 1503-1512). Complement component 4 (C4) and C3 complexes and activated C3 products are elevated in up to 30% of patients with IgAN. Activated C3 products are associated with elevated levels of proteinuria and hematuria compared to patients with IgAN who have normal levels, and correlate with deterioration of renal function (see, e.g., Zwirner et al., Kidney Int. 1997;51(4): 1257-64). Complement activity on kidney biopsy and circulating complement proteins are associated with disease activity and progression of CKD. Together these findings suggest a role of complement in the pathophysiology and the prognostic value of complement biomarkers in IgAN (see, e.g., Rizk et al., Front Immunol.

[0060] 2019;10:504).ALXN-1004-PCT01-NP (PCT) Treatments for IgAN include RAS blocking agents, such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). These therapies are aimed at controlling blood pressure, preserving kidney function through decreasing intraglomerular pressure which in turn reduces proteinuria, and suppressing the immune response. These treatments are insufficient in preserving renal function as the proportions of patients who progress to CKD and ESRD are high. Patients with baseline hypertension and proteinuria > 1 g / day are at increased risk for progression (see Reich, et al., J Am Soc Nephrol. 2007;18(12):3177-3183.).

[0061] As used herein, “effective treatment” refers to treatment producing a beneficial effect, e.g., amelioration of at least one symptom of a disease or disorder. A beneficial effect can take the form of an improvement over baseline, e.g., an improvement over a measurement or observation made prior to initiation of therapy according to the method. Effective treatment may refer to alleviation of at least one symptom of LN (e.g., foamy urine (due to proteinuria, excess protein in urine), edema (e.g., in the hands, ankles or feet), high blood pressure (hypertension), kidney inflammation, kidney impairmentjoint pain or swelling, muscle pain, fever with no known cause, high levels of creatinine in the blood, and / or a red rash (e.g., often on the face, across the nose and cheeks, sometimes called a butterfly rash because of its shape). Effective treatment may refer to alleviation of at least one symptom of IgAN (e.g., hematuria (blood in the urine that can sometimes make it pink, dark brown or cola colored), edema (e.g., in the hands, ankles or feet), pain on the side of the back (flank pain), high blood pressure (hypertension), and / or foamy urine (due to proteinuria, excess protein in urine)).

[0062] The term “effective amount” refers to an amount of an agent that provides the desired biological, therapeutic and / or prophylactic result. That result can be reduction, amelioration, palliation, lessening, delaying and / or alleviation of one or more of the signs, symptoms or causes of a disease, or any other desired alteration of a biological system. In one example, an “effective amount” is the amount of anti-C5 antibody, or antigen binding fragment thereof, clinically proven to alleviate at least one symptom of LN (e.g., foamy urine (due to proteinuria, excess protein in urine), edema (e.g., in the hands, ankles or feet), high blood pressure (hypertension), kidney inflammation, kidney impairmentjoint pain or swelling, muscle pain, fever with no known cause, high levels of creatinine in the blood, and / or a red rash (e.g., often on the face, across the nose and cheeks, sometimes called a butterfly rash because of its shape)) and / or IgAN (e.g., hematuria (blood in the urine that can sometimes make it pink, dark brown or cola colored), edema (e.g., in the hands, ankles or feet), pain onALXN-1004-PCT01-NP (PCT) the side of the back (flank pain), high blood pressure (hypertension), and / or foamy urine (due to proteinuria, excess protein in urine)).

[0063] An effective amount can be administered in one or more administrations.

[0064] As used herein, the term “loading dose” refers to the first dose administered (e.g., during an administration cycle).

[0065] As used herein, the terms “maintenance” and “maintenance phase” are used interchangeably and refer to the second phase of treatment. In certain embodiments, treatment is continued as long as clinical benefit is observed or until unmanageable toxicity or disease progression occurs.

[0066] As used herein, the term “serum trough level” refers to the lowest level that the agent (e.g., the anti-C5 antibody, or antigen binding fragment thereof) or medicine is present in the serum. In contrast, a “peak serum level,” refers to the highest level of the agent in the serum. The “average serum level,” refers to the mean level of the agent in the serum over time.

[0067] The term “antibody” describes a polypeptide comprising at least one antibody-derived antigen binding site (e.g., VH / VL region or Fv, or CDR). Antibodies include known forms of antibodies, e.g., the antibody can be a human antibody, a humanized antibody, a bispecific antibody or a chimeric antibody. The antibody also can be a Fab, Fab’2, ScFv, SMIP, Affibody®, nanobody or a single-domain antibody. The antibody also can be of any of the following isotypes: IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgAsec, IgD, IgE or combinations thereof. The antibody can be a naturally occurring antibody or an antibody that has been altered by a protein engineering technique (e.g., by mutation, deletion, substitution, conjugation to a non-antibody moiety). An antibody can include, for example, one or more variant amino acids (compared to a naturally occurring antibody) that change a property (e.g., a functional property) of the antibody. Numerous such alterations are known in the art that affect, e.g., half-life, effector function, and / or immune responses to the antibody in a patient. The term antibody also includes artificial or engineered polypeptide constructs that comprise at least one antibody-derived antigen binding site.

[0068] II. Anti-C5 Antibodies

[0069] Anti-C5 antibodies described herein bind to complement component C5 (e.g., human C5) and inhibit the cleavage of C5 into fragments C5a and C5b. As described above, such antibodies also have, for example, improved pharmacokinetic properties relative to other anti-C5 antibodies (e.g., eculizumab) used for therapeutic purposes.ALXN-1004-PCT01-NP (PCT) Anti-C5 antibodies (or VH / VL domains derived therefrom) suitable for use in the methods described herein can be generated using methods known in the art. Alternatively, art recognized anti-C5 antibodies can be used. Antibodies that compete for binding to C5 with any of these art recognized antibodies or antibodies described herein can also be used.

[0070] An exemplary anti-C5 antibody is ravulizumab comprising heavy and light chains having the sequences shown in SEQ ID NOs: 14 and 11, respectively, or antigen binding fragments and variants thereof. Ravulizumab (also known as ULTOMIRIS®, BNJ441 and ALXN1210) is described in WO2015134894 and US Patent No: 9,079,949, the entire teachings of which are hereby incorporated by reference. The terms ravulizumab, BNJ441, and ALXN1210 may be used interchangeably throughout this document, but all refer to the same antibody. Ravulizumab selectively binds to human complement protein C5, inhibiting its cleavage to C5a and C5b during complement activation. This inhibition prevents the release of the proinfl ammatory mediator C5a and the formation of the cytolytic pore-forming membrane attack complex (MAC) C5b-9 while preserving the proximal or early components of complement activation (e.g., C3 and C3b) essential for the opsonization of microorganisms and clearance of immune complexes.

[0071] In other embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of ravulizumab. Accordingly, in one embodiment, the antibody comprises the CDR1, CDR2 and CDR3 domains of the VH region of ravulizumab having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2 and CDR3 domains of the VL region of ravulizumab having the sequence set forth in SEQ ID NO: 8. In another embodiment, the antibody comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 19, 18 and 3, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:4, 5 and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO:8, respectively.

[0072] Another exemplary anti-C5 antibody is antibody BNJ421 comprising heavy and light chains having the sequences shown in SEQ ID NOs:20 and 11, respectively, or antigen binding fragments and variants thereof. BNJ421 (also known as ALXN1211) is described in WO2015134894 and US Patent No.9, 079, 949, the entire teachings of which are hereby incorporated by reference.

[0073] In other embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of BNJ421. Accordingly, in one embodiment, the antibody comprises theALXN-1004-PCT01-NP (PCT) CDR1, CDR2 and CDR3 domains of the VH region of BNJ421 having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2 and CDR3 domains of the VL region of BNJ421 having the sequence set forth in SEQ ID NO: 8. In another embodiment, the antibody comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:19, 18 and 3, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:4, 5 and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO:8, respectively.

[0074] The exact boundaries of CDRs are defined differently according to different methods. In some embodiments, the positions of the CDRs or framework regions within a light or heavy chain variable domain are as defined by Kabat et al. [(1991) “Sequences of Proteins of Immunological Interest.” NIH Publication No. 91-3242, U.S. Department of Health and Human Services, Bethesda, MD], In such cases, the CDRs can be referred to as “Kabat CDRs” (e.g., “Kabat LCDR2” or “Kabat HCDR1”). In some embodiments, the positions of the CDRs of a light or heavy chain variable region are as defined by Chothia et al. (Nature, 342:877-83, 1989). Accordingly, these regions can be referred to as “Chothia CDRs” (e.g., “Chothia LCDR2” or “Chothia HCDR3”). In some embodiments, the positions of the CDRs of the light and heavy chain variable regions can be defined by a Kabat-Chothia combined definition. In such embodiments, these regions can be referred to as “combined

[0075] Kabat-Chothia CDRs.” Thomas, C. et al. (Mol. Immunol., 33:1389-401, 1996) exemplifies the identification of CDR boundaries according to Kabat and Chothia numbering schemes.

[0076] Another exemplary anti-C5 antibody is the 7086 antibody described in US Patent Nos.

[0077] 8,241,628 and 8,883,158. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 7086 antibody (see US Patent Nos. 8,241,628 and 8,883,158). In another embodiment, the antibody, or antigen binding fragment thereof, comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:21, 22 and 23, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:24, 25 and 26, respectively. In another embodiment, the antibody, or antigen binding fragment thereof, comprises the VH region of the 7086 antibody having the sequence set forth in SEQ ID NO:27, and the VL region of the 7086 antibody having the sequence set forth in SEQ ID NO:28.

[0078] Another exemplary anti-C5 antibody is the 8110 antibody also described in US Patent Nos. 8,241,628 and 8,883,158. In one embodiment, the antibody comprises the heavy andALXN-1004-PCT01-NP (PCT) light chain CDRs or variable regions of the 8110 antibody. In another embodiment, the antibody, or antigen binding fragment thereof, comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:29, 30 and 31, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:32, 33 and 34, respectively. In another embodiment, the antibody comprises the VH region of the 8110 antibody having the sequence set forth in SEQ ID NO:35, and the VL region of the 8110 antibody having the sequence set forth in SEQ ID NO:36.

[0079] Another exemplary anti-C5 antibody is the 305LO5 antibody described in US Patent No. 9,765,135. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 305LO5 antibody. In another embodiment, the antibody, or antigen binding fragment thereof, comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:37, 38 and 39, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:40, 41 and 42, respectively. In another embodiment, the antibody comprises the VH region of the 305LO5 antibody having the sequence set forth in SEQ ID NO:43, and the VL region of the 305LO5 antibody having the sequence set forth in SEQ ID NO:44.

[0080] Another exemplary anti-C5 antibody is the SKY59 antibody (Fukuzawa, T. et a!.. Set. Rep., 7:1080, 2017). In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the SKY59 antibody. In another embodiment, the antibody, or antigen binding fragment thereof, comprises a heavy chain comprising SEQ ID NO:45 and a light chain comprising SEQ ID NO:46.

[0081] In some embodiments, the anti-C5 antibody comprises the heavy and light chain variable regions or heavy and light chains of the REGN3918 antibody (see US Patent No. 10,633,434). In some embodiments, the anti-C5 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region sequence set forth in SEQ ID NO: 47 and a light chain variable region comprising the sequence set forth in SEQ ID NO: 48. In some embodiments, the anti-C5 antibody, or antigen-binding fragment thereof, comprises a heavy chain sequence set forth in SEQ ID NO: 49 and a light chain sequence set forth in SEQ ID NO: 50.

[0082] In some embodiments, an anti-C5 antibody described herein comprises a heavy chain CDR1 comprising, or consisting of, the following amino acid sequence: GHIFSNYWIQ (SEQ ID NO: 19). In some embodiments, an anti-C5 antibody described herein comprises a heavy chain CDR2 comprising, or consisting of, the following amino acid sequence:ALXN-1004-PCT01-NP (PCT) EILPGSGHTEYTENFKD (SEQ ID NO: 18). In some embodiments, an anti-C5 antibody described herein comprises a heavy chain variable region comprising the following amino acid sequence:

[0083] QVQLVQSGAE VKKPGASVKV SCKASGHIFS NYWIQWVRQA PGQGLEWMGE ILPGSGHTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYF FGSSPNWYFD VWGQGTLVTV SS (SEQ ID NO: 12 ) .

[0084] In some embodiments, an anti-C5 antibody described herein comprises a light chain variable region comprising the following amino acid sequence:

[0085] DIQMTQSPSS LSASVGDRVT ITCGASENIY GALNWYQQKP GKAPKLLIYG ATNLADGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQN VLNTPLTFGQ GTKVEIK (SEQ ID NO : 8 ) .

[0086] An anti-C5 antibody described herein can, in some embodiments, comprise a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn) with greater affinity than that of the native human Fc constant region from which the variant human Fc constant region was derived. The Fc constant region can, for example, comprise one or more (e.g., two, three, four, five, six, seven, or eight or more) amino acid substitutions relative to the native human Fc constant region from which the variant human Fc constant region was derived. The substitutions can increase the binding affinity of an IgG antibody containing the variant Fc constant region to FcRn at pH 6.0, while maintaining the pH dependence of the interaction. Methods for testing whether one or more substitutions in the Fc constant region of an antibody increase the affinity of the Fc constant region for FcRn at pH 6.0 (while maintaining pH dependence of the interaction) are known in the art and exemplified in the working examples. See, e.g., WO2015134894 and US Patent No.9, 079949 the disclosures of each of which are incorporated herein by reference in their entirety.

[0087] Substitutions that enhance the binding affinity of an antibody Fc constant region for FcRn are known in the art and include, e.g., (1) the M252Y / S254T / T256E triple substitution (Dall’Acqua, W. et al., J. Biol. Chem., 281:23514-24, 2006); (2) the M428L or T250Q / M428L substitutions (Hinton, P. et al., J. Biol. Chem., 279:6213-6, 2004; Hinton, P. et al., J. Immunol., 176:346-56, 2006); and (3) the N434A or T307 / E380A / N434A substitutions (Petkova, S. etal., Int. Immunol., 18:1759-69, 2006). The additional substitution pairings: P257VQ31 II, P257I / N434H and D376V / N434H (Datta-Mannan, A. et al., J. Biol. Chem., 282:1709-17, 2007), the disclosures of each of which are incorporated herein by reference in their entirety.ALXN-1004-PCT01-NP (PCT) In some embodiments, the variant constant region has a substitution at EU amino acid posaition 255 for valine. In some embodiments, the variant constant region has a substitution at EU amino acid position 309 for asparagine. In some embodiments, the variant constant region has a substitution at EU amino acid position 312 for isoleucine. In some embodiments, the variant constant region has a substitution at EU amino acid position 386.

[0088] In some embodiments, the variant Fc constant region comprises no more than 30 (e.g., no more than 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 or 2) amino acid substitutions, insertions, or deletions relative to the native constant region from which it was derived. In some embodiments, the variant Fc constant region comprises one or more amino acid substitutions selected from the group consisting of: M252Y, S254T, T256E, N434S, M428L, V259I, T250I and V308F. In some embodiments, the variant human Fc constant region comprises a methionine at position 428 and an asparagine at position 434 of a native human IgG Fc constant region, each in EU numbering. In some embodiments, the variant Fc constant region comprises a 428L / 434S double substitution as described in, e.g., U.S. Patent No. 8,088,376.

[0089] In some embodiments the precise location of these mutations may be shifted from the native human Fc constant region position due to antibody engineering. For example, the 428L / 434S double substitution when used in a IgG2 / 4 chimeric Fc may correspond to 429L and 435 S as in the M429L and N435S variants found in ravulizumab and described in US Patent Number 9,079,949 the disclosure of which is incorporated herein by reference in its entirety.

[0090] In some embodiments, the variant constant region comprises a substitution at amino acid position 237, 238, 239, 248, 250, 252, 254, 255, 256, 257, 258, 265, 270, 286, 289, 297, 298, 303, 305, 307, 308, 309, 311, 312, 314, 315, 317, 325, 332, 334, 360, 376, 380, 382, 384, 385, 386, 387, 389, 424, 428, 433, 434 or 436 (EU numbering) relative to the native human Fc constant region. In some embodiments, the substitution is selected from the group consisting of: methionine for glycine at position 237; alanine for proline at position 238; lysine for serine at position 239; isoleucine for lysine at position 248; alanine, phenylalanine, isoleucine, methionine, glutamine, serine, valine, tryptophan, or tyrosine for threonine at position 250; phenylalanine, tryptophan, or tyrosine for methionine at position 252; threonine for serine at position 254; glutamic acid for arginine at position 255; aspartic acid, glutamic acid, or glutamine for threonine at position 256; alanine, glycine, isoleucine, leucine, methionine, asparagine, serine, threonine, or valine for proline at position 257; histidine for glutamic acidALXN-1004-PCT01-NP (PCT) at position 258; alanine for aspartic acid at position 265; phenylalanine for aspartic acid at position 270; alanine, or glutamic acid for asparagine at position 286; histidine for threonine at position 289; alanine for asparagine at position 297; glycine for serine at position 298; alanine for valine at position 303; alanine for valine at position 305; alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, valine, tryptophan, or tyrosine for threonine at position 307; alanine, phenylalanine, isoleucine, leucine, methionine, proline, glutamine, or threonine for valine at position 308; alanine, aspartic acid, glutamic acid, proline, or arginine for leucine or valine at position 309; alanine, histidine, or isoleucine for glutamine at position 311; alanine or histidine for aspartic acid at position 312;lysine or arginine for leucine at position 314; alanine or histidine for asparagine at position 315; alanine for lysine at position 317; glycine for asparagine at position 325; valine for isoleucine at position 332; leucine for lysine at position 334; histidine for lysine at position 360; alanine for aspartic acid at position 376; alanine for glutamic acid at position 380; alanine for glutamic acid at position 382; alanine for asparagine or serine at position 384; aspartic acid or histidine for glycine at position 385; proline for glutamine at position 386; glutamic acid for proline at position 387; alanine or serine for asparagine at position 389; alanine for serine at position 424; alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, asparagine, proline, glutamine, serine, threonine, valine, tryptophan, or tyrosine for methionine at position 428; lysine for histidine at position 433; alanine, phenylalanine, histidine, serine, tryptophan, or tyrosine for asparagine at position 434; and histidine for tyrosine or phenylalanine at position 436, all in EU numbering.

[0091] Suitable anti-C5 antibodies for use in the methods described herein, in some embodiments, comprise a heavy chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 14 and / or a light chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 11. Alternatively, the anti-C5 antibodies for use in the methods described herein, in some embodiments, comprise a heavy chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO:20 and / or a light chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 11.

[0092] In one embodiment, the antibody binds to C5 at pH 7.4 and 25°C (and, otherwise, under physiologic conditions) with an affinity dissociation constant (KD) that is at least 0.1 (e.g., at least 0.15, 0.175, 0.2, 0.25, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775, 0.8, 0.825, 0.85, 0.875, 0.9,ALXN-1004-PCT01-NP (PCT) 0.925, 0.95, or 0.975) nM. In one embodiment, the antibody binds to C5 at pH 7.4 and 25°C (and, otherwise, under physiologic conditions) with an affinity dissociation constant (KD) that is about 0.5 nM. In some embodiments, the KD of the anti-C5 antibody, or antigen binding fragment thereof, is no greater than 1 (e.g., no greater than 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, or 0.2) nM. In some embodiments, the antibody binds to C5 at pH 6.0 and 25°C (and, otherwise, under physiologic conditions) with a KD that is about 22 nM.

[0093] In other embodiments, the [(KD of the antibody for C5 at pH 6.0 at 25°C) / (KD of the antibody for C5 at pH 7.4 at 25C)] is greater than 21 (e.g., greater than 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500 or 8000).

[0094] Methods for determining whether an antibody binds to a protein antigen and / or the affinity for an antibody to a protein antigen are known in the art. The binding of an antibody to a protein antigen, for example, can be detected and / or quantified using a variety of techniques such as, but not limited to, Western blot, dot blot, surface plasmon resonance (SPR) detection (e.g., BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.), or enzyme-linked immunosorbent assay (ELISA; Benny K. C. Lo (2004) “Antibody Engineering: Methods and Protocols,” Humana Press (ISBN: 1588290921); Johne, B. etal., J. Immunol. Meth., 160:191-8, 1993; Jonsson, U. et al., Ann. Biol. Clin., 51:19-26, 1993; Jonsson, U. et al., Biotechniques, 11 :620-7, 1991). In addition, methods for measuring the affinity (e.g., dissociation and association constants) are set forth in the working examples.

[0095] As used herein, the term “ka” refers to the rate constant for association of an antibody to an antigen. The term “kd” refers to the rate constant for dissociation of an antibody from the antib ody / antigen complex. And the term “KD” refers to the equilibrium dissociation constant of an antibody-antigen interaction. The equilibrium dissociation constant is deduced from the ratio of the kinetic rate constants, KD = ka / kd. Such determinations can be measured, for example, at 25C or 37C (see the working examples). The kinetics of antibody binding to human C5 can be determined, for example, at pH 8.0, 7.4, 7.0, 6.5 and 6.0 via SPR on a BIAcore 3000 instrument using an anti-Fc capture method to immobilize the antibody.

[0096] In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, blocks the cleavage of C5 into C5a and C5b. Through this blocking effect, for example, theALXN-1004-PCT01-NP (PCT) pro-inflammatory effects of C5a and the generation of the C5b-9 membrane attack complex (MAC) at the surface of a cell are inhibited.

[0097] Methods for determining whether a particular antibody described herein inhibits C5 cleavage are known in the art. Inhibition of human complement component C5 can reduce the cell-lysing ability of complement in a subject’s body fluids. Such reductions of the cell-lysing ability of complement present in the body fluid(s) can be measured by methods known in the art such as, for example, by a conventional hemolytic assay such as the hemolysis assay (Kabat and Mayer (eds.), “Experimental Immunochemistry, 2ndEdition,” 135-240, Springfield, IL, CC Thomas (1961), pages 135-139), or a conventional variation of that assay such as the chicken erythrocyte hemolysis method (Hillmen, P. et aL, N. Engl. J. Med., 350:552-9, 2004). Methods for determining whether a candidate compound inhibits the cleavage of human C5 into forms C5a and C5b are known in the art (Evans, M. et al., Mol. Immunol., 32: 1183-95, 1995). The concentration and / or physiologic activity of C5a and C5b in a body fluid can be measured, for example, by methods known in the art. For C5b, hemolytic assays or assays for soluble C5b-9 as discussed herein can be used. Other assays known in the art can also be used. Using assays of these or other suitable types, candidate agents capable of inhibiting human complement component C5 can be screened.

[0098] Immunological techniques such as, but not limited to, ELISA can be used to measure the protein concentration of C5 and / or its split products to determine the ability of an anti-C5 antibody, or antigen binding fragment thereof, to inhibit conversion of C5 into biologically active products. In some embodiments, C5a generation is measured. In some embodiments, C5b-9 neoepitope-specific antibodies are used to detect MAC formation.

[0099] Hemolytic assays can be used to determine the inhibitory activity of an anti-C5 antibody, or antigen binding fragment thereof, on complement activation. To determine the effect of an anti-C5 antibody, or antigen binding fragment thereof, on classical complement pathway-mediated hemolysis in a serum test solution in vitro, for example, sheep erythrocytes coated with hemolysin or chicken erythrocytes sensitized with anti-chicken erythrocyte antibody are used as target cells. The percentage of lysis is normalized by considering 100% lysis equal to the lysis occurring in the absence of the inhibitor. In some embodiments, the classical complement pathway is activated by a human IgM antibody, for example, as utilized in the Wieslab® Classical Pathway Complement Kit (Wieslab® COMPL CP310,

[0100] Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with an anti-C5 antibody, or antigen binding fragment thereof, in the presence of a human IgM antibody. The amount ofALXN-1004-PCT01-NP (PCT) C5b-9 that is generated is measured by contacting the mixture with an enzyme conjugated anti-C5b-9 antibody and a fluorogenic substrate and measuring the absorbance at the appropriate wavelength. As a control, the test serum is incubated in the absence of the anti-C5 antibody, or antigen binding fragment thereof. In some embodiments, the test serum is a C5-deficient serum reconstituted with a C5 polypeptide.

[0101] To determine the effect of an anti-C5 antibody, or antigen binding fragment thereof, on alternative pathway-mediated hemolysis, unsensitized rabbit or guinea pig erythrocytes can be used as the target cells. In some embodiments, the serum test solution is a C5-deficient serum reconstituted with a C5 polypeptide. The percentage of lysis is normalized by considering 100% lysis equal to the lysis occurring in the absence of the inhibitor. In some embodiments, the alternative complement pathway is activated by lipopolysaccharide molecules, for example, as utilized in the Wieslab® Alternative Pathway Complement Kit (Wieslab® COMPL AP330, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with an anti-C5 antibody, or antigen binding fragment thereof, in the presence of lipopolysaccharide. The amount of C5b-9 that is generated is measured by contacting the mixture with an enzyme conjugated anti-C5b-9 antibody and a fluorogenic substrate and measuring the fluorescence at the appropriate wavelength. As a control, the test serum is incubated in the absence of the anti-C5 antibody, or antigen binding fragment thereof.

[0102] In some embodiments, C5 activity, or inhibition thereof, is quantified using a CH50eq assay. The CH50eq assay is a method for measuring the total classical complement activity in serum. This test is a lytic assay, which uses antibody-sensitized erythrocytes as the activator of the classical complement pathway and various dilutions of the test serum to determine the amount required to give 50% lysis (CH50). The percent hemolysis can be determined, for example, using a spectrophotometer. The CH50eq assay provides an indirect measure of terminal complement complex (TCC) formation, since the TCC themselves are directly responsible for the hemolysis that is measured. The assay is known and commonly practiced by those of skill in the art. Briefly, to activate the classical complement pathway, undiluted serum samples (e.g., reconstituted human serum samples) are added to microassay wells containing the antibody-sensitized erythrocytes to thereby generate TCC. Next, the activated sera are diluted in microassay wells, which are coated with a capture reagent (e.g., an antibody that binds to one or more components of the TCC). The TCC present in the activated samples bind to the monoclonal antibodies coating the surface of the microassay wells. The wells are washed and to each well is added a detection reagent that is detectably labeled and recognizesALXN-1004-PCT01-NP (PCT) the bound TCC. The detectable label can be, e.g., a fluorescent label or an enzymatic label. The assay results are expressed in CH50 unit equivalents per milliliter (CH50 U Eq / mL).

[0103] Inhibition, e.g., as it pertains to terminal complement activity, includes at least a 5 (e.g., at least a 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60) % decrease in the activity of terminal complement in, e.g., a hemolytic assay or CH50eq assay as compared to the effect of a control antibody (or antigen-binding fragment thereof) under similar conditions and at an equimolar concentration. Substantial inhibition, as used herein, refers to inhibition of a given activity (e.g., terminal complement activity) of at least 40 (e.g., at least 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 or greater) %. In some embodiments, an anti-C5 antibody described herein contains one or more amino acid substitutions relative to the CDRs of eculizumab (i.e., SEQ ID NOs:l-6), yet retains at least 30 (e.g., at least 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95) % of the complement inhibitory activity of eculizumab in a hemolytic assay or CH50eq assay.

[0104] An anti-C5 antibody described herein has a serum half-life in humans that is at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 or 55) days. In another embodiment, the anti-C5 antibody described herein has a serum half-life in humans that is at least 40 days. In another embodiment, the anti-C5 antibody described herein has a serum half-life in humans that is approximately 43 days. In another embodiment, the anti-C5 antibody described herein has a serum half-life in humans that is between 39-48 days. Methods for measuring the serum half-life of an antibody are known in the art. In some embodiments, an anti-C5 antibody, or antigen binding fragment thereof, described herein has a serum half-life that is at least 20 (e.g., at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250, 300, 400 or 500) % greater than the serum half-life of eculizumab, e.g., as measured in one of the mouse model systems described in the working examples (e.g., the

[0105] C5-deficient / NOD / scid mouse or hFcRn transgenic mouse model system).

[0106] In one embodiment, the antibody competes for binding with, and / or binds to the same epitope on C5 as an antibody described herein. The term “binds to the same epitope” with reference to two or more antibodies means that the antibodies bind to the same segment of amino acid residues, as determined by a given method. Techniques for determining whether antibodies bind to the same epitope on C5 with an antibody described herein include, for example, epitope mapping methods, such as, x-ray analyses of crystals of antigemantibody complexes, and hydrogen / deuterium exchange mass spectrometry (HDX-MS). Other methodsALXN-1004-PCT01-NP (PCT) monitor the binding of the antibody to peptide antigen fragments or mutated variations of the antigen where loss of binding due to a modification of an amino acid residue within the antigen sequence is often considered an indication of an epitope component. In addition, computational combinatorial methods for epitope mapping can also be used. These methods rely on the ability of the antibody of interest to affinity isolate specific short peptides from combinatorial phage display peptide libraries. Antibodies having the same VH and VL or the same CDR1, CDR2 and CDR3 sequences are expected to bind to the same epitope.

[0107] Antibodies that “compete with another antibody for binding to a target” refer to antibodies that inhibit (partially or completely) the binding of the other antibody to the target. Whether two antibodies compete with each other for binding to a target, / .< ., whether and to what extent one antibody inhibits the binding of the other antibody to a target, may be determined using known competition experiments. In certain embodiments, an antibody competes with, and inhibits binding of another antibody to a target by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%. The level of inhibition or competition may be different depending on which antibody is the “blocking antibody” ( / .< ., the antibody that is incubated first with the target). Competing antibodies can bind to, for example, the same epitope, an overlapping epitope or to adjacent epitopes (e.g., as evidenced by steric hindrance).

[0108] Anti-C5 antibodies, or antigen-binding fragments thereof described herein, used in the methods described herein can be generated using a variety of art-recognized techniques. Monoclonal antibodies can be obtained by various techniques familiar to those skilled in the art. Briefly, spleen cells from an animal immunized with a desired antigen are immortalized, commonly by fusion with a myeloma cell (Kohler, G. & Milstein, C., Eur. J. Immunol., 6:511-9, 1976)). Methods of immortalization include transformation with Epstein Barr Virus, oncogenes, or retroviruses or other methods known in the art. Colonies arising from single immortalized cells are screened for production of antibodies of the desired specificity and affinity for the antigen, and yield of the monoclonal antibodies produced by such cells may be enhanced by various techniques, including injection into the peritoneal cavity of a vertebrate host. Alternatively, one may isolate DNA sequences that encode a monoclonal antibody or a binding fragment thereof by screening a DNA library from human B cells (Huse, W. et al., Science, 246:1275-81, 1989).

[0109] In some embodiments, the anti-C5 antibody does not comprise eculizumab (SOLIRIS®) or an antigen-binding fragment thereof (e.g., comprising heavy and light chainALXN-1004-PCT01-NP (PCT) complementarity determining regions (HCDR1-3 and LCDR1-3, respectively) of eculizumab). In some embodiments, the anti-C5 antibody is not a biosimilar of eculizumab (SOLIRIS®), e.g., ABP 959 antibody (manufactured by Amgen Inc., USA), ELIZARIA® (manufactured by Generium JNC, Russia), or SB 12 (manufactured by Samsung Bioepis, Incheon, South Korea). III. Compositions

[0110] Also provided herein are compositions comprising an anti-C5 antibody, or antigen binding fragment thereof. In one embodiment, the composition comprises an anti-C5 antibody comprising the CDR1, CDR2 and CDR3 domains in a heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2 and CDR3 domains in a light chain variable region having the sequence set forth in SEQ ID NO:8. In another embodiment, the anti-C5 antibody comprises heavy and light chains having the sequences shown in SEQ ID NOs: 14 and 11, respectively. In another embodiment, the anti-C5 antibody comprises heavy and light chains having the sequences shown in SEQ ID NOs:20 and 11, respectively.

[0111] The compositions can be formulated as a pharmaceutical solution, e.g., for administration to a subject for the treatment IgAN. The pharmaceutical compositions generally include a pharmaceutically acceptable carrier. As used herein, a “pharmaceutically acceptable carrier” refers to, and includes, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. The compositions can include a pharmaceutically acceptable salt, e.g., an acid addition salt or abase addition salt, sugars, carbohydrates, polyols and / or tonicity modifiers.

[0112] The compositions can be formulated according to standard methods. Pharmaceutical formulation is an established art (see, for example, Gennaro (2000) “Remington: The Science and Practice of Pharmacy,” 20thEdition, Lippincott, Williams & Wilkins (ISBN:

[0113] 0683306472); Ansel et al. (1999) “Pharmaceutical Dosage Forms and Drug Delivery Systems,” 7thEdition, Lippincott Williams & Wilkins Publishers (ISBN: 0683305727); and Kibbe (2000) “Handbook of Pharmaceutical Excipients American Pharmaceutical Association,” 3rdEdition (ISBN: 091733096X)). In some embodiments, a composition can be formulated, for example, as a buffered solution at a suitable concentration and suitable for storage at 2-8C (e.g., 4°C). In some embodiments, a composition can be formulated for storage at a temperature below 0C (e.g., -20°C or -80°C). In some embodiments, the composition can be formulated for storage for up to 2 years (e.g., 1 month, 2 months, 3ALXN-1004-PCT01-NP (PCT) months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, V / 2 years or 2 years) at 2-8°C (e.g., 4°C). Thus, in some embodiments, the compositions described herein are stable in storage for at least 1 year at 2-8°C (e.g., 4°C). The pharmaceutical compositions can be in a variety of forms. These forms include, e.g., liquid, semi-solid and solid dosage forms, such as liquid solutions e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The preferred form depends, in part, on the intended mode of administration and therapeutic application. Compositions containing a composition intended for systemic or local delivery, for example, can be in the form of injectable or infusible solutions.

[0114] Accordingly, the compositions can be formulated for administration by a parenteral mode (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection). “Parenteral administration,” “administered parenterally” and other grammatically equivalent phrases, as used herein, refer to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intranasal, intraocular, pulmonary, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid and intrasternal injection and infusion.

[0115] In some embodiments, the disclosure relates to a composition, e.g., pharmaceutical composition or a medicament, comprising an effective amount of an anti-C5 antibody or an antigen binding fragment thereof, comprising heavy chain complementarity determining regions (HCDRs) comprising HCDR1, HCDR2 and HCDR3 sequences as set forth in SEQ ID NOs:19, 18 and 3, respectively, and light chain complementarity determining regions (LCDRs) comprising LCDR1, LCDR2 and LCDR3 sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively, for use in the IgAN, in a human patient

[0116] IV. Methods and Uses

[0117] Provided herein are methods for treating IgAN in a human patient, as well as methods of monitoring responsiveness of a patient having IgAN to treatment with an anti-C5 antibody.

[0118] In one aspect, provided herein is method for treating a patient with IgAN who has been determined to have a 24 hour urine protein (UP) measurement > 1 g / day, the method comprising administering to the patient an anti-C5 antibody in an amount and with a frequency sufficient to decrease albumin to creatinine ratio in a urine sample from the patientALXN-1004-PCT01-NP (PCT) compared to Baseline, wherein the decrease is assessed by a spot urine albumin-creatinine ratio (UACR), thereby treating IgAN in the patient.

[0119] In another aspect, provided herein is a method for treating a patient with IgAN comprising:

[0120] (1) determining or having determined that the patient has a 24 hour UP measurement > 1 g / day, and

[0121] (2) administering to the patient an anti-C5 antibody in an amount and with a frequency sufficient to decrease albumin to creatinine ratio in a urine sample from the patient compared to Baseline, wherein the decrease is assessed by a UACR, thereby treating IgAN in the patient.

[0122] In another aspect, provided herein is a method for monitoring responsiveness of a patient having IgAN to treatment with an anti-C5 antibody, the method comprising: determining a UACR in urine samples from the patient obtained during and after treatment, wherein: a decrease in albumin to creatinine ratio in a urine sample from the patient after treatment compared to Baseline, indicates that the patient is responsive to treatment with the anti -C 5 antibody.

[0123] In some embodiments, the method further comprising determining a Urine Protein-to-Creatinine Ratio (UPCR) in urine samples from the patient obtained during and after treatment, wherein: a decrease in albumin to creatinine ratio in a urine sample from the patient after treatment compared to Baseline as assessed by UACR and UPCR, indicates that the patient is responsive to treatment with the anti-C5 antibody.

[0124] In some embodiments, the patient has an estimated glomerular filtration rate (eGFR) > 30 mL / min / 1.73m2 prior to treatment.

[0125] In some embodiments, the patient is an IgAN patient who has previously been treated with a renin-angiotensin system (RAS) inhibiting medication, such as an angiotensinconverting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB).

[0126] In some embodiments, a UACR of less than 30 mg / g is considered normal for a healthy patient (e.g., 29 mg / g, 28 mg / g, 27 mg / g, 26 mg / g, 25 mg / g, 24 mg / g, 23 mg / g, 22 mg / g, 21 mg / g, 20 mg / g, 19 mg / g, 18 mg / g, 17 mg / g, 16 mg / g, 15 mg / g, 14 mg / g, 13 mg / g, 12 mg / g, 11 mg / g, 10 mg / g, 9 mg / g, 8 mg / g, 7 mg / g, 6 mg / g, 5 mg / g, 4 mg / g, 3 mg / g, 2 mg / g, 1 mg / g, or 0 mg / g. In some embodiments, the treatment results in a UACR of less than 10 mg / g (e.g., 10 mg / g, 9 mg / g, 8 mg / g, 7 mg / g, 6 mg / g, 5 mg / g, 4 mg / g, 3 mg / g, 2 mg / g, 1 mg / g, or 0 mg / g). In some embodiments, the treatment results in a UACR of less than 5ALXN-1004-PCT01-NP (PCT) mg / g (e.g., 5 mg / g, 4 mg / g, 3 mg / g, 2 mg / g, 1 mg / g, or 0 mg / g). In some embodiments, the treatment results in a UACR of less than 3 mg / g (e.g., 3 mg / g, 2 mg / g, 1 mg / g, or 0 mg / g). In some embodiments, the treatment results a UACR of about 0 mg / g.

[0127] In some embodiments, the treatment results in a 20% or more decrease in albumin to creatinine ratio in a urine sample from the patient compared to Baseline, as assessed by a UACR. For example, in some embodiments, the treatment results in a 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% decrease in albumin to creatinine ratio in a urine sample from the patient compared to Baseline, as assessed by a UACR.

[0128] In some embodiments, a UPCR of less than 0.2 mg / mg is considered normal for a healthy patient. In some embodiments, the treatment results in a 20% or more decrease in albumin to creatinine ratio in a urine sample from the patient compared to Baseline, as assessed by a UPCR. For example, in some embodiments, the treatment results in a 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% decrease in albumin to creatinine ratio in a urine sample from the patient compared to Baseline, as assessed by a UPCR.

[0129] In some embodiments, the methods comprise administering to the patient an anti-C5 antibody according to a particular clinical dosage regimen e.g., at a particular dose amount and according to a specific dosing schedule). In some embodiments, the dose of the anti-C5 antibody, or antigen binding fragment thereof, is based on the weight of the patient. In certain embodiments, dosage regimens are adjusted to provide the optimum desired response (e.g., an effective response).

[0130] In some embodiments, the anti-C5 antibody is administered:

[0131] (a) once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 40 to < 60 kg;ALXN-1004-PCT01-NP (PCT) (b) once on Day 1 at a dose of 2700 mg, followed by a dose of 3900 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 60 to < 100 kg; or

[0132] (c) once on Day 1 at a dose of 3000 mg, followed by a dose of 5400 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 100 kg.

[0133] In some embodiments, the anti-C5 antibody is administered:

[0134] (a) once on Day 1 at a dose of 1200 mg, followed by a dose of 2700 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 30 to < 40 kg;

[0135] (b) once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 40 to < 60 kg;

[0136] (c) once on Day 1 at a dose of 2700 mg, followed by a dose of 3300 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 60 to < 100 kg; or

[0137] (d) once on Day 1 at a dose of 3000 mg, followed by a dose of 3600 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 100 kg.

[0138] In some embodiments, the patient is an adult patient. In some embodiments, the patient is a pediatric patient. In some embodiments, the pediatric patient is treated according to the dosing regimen described in U.S. Provisional Application No. 63 / 746,039 (filed January 16, 2025), the contents of which are expressly incorporated herein by reference.

[0139] In another aspect, provided herein is an anti-C5 antibody, for use in treatment of a patient having IgAN who has been determined to have a 24 hour urine protein (UP) measurement > 1 g / day, wherein the anti-C5 antibody is administered to the patient in an amount and with a frequency sufficient to decrease albumin to creatinine ratio in a urine sample from the patient compared to Baseline, wherein the decrease is assessed by a spot urine albumin-creatinine ratio (UACR).

[0140] In another aspect, provided herein is an anti-C5 antibody, for use in monitoring responsiveness of a patient having IgAN to treatment with the anti-C5 antibody, comprising: determining a UACR in urine samples from the patient obtained during and after treatment, wherein a decrease in albumin to creatinine ratio in a urine sample from the patient after treatment compared to Baseline, indicates that the patient is responsive to treatment with the anti -C 5 antibody.

[0141] In another aspect, provided herein is the use of an anti-C5 for treatment of a patient having IgAN who has been determined to have a 24 hour urine protein (UP) measurement > 1 g / day, wherein the anti-C5 antibody is administered to the patient in an amount and with a frequency sufficient to decrease albumin to creatinine ratio in a urine sample from the patientALXN-1004-PCT01-NP (PCT) compared to Baseline, wherein the decrease is assessed by a spot urine albumin-creatinine ratio (UACR).

[0142] In another aspect, provided herein is the use of an anti-C5 antibody in monitoring responsiveness of a patient having IgAN to treatment with the anti-C5 antibody, comprising: determining a UACR in urine samples from the patient obtained during and after treatment, wherein a decrease in albumin to creatinine ratio in a urine sample from the patient after treatment compared to Baseline, indicates that the patient is responsive to treatment with the anti -C 5 antibody.

[0143] V. Outcomes

[0144] Provided herein are methods for treating IgAN in a patient comprising administering to the patient an anti-C5 antibody.

[0145] Symptoms of IgAN include, but are not limited to, e.g., hematuria (blood in the urine that can sometimes make it pink, dark brown or cola colored), edema (e.g., in the hands, ankles or feet), pain on the side of the back (flank pain), high blood pressure (hypertension), and / or foamy urine (due to proteinuria, excess protein in urine).

[0146] In some embodiments, the treatment results in a reduction or cessation in one or more of the following symptoms compared to baseline: foamy urine, proteinuria, edema, high blood pressure, kidney inflammation, kidney impairmentjoint pain,joint swelling, muscle pain, fever with no known cause, high levels of creatinine in the blood, and / or a red rash.

[0147] In some embodiments, the treatment results in a decrease in albumin to creatinine ratio in a urine sample from the patient at 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, or 30 weeks after treatment compared to baseline, as assessed by a UACR. In some embodiments, the treatment results in a decrease in albumin to creatinine ratio in a urine sample from the patient at 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, or 30 weeks after treatment compared to baseline, as assessed by a UACR and UPCR.

[0148] In some embodiments, the treatment results in a Partial Renal Response (PRR). In some embodiments, the treatment results in a Complete Renal Response (CRR).

[0149] In some embodiments, patients treated according to the disclosed methods maintain a serum trough concentration of the anti-C5 antibody, or antigen binding fragment thereof, of at least 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 205, 210, 215, 220, 225, 230, 240, 245,ALXN-1004-PCT01-NP (PCT) 250, 255, 260, 265, 270, 280, 290, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395 or 400 pg / mL or greater. In one embodiment, patients treated according to the disclosed methods maintain a serum trough concentration of the anti-C5 antibody, or antigen binding fragment thereof, of at least 175 pg / mL or greater.

[0150] In some embodiments, patients treated according to the disclosed methods have a free C5 concentration of 0.5 pg / mL or less (e.g., 0.4 pg / mL, 0.3 pg / mL, 0.2 pg / mL, or 0.1 pg / mL or less).

[0151] VI. Kits

[0152] Also provided herein are kits that include a pharmaceutical composition containing an anti-C5 antibody, such as ravulizumab, and a pharmaceutically acceptable carrier, in a therapeutically effective amount adapted for use in the preceding methods. The kits optionally also can include instructions, e.g., comprising administration schedules, to allow a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to administer the composition to a patient having IgAN. The kit also can include a syringe.

[0153] Optionally, the kits include multiple packages of the single-dose pharmaceutical compositions each containing an effective amount of the anti-C5 antibody for a single administration in accordance with the methods provided above. Instruments or devices necessary for administering the pharmaceutical composition(s) also may be included in the kits. For instance, a kit may provide one or more pre-filled syringes containing an amount of the anti-C5 antibody or antigen binding fragment thereof.

[0154] In some embodiments, a kit for treating IgAN in a human patient comprises:

[0155] (a) a dose of an anti-C5 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:8; and

[0156] (b) instructions for using the anti-C5 antibody in any of the methods described herein.

[0157] The following example is merely illustrative and should not be construed as limiting the scope of this disclosure in any way as many variations and equivalents will become apparent to those skilled in the art upon reading the present disclosure. The contents of all references, Genbank entries, patents and published patent applications cited throughout this application are expressly incorporated herein by reference.ALXN-1004-PCT01-NP (PCT)

[0158] EXAMPLE EXAMPLE: SPOT AND 24-HOUR ASSESSMENTS OF PROTEINURIA AND ALBUMINURIA IN IGA NEPHROPATHY: A PRESPECIFIED ANALYSIS OF THE SANCTUARY TRIAL (NCT04564339)

[0159] Globally, immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease (see KDIGO 2021. Kidney Int. 2021;100(4S):Sl-S276). Proteinuria is essential for diagnosing, guiding intervention, and monitoring patients with IgAN (see Habas E, et al. Medicine (Baltimore). 2022; 101(48):e31219). Proteinuria at>l g / day is predictive of kidney failure (see, e.g., Pitcher D, et al., Clin. J. Am. Soc. Nephrol. 2023;18(6):727-738 and Tang C, et al., Am. J. Kidney Dis. 2024;84(2): 170-178). Recent large cohort studies have noted high rates of kidney failure even in those with proteinuria between 0.5 and 1.0 g / day (see, e.g., Pitcher D, et al. (2023) and Tang C, et al. (2024)). The gold standard method for evaluating proteinuria is measuring protein concentration in 24-hour (24h) urine samples (see, e.g., Yu G, et al. Front Med (Lausanne). 2022;9:809245). The 24h urine protein (UP) measurement is used in clinical trials because of the circadian variability in protein excretion. However, it is challenging to operationalize, requires complete collection, and contributes to patient burden (see, e.g., KDIGO 2021 and Yang, C, et al. Urine.

[0160] 2021;3:7-13). Spot urine protein: creatinine ratio (UPCR) and spot urine albumin: creatinine ratio (UACR) measurements are convenient methods for evaluating proteinuria clinically (see Yu G, (2022)). However, studies have reported varying correlations between spot UPCR or UACR and 24h UP measurements (see Yu G, (2022)). Ravulizumab, a second-generation complement C5 inhibitor, demonstrated an early, sustained, and clinically meaningful reduction in proteinuria in adult patients with IgAN in the phase 2 SANCTUARY trial (see Lafayette R, et al., J. Am. Soc. Nephrol. 2024.

[0161] SANCTUARY, a randomized, double-blind, placebo-controlled trial evaluated efficacy and safety of ravulizumab in adults with IgAN. The SANCTUARY clinical trial protocol is described in W02022060931, the entire contents of which are expressly incorporated herein by reference. Key eligibility criteria include: patients aged 18-75 years, with biopsy-confirmed IgAN, eGFR >30 mL / min / 1.73m2, mean UP >lg / day (from two valid 24h urine collections), and on stable / optimal renin-angiotensin blockade. Patients were randomized (2: 1) to ravulizumab or placebo (IV every 8 weeks) for 26 weeks. All patients received ravulizumab at weeks 26-50 (Figure 1).ALXN-1004-PCT01-NP (PCT) This analysis of the SANCTUARY trial evaluates the correlation between spot urine measurements and 24h urine measurements. The objective of this study is to explore the efficacy of ravulizumab in adults with IgAN using spot UPCR and UACR in comparison with 24h measurements. The primary endpoint is percentage change from baseline to week 26 in 24h proteinuria. As part of the prespecified schedule of activities, UP, albumin, and creatinine from morning spot urine samples were measured. A post hoc analysis was performed on the correlation between spot UPCR and UACR and 24h UPCR, UP, and UACR.

[0162] Forty-three patients were randomized to ravulizumab and 23 to placebo

[0163] Spot UPCR and 24h UPCR and UP yielded similar estimates of proteinuria, as set forth in Table 1

[0164] Table 1:

[0165] Ravulizumab, n=43 Placebo, n=23 Treatment effect % reduction (95% CI) % reduction (95% CI) (90% CI)

[0166] 24h UP -41.9% (-50.2, -32.0) -16.8% (-31.8, 1.6) -30.1% (-43.5, -13.7) 24h UPCR -40.4% (-48.5, -31.1) -10.9% (-26.6, 8.3) -33.2% (-45.5, -18.1) Spot UPCR -38.1% (-48.3, -26.0) -15.3% (-34.0, 8.8) -27.0% (-43.5, -5.7) Post hoc

[0167] Spot UACR -38.4% (-49.2, -25.3) -17.6% (-36.7, 7.2) -25.2% (-43.1, -1.8) 24h UACR -41.3% (-50.0,-31.1) -12.8% (-29.4, 7.7) -32.7% (-46.0, -16.2)

[0168]

[0169] The post hoc correlation analysis indicated moderate-to-strong correlation among spot and 24h urine measurements (FIGs. 2A-2D). There was a strong correlation between spot UPCR and 24h UPCR, spot UPCR and spot UACR, and spot UACR and 24h UACR.

[0170] Results for spot UPCR vs 24h UPCR in the ravulizumab group at the initial evaluation at baseline are set forth in FIG. 3A. Results for the placebo group at the initial evaluation at baseline are set forth in FIG. 3A. Results for spot UPCR vs 24h UPCR in the ravulizumab group at week 26 are set forth in FIG. 3B. Results for the placebo group at week 26 are set forth in FIG. 3C.

[0171] In conclusion, the results from the prespecified analysis of the phase 2 SANCTUARY trial indicate a moderate-to-strong correlation among spot and 24h urine measurements The implementation of spot UPCR in trials may facilitate recruitment and encourage patients’ adherence to study visits without impacting the quality of the outcome assessmentALXN-1004-PCT01-NP (PCT) A phase 3 trial of ravulizumab in adults with IgAN (I CAN study, NCT06291376; EU CT 2023-507851-31-00) is ongoing.

[0172] SEQUENCE SUMMARY SEQ ID NO: 1

[0173] GYIFSNYWIQ _

[0174] SEQ ID NO: 2

[0175] EILPGSGSTEYTENFKD _

[0176] SEQ ID NO: 3

[0177] YFFGSSPNWYFDV SEQ ID NO: 4

[0178] GASENIYGALN _

[0179] SEQ ID NO: 5

[0180] GATNLAD SEQ ID NO: 6

[0181] QNVLNTPLT SEQ ID NO: 7

[0182] QVQLVQSGAE VKKPGASVKV SCKASGYIFS NYWIQWVRQA PGQGLEWMGE ILPGSGSTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYF FGSSPNWYFD VWGQGTLVTV SS _

[0183] SEQ ID NO: 8

[0184] DIQMTQSPSS LSASVGDRVT ITCGASENIY GALNWYQQKP GKAPKLLIYG ATNLADGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQN VLNTPLTFGQ GTKVEIK _

[0185] SEQ ID NO: 9

[0186] ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSNFGTQT YTCNVDHKPS NTKVDKTVER KCCVECPPCP APPVAGPSVF LFPPKPKDTL MISRTPEVTC VWDVSQEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTYR WSVLTVLHQ DWLNGKEYKC KVSNKGLPSS IEKTISKAKG QPREPQVYTL PPSQEEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD GSFFLYSRLT VDKSRWQEGN VFSCSVMHEA LHNHYTQKSL SLSLGK _

[0187] SEQ ID NO: 10

[0188] QVQLVQSGAE VKKPGASVKV SCKASGYIFS NYWIQWVRQA PGQGLEWMGE ILPGSGSTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYF FGSSPNWYFD VWGQGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSNFGT QTYTCNVDHK PSNTKVDKTV ERKCCVECPP CPAPPVAGPS VFLFPPKPKD TLMISRTPEV TCVWDVSQE DPEVQFNWYV DGVEVHNAKT KPREEQFNST YRWSVLTVL HQDWLNGKEY KCKVSNKGLP SSIEKTISKA KGQPREPQVY TLPPSQEEMT NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSRL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLGK SEQ ID NO: 11

[0189] DIQMTQSPSS LSASVGDRVT ITCGASENIY GALNWYQQKP GKAPKLLIYG ATNLADGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQN VLNTPLTFGQ GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SWCLLNNFY PREAKVQWKV

[0190]

[0191] DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQGALXN-1004-PCT01-NP (PCT) LSSPVTKSFN RGEC _

[0192] SEQ ID NO: 12

[0193] QVQLVQSGAE VKKPGASVKV SCKASGHIFS NYWIQWVRQA PGQGLEWMGE ILPGSGHTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYF FGSSPNWYFD VWGQGTLVTV SS _

[0194] SEQ ID NO: 13

[0195] ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSNFGTQT YTCNVDHKPS NTKVDKTVER KCCVECPPCP APPVAGPSVF LFPPKPKDTL MISRTPEVTC VWDVSQEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTYR WSVLTVLHQ DWLNGKEYKC KVSNKGLPSS IEKTISKAKG QPREPQVYTL PPSQEEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD GSFFLYSRLT VDKSRWQEGN VFSCSVLHEA LHSHYTQKSL SLSLGK _

[0196] SEQ ID NO: 14

[0197] QVQLVQSGAE VKKPGASVKV SCKASGHIFS NYWIQWVRQA PGQGLEWMGE ILPGSGHTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYF FGSSPNWYFD VWGQGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSNFGT QTYTCNVDHK PSNTKVDKTV ERKCCVECPP CPAPPVAGPS VFLFPPKPKD TLMISRTPEV TCVWDVSQE DPEVQFNWYV DGVEVHNAKT KPREEQFNST YRWSVLTVL HQDWLNGKEY KCKVSNKGLP SSIEKTISKA KGQPREPQVY TLPPSQEEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD SDGSFFLYSR LTVDKSRWQE GNVFSCSVLH EALHSHYTQK SLSLSLGK _ SEQ ID NO: 15

[0198] ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VTSSNFGTQT YTCNVDHKPS NTKVDKTVER KCCVECPPCP APPVAGPSVF LFPPKPKDTL YITREPEVTC VWDVSHEDP EVQFNWYVDG MEVHNAKTKP REEQFNSTFR WSVLTWHQ DWLNGKEYKC KVSNKGLPAP IEKTISKTKG QPREPQVYTL PPSREEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPMLDSD GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL SLSPGK _

[0199] SEQ ID NO: 16

[0200] QVQLVQSGAE VKKPGASVKV SCKASGYIFS NYWIQWVRQA PGQGLEWMGE ILPGSGSTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYF FGSSPNWYFD VWGQGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVTSSNFGT QTYTCNVDHK PSNTKVDKTV ERKCCVECPP CPAPPVAGPS VFLFPPKPKD TLYITREPEV TCVWDVSHE DPEVQFNWYV DGMEVHNAKT KPREEQFNST FRWSVLTW HQDWLNGKEY KCKVSNKGLP APIEKTISKT KGQPREPQVY TLPPSREEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPMLD SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK SEQ ID NO: 17

[0201] GASENIYHALN _

[0202] SEQ ID NO: 18

[0203] EILPGSGHTEYTENFKD _

[0204] SEQ ID NO: 19

[0205] GHIFSNYWIQ SEQ ID NO: 20

[0206] QVQLVQSGAE VKKPGASVKV SCKASGHIFS NYWIQWVRQA PGQGLEWMGE

[0207]

[0208] ILPGSGHTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYFALXN-1004-PCT01-NP (PCT) FGSSPNWYFD VWGQGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSNFGT QTYTCNVDHK PSNTKVDKTV ERKCCVECPP CPAPPVAGPS VFLFPPKPKD TLMISRTPEV TCVWDVSQE DPEVQFNWYV DGVEVHNAKT KPREEQFNST YRWSVLTVL HQDWLNGKEY KCKVSNKGLP SSIEKTISKA KGQPREPQVY TLPPSQEEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD SDGSFFLYSR LTVDKSRWQE GNVFSCSVMH EALHNHYTQK SLSLSLGK SEQ ID NO: 21

[0209] SYAIS SEQ ID NO: 22

[0210] GIGPFFGTANYAQKFQG SEQ ID NO: 23

[0211] DTPYFDY SEQ ID NO: 24

[0212] SGDSIPNYYVY SEQ ID NO: 25

[0213] DDSNRPS SEQ ID NO: 26

[0214] QSFDSSLNAEV SEQ ID NO: 27

[0215] QVQLVQSGAE VKKPGSSVKV SCKASGGTFS SYAISVWRQA PGQGLEWMGG IGPFFGTANY AQKFQGRVTI TADESTSTAY MELSSLRSED TAVYYCARDT PYFDYWGQGT LVTVSS SEQ ID NO: 28

[0216] DIELTQPPSV SVAPGQTARI SCSGDSIPNY YVYWYQQKPG QAPVLVIYDD SNRPSGIPER FSGSNSGNTA TLTISGTQAE DEADYYCQSF DSSLNAEVFG GGTKLTVL SEQ ID NO: 29

[0217] NYIS SEQ ID NO: 30

[0218] I IDPDDSYTEYSPSFQG SEQ ID NO: 31

[0219] YEYGGFDI SEQ ID NO: 32

[0220] SGDNIGNSYVH SEQ ID NO: 33

[0221] KDNDRPS SEQ ID NO: 34

[0222] GTYDIESYV SEQ ID NO: 35

[0223] EVQLVQSGAE VKKPGESLKI SCKGSGYSFT NYISWVRQMP GKGLEWMGII DPDDSYTEYS PSFQGQVTIS ADKSISTAYL QWSSLKASDT AMYYCARYEY GGFDIWGQGT LVTVSS SEQ ID NO: 36

[0224] SYELTQPPSV SVAPGQTARI SCSGDNIGNS YVHWYQQKPG QAPVLVIYKD NDRPSGIPER FSGSNSGNTA TLTISGTQAE DEADYYCGTY DIESYVFGGG TKLTVL SEQ ID NO: 37

[0225] SSYYVA

[0226]

[0227] SEQ ID NO: 38ALXN-1004-PCT01-NP (PCT) AIYTGSGATYKASWAKG SEQ ID NO: 39

[0228] DGGYDYPTHAMHY SEQ ID NO: 40

[0229] QASQNIGSSLA SEQ ID NO: 41

[0230] GASKTHS SEQ ID NO: 42

[0231] QSTKVGSSYGNH SEQ ID NO: 43

[0232] QVQLVESGGG LVQPGGSLRL SCAASGFTSH SSYYVAWVRQ APGKGLEWVG AIYTGSGATY KASWAKGRFT ISKDTSKNQV VLTMTNMDPV DTATYYCASD GGYDYPTHAM HYWGQGTLVT VSS SEQ ID NO: 44

[0233] DWMTQSPSS LSASVGDRVT ITCQASQNIG SSLAWYQQKP GQAPRLLIYG ASKTHSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCQS TKVGSSYGNH FGGGTKVEIK SEQ ID NO: 45

[0234] QVQLVESGGG LVQPGRSLRL SCAASGFTVH SSYYMAWVRQ APGKGLEWVG AIFTGSGAEY KAEWAKGRVT ISKDTSKNQV VLTMTNMDPV DTATYYCASD AGYDYPTHAM HYWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS WTVPSSSLG TQTYICNVNH KPSNTKVDKK VEPKSCDKTH TCPPCPAPEL RRGPKVFLFP PKPKDTLMIS RTPEVTCVW DVSHEDPEVK FNWYVDGVEV HNAKTKPREE QYNSTYRWS VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR EPQVYTLPPS REEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF FLYSKLTVDK SRWQQGNVFS CSVLHEALHA HYTRKELSLS P SEQ ID NO: 46

[0235] DIQMTQSPSS LSASVGDRVT ITCRASQGIS SSLAWYQQKP GKAPKLLIYG ASETESGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQN TKVGSSYGNT FGGGTKVEIK RTVAAPSVFI FPPSDEQLKS GTASWCLLN NFYPREAKVQ WKVDNALQSG NSQESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC SEQ ID NO: 47 QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYI YYSGSSN YNPSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWGQGTLV TVSS SEQ ID NO: 48 AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVP SRFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIK SEQ ID NO: 49 QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYI YYSGSSNY NPSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWGQGTLVTV SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLG GPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ FNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPS

[0236]

[0237] QEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDALXN-1004-PCT01-NP (PCT) KSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK _

[0238] SEQ ID NO: 50 AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVP SRFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIKRTVAAPSVFIF PPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSS

[0239]

[0240] TLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Claims

ALXN-1004-PCT01-NP (PCT)CLAIMSWhat is claimed is:

1. A method for treating a patient with immunoglobulin A nephropathy (IgAN) who has been determined to have a 24-hour urine protein (UP) measurement > 1 g / day, the method comprising administering to the patient an anti-C5 antibody in an amount and with a frequency sufficient to decrease albumin to creatinine ratio in a urine sample from the patient compared to Baseline, wherein the decrease is assessed by a spot urine albumin-creatinine ratio (UACR), thereby treating IgAN in the patient.

2. A method for treating a patient with IgAN comprising:(1) determining or having determined that the patient has a 24-hour UP measurement > 1 g / day, and(2) administering to the patient an anti-C5 antibody in an amount and with a frequency sufficient to decrease albumin to creatinine ratio in a urine sample from the patient compared to Baseline, wherein the decrease is assessed by a UACR, thereby treating IgAN in the patient.

3. A method for monitoring responsiveness of a patient having IgAN to treatment with an anti-C5 antibody, the method comprising: determining a UACR in urine samples from the patient obtained before, during and after treatment, wherein: a decrease in albumin to creatinine ratio in a urine sample from the patient after treatment compared to Baseline, indicates that the patient is responsive to treatment with the anti-C5 antibody.

4. The method of claim 3, further comprising determining a Urine Protein-to-Creatinine Ratio (UPCR) in urine samples from the patient obtained during and after treatment, wherein: a decrease in albumin to creatinine ratio in a urine sample from the patient after treatment compared to Baseline as assessed by UACR and UPCR, indicates that the patient is responsive to treatment with the anti-C5 antibody.

5. The method of any of the preceding claims, wherein the treatment results in a UACR of about 0 mg / g.ALXN-1004-PCT01-NP (PCT) 6. The method of any one of the preceding claims, wherein the anti-C5 antibody is a human antibody, a humanized antibody, a bispecific antibody, a chimeric antibody, a Fab, a Fab ’2, a ScFv, a SMIP, an Affibody®, a nanobody, or a domain antibody which inhibits C5.

7. The method of any one of the preceding claims, wherein the anti-C5 antibody comprises CDR1, CDR2, and CDR3 heavy chain sequences as set forth in SEQ ID NOs:19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5, and 6, respectively.

8. The method of claim 7, wherein the anti-C5 antibody further comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each in EU numbering.

9. The method of claim 7 or 8, wherein the anti-C5 antibody comprises a heavy chain variable region comprising SEQ ID NO: 12 and a light chain variable region comprising SEQ ID N0:8.

10. The method of any one of claims 7-9, wherein the anti-C5 antibody further comprises a heavy chain constant region depicted in SEQ ID NO: 13.

11. The method of any one of claims 7-10, wherein the anti-C5 antibody comprises a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO: 14 and a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO: 11.

12. The method of any one of the preceding claims, wherein the anti-C5 antibody is ULTOMIRIS®.

13. The method of any of the preceding claims, wherein the anti-C5 antibody is administered intravenously.ALXN-1004-PCT01-NP (PCT) 14. The method of any one of the preceding claims, wherein the patient has an estimated glomerular filtration rate (eGFR) > 30 mL / min / 1.73m2 prior to treatment.

15. The method of any one of the preceding claims, wherein the anti-C5 antibody is administered:(a) once on Day 1 at a dose of 1200 mg, followed by a dose of 2700 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 30 to < 40 kg; (b) once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 40 to < 60 kg; (b) once on Day 1 at a dose of 2700 mg, followed by a dose of 3300 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 60 to < 100 kg; or(c) once on Day 1 at a dose of 3000 mg, followed by a dose of 3600 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 100 kg.

16. The method of any one of the preceding claims, wherein the treatment results in a 20% or more decrease in albumin to creatinine ratio in a urine sample from the patient compared to Baseline, as assessed by a UACR.

17. The method of any one of the preceding claims, wherein the treatment results in a decrease in albumin to creatinine ratio in a urine sample from the patient at 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, or 30 weeks after treatment compared to baseline, as assessed by a UACR.

18. The method of any one of the preceding claims, wherein the treatment results in a reduction or cessation in one or more of the following symptoms compared to baseline: foamy urine, proteinuria, edema, high blood pressure, kidney inflammation, kidney impairmentjoint pain,joint swelling, muscle pain, fever with no known cause, high levels of creatinine in the blood, and / or a red rash.

19. The method of any one of the preceding claims, wherein the treatment results in a Partial Renal Response (PRR).ALXN-1004-PCT01-NP (PCT)20. The method of any one of the preceding claims, wherein the treatment results in a Complete Renal Response (CRR).

21. A kit for treating IgAN in a human patient, the kit comprising:(a) a dose of an anti-C5 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:8; and(b) instructions for using the anti-C5 antibody in the method of any one of the preceding claims.

22. An anti-C5 antibody, for use in treatment of a patient having IgAN who has been determined to have a 24 hour urine protein (UP) measurement > 1 g / day, wherein the anti-C5 antibody is administered to the patient in an amount and with a frequency sufficient to decrease albumin to creatinine ratio in a urine sample from the patient compared to Baseline, wherein the decrease is assessed by a spot urine albumin-creatinine ratio (UACR).

23. An anti-C5 antibody, for use in monitoring responsiveness of a patient having IgAN to treatment with the anti-C5 antibody, comprising: determining a UACR in urine samples from the patient obtained during and after treatment, wherein a decrease in albumin to creatinine ratio in a urine sample from the patient after treatment compared to Baseline, indicates that the patient is responsive to treatment with the anti-C5 antibody.

24. Use of an anti-C5 for treatment of a patient having IgAN who has been determined to have a 24 hour urine protein (UP) measurement > 1 g / day, wherein the anti-C5 antibody is administered to the patient in an amount and with a frequency sufficient to decrease albumin to creatinine ratio in a urine sample from the patient compared to Baseline, wherein the decrease is assessed by a spot urine albumin-creatinine ratio (UACR).

25. Use of an anti-C5 antibody in monitoring responsiveness of a patient having IgAN to treatment with the anti-C5 antibody, comprising: determining a UACR in urine samples from the patient obtained during and after treatment, wherein a decrease in albumin to creatinineALXN-1004-PCT01-NP (PCT) ratio in a urine sample from the patient after treatment compared to Baseline, indicates that the patient is responsive to treatment with the anti-C5 antibody.

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