Methods for treating pregnancy-associated atypical hemolytic uremic syndrome using anti-C5 antibodies

Abstract

Provided is a clinical method for treating pregnancy-associated atypical hemolytic uremic syndrome (p-aHUS), e.g., postpartum aHUS, using an anti-C5 antibody, or an antigen-binding fragment thereof, e.g., ravulizumab (ULTOMIRIS®).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 952,971, filed December 23, 2019, U.S. Provisional Patent Application No. 63 / 007,489, filed April 9, 2020, and U.S. Provisional Patent Application No. 62 / 704,879, filed June 1, 2020, each of which is incorporated herein by reference in its entirety. [Background technology]

[0002] Hemolytic uremic syndrome (HUS) is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. HUS is classified as one of two types: diarrhea-associated (D+HUS; also called Shiga toxin-producing Escherichia coli (STEC)-HUS or typical HUS) and non-diarrheal or atypical HUS (aHUS). D+HUS is the most common form, accounting for over 90% of cases, and is caused by a preceding illness with Shiga-like toxin-producing bacteria, such as E. coli O157:H7.

[0003] aHUS can be hereditary, acquired, or idiopathic. Hereditary forms of aHUS can be associated with mutations in multiple human complement components, such as complement factor H (CFH), membrane cofactor protein (MCP), complement factor I (CFI), C4b-binding protein (C4BP), complement factor B (CFB), and complement component 3 (C3) (see, e.g., Caprioli et al. (2006) Blood 108:1267-1279). Certain mutations in the gene encoding CD55, while not yet associated with aHUS, are associated with the severity of aHUS (see, e.g., Esparza-Gordillo et al. (2005) Hum Mol Genet 14:703-712).

[0004] Pregnancy-induced aHUS ("p-aHUS") is a rare and severe systemic disease associated with dysfunction of the alternative complement pathway, occurring in approximately 1 in 25,000 pregnant women. Complement overactivation leads to diffuse endothelial injury and subsequent formation of fibrin and platelet microthrombi in blood vessels, which result in hemolysis, thrombocytopenia, and end-organ dysfunction (mainly in the form of acute kidney injury) from ischemia (see, e.g., Saad, et al., AJP Reports vol. 6, 1 (2016)). The majority of p-aHUS cases occur during the postpartum period and are known as postpartum aHUS (see, e.g., Fakhouri F, et al., J. Am. Soc. Nephrol. 2010;21(5):859-867).

[0005] Patients with p-aHUS (e.g., postpartum aHUS) are at risk for significant morbidity and mortality. Accordingly, it is an object of the present invention to provide improved methods of treating patients with p-aHUS. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Caprioli et al. (2006)Blood 108:1267-1279 [Non-patent document 2] Esparza-Gordillo et al. (2005) Hum Mol Genet 14:703-712 [Non-patent document 3] Saad,et al.,AJP Reports vol.6,1(2016) [Non-patent document 4] Fakhouri F,et al.,J.Am.Soc.Nephrol.2010;21(5):859-867 Summary of the Invention [Means for solving the problem]

[0007] Provided herein are compositions and methods for treating pregnancy-associated atypical hemolytic uremic syndrome (p-aHUS) (e.g., postpartum aHUS) in a human patient, comprising administering to the patient an anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab). In some embodiments, the anti-C5 antibody, or antigen-binding fragment thereof, is administered (or is for administration) according to a specific clinical dosage regimen (i.e., at a specific dose and according to a defined dosing schedule). In some embodiments, the patient has severe or early-onset p-aHUS. In some embodiments, the patient also has preeclampsia (PE) and / or HELLP syndrome.

[0008] Any suitable anti-C5 antibody, or antigen-binding fragment thereof, can be used in the methods described herein. An exemplary anti-C5 antibody is eculizumab. Eculizumab (also known as SOLIRIS®) is an anti-C5 antibody comprising heavy chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 1, 2, 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. Eculizumab comprises a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7 and a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 8. Eculizumab comprises a heavy chain having the amino acid sequence set forth in SEQ ID NO: 10 and a light chain having the amino acid sequence set forth in SEQ ID NO: 11.

[0009] Another exemplary anti-C5 antibody is ravulizumab (also known as ULTOMIRIS®, ALXN1210, and antibody BNJ441), which comprises heavy and light chains having the sequences set forth 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. Thus, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable (VH) region of ravulizumab having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of the light chain variable (VL) region of ravulizumab having the sequence set forth in SEQ ID NO: 8. In another embodiment, the antibody comprises the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain 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. In another embodiment, the antibody comprises a heavy chain constant region set forth in SEQ ID NO: 13.

[0010] In another embodiment, the antibody comprises a variant human Fc constant region that binds to the human fetal 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, respectively, in EU numbering, of the native human IgG Fc constant region.

[0011] In another embodiment, the antibody comprises the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively; the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively; and a variant human Fc constant region that binds to the human fetal 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, respectively, in EU numbering, of the native human IgG Fc constant region.

[0012] In another embodiment, the antibody binds to human C5 with an affinity dissociation constant (KD) within the range of 0.1 nM≦KD≦1 nM at pH 7.4 and 25° C. In another embodiment, the antibody binds to human C5 with a KD≧10 nM at pH 6.0 and 25° C. In yet another embodiment, the antibody's [(KD of the antibody or antigen-binding fragment thereof for human C5 at pH 6.0 and 25° C.) / (KD of the antibody or antigen-binding fragment thereof for human C5 at pH 7.4 and 25° C.)] is greater than 25.

[0013] Another exemplary anti-C5 antibody is described in U.S. Patent Nos. 8,241,628 and 8,883,158. In one 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 a VH region having the sequence set forth in SEQ ID NO:27 and a VL region having the sequence set forth in SEQ ID NO:28.

[0014] Other exemplary anti-C5 antibodies are also described in U.S. Patent Nos. 8,241,628 and 8,883,158. In one 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 a VH region having the sequence set forth in SEQ ID NO: 35 and a VL region having the sequence set forth in SEQ ID NO: 36.

[0015] Another exemplary anti-C5 antibody is described in U.S. Patent Application Publication No. 2016 / 0176954A1. In one 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 a VH region having the sequence set forth in SEQ ID NO: 43 and a VL region having the sequence set forth in SEQ ID NO: 44.

[0016] Another exemplary anti-C5 antibody is described in Fukuzawa T. et al. (Sci. Rep. 7:1080, 2017). 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.

[0017] Another exemplary anti-C5 antibody is described in U.S. Patent Application Publication No. 20170355757. In one embodiment, the antibody comprises a heavy chain variable region comprising SEQ ID NO: 47 and a light chain variable region comprising SEQ ID NO: 48. In another embodiment, the antibody comprises a heavy chain comprising SEQ ID NO: 49 and a light chain comprising SEQ ID NO: 50.

[0018] In another embodiment, the antibody competes for binding to and / or binds to the same epitope on C5 as the above-mentioned antibody, hi another embodiment, the antibody has at least about 90% variable region amino acid sequence identity (e.g., at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% variable region identity) with the above-mentioned antibody.

[0019] In one embodiment, a method is provided for treating a human patient with p-aHUS, comprising administering to the patient an effective amount of an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody, or antigen-binding fragment thereof, comprises the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively. In another embodiment, a method is provided for treating a human patient with p-aHUS, comprising administering to the patient an effective amount of an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7 and a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 8. In another embodiment, a method of treating a human patient with p-aHUS is provided, comprising administering to the patient an effective amount of an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody, or antigen-binding fragment thereof, comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 10 and a light chain having the amino acid sequence set forth in SEQ ID NO: 11.

[0020] In one embodiment, a method of treating a human patient with p-aHUS is provided, comprising administering to the patient an effective amount of an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody, or antigen-binding fragment thereof, comprises the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively. In another embodiment, the antibody further comprises a variant human Fc constant region that binds to a human fetal 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, respectively, in EU numbering, of the native human IgG Fc constant region.

[0021] In one embodiment, the anti-C5 antibody or antigen-binding fragment is administered as a fixed dose. For example, in one embodiment, the anti-C5 antibody or antigen-binding fragment is administered at a fixed dose of 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 1000 mg, 1250 mg, 1500 mg, 1750 mg, 1800 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2250 mg, 250 mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, 1600mg, 1700mg, 1800mg, 1900mg, 2000mg, 2 38 00mg,3900mg,4000mg,4100mg,4200mg,4300mg,4400mg,4500mg,4600mg,4700mg,4800mg,4900mg,5000mg,5100mg,5200mg,5300mg,5400mg,550 0mg, 5600mg, 5700mg, 5800mg, 5900mg, 6000mg, 6100mg, 6200mg, 6300mg, 6400mg, 6500mg, 6600mg, 6700mg, 6800mg, 6900mg, 7000mg, 7100mg, 7200 mg, 7300mg, 7400mg, 7500mg, 7600mg, 7700mg, 7800mg, 7900mg, 8000mg, 8100mg, 8200mg, 8300mg, 8400mg, 8500mg, 8600mg, 8700mg, 8800mg, 8900m g.In another embodiment, the anti-C5 antibody or antigen-binding fragment is administered at a sub-therapeutic dose.

[0022] In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab) is administered at a dose of 2400 mg, 2700 mg, 3000 mg, 3300 mg, or 3600 mg.

[0023] In another embodiment, the dose of the anti-C5 antibody or antigen-binding fragment is based on the patient's weight. For example, in one embodiment, the dose is 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 92 5mg, 950mg, 975mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, 1600mg, 1700mg, 1800mg, 1900mg, 2000mg, 2100mg, 2200mg, 2300mg, 2400m g, 2500mg, 2600mg, 2700mg, 2800mg, 2900mg, 3000mg, 3100mg, 3200mg, 3300mg, 3400mg, 3500mg, 3600mg, 3700mg, 3800mg, 3900mg, 4000mg, 4100mg ,4200mg,4300mg,4400mg,4500mg,4600mg,4700mg,4800mg,4900mg,5000mg,5100mg,5200mg,5300mg,5400mg,5500mg,5600mg,5700mg,5800mg , 5900mg, 6000mg, 6100mg, 6200mg, 6300mg, 6400mg, 6500mg, 6600mg, 6700mg, 6800mg, 6900mg, 7000mg, 7100mg, 7200mg, 7300mg, 7400mg, 7500mg, 7600mg, 7700mg, 7800mg, 7900mg, 8000mg, 8100mg, 8200mg, 8300mg, 8400mg, 8500mg, 8600mg, 8700mg, 8800mg, 8900mg, 9000mg, 9100mg, 9200mg, 9 300mg, 9400mg, 9500mg, 9600mg, 9700mg, 9800mg, 9900mg, 10000mg, 10100mg, 10200mg, 10300mg, 10400mg, 10500mg, 10600mg, 10700mg, 10800mg,In another embodiment, 10,900 mg or 11,000 mg of an anti-C5 antibody or antigen-binding fragment is administered to a patient weighing ≥ 40 kg to < 60 kg. In another embodiment, 2,400 mg or 3,000 mg of an anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to a patient weighing ≥ 40 kg to < 60 kg. In another embodiment, 2,400 mg or 3,000 mg of an anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered every two weeks to a patient weighing ≥ 40 kg to < 60 kg. In another embodiment, 2,400 mg or 3,000 mg of an anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered every eight weeks to a patient weighing ≥ 40 kg to < 60 kg.

[0024] In another embodiment, the saturates are 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 960 mg, 980 mg, 990 mg, 1000 mg, 1010 mg, 1020 mg, 1030 mg, 1040 mg, 1050 mg, 1060 mg, 1070 mg, 1080 mg, 1090 mg, 1100 mg, 1110 mg, 1120 mg, 1130 mg, 1140 mg, 1150 mg, 1160 mg, 1170 mg, 1180 mg, 1190 mg, 1200 mg, 1210 mg, 1220 mg, 1230 mg, 1240 mg, 1250 mg, 1260 mg, 1270 mg, 1280 mg, 1290 mg, 1300 mg, 1310 mg, 1320 mg, 1330 mg, 1340 mg, 13 75mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, 1600mg, 1700mg, 1800mg, 1900mg, 2000mg, 2100mg, 2200mg, 2300mg, 2400mg, 2500mg, 2600mg, 2700mg, 2800mg, 2900mg, 3000mg, 3100mg, 3200mg, 3300mg, 3400mg, 3500mg, 3600mg, 3700mg, 3800mg, 3900mg, 4000mg, 4100mg, 4200mg, 4300mg, 4400m g, 4500mg, 4600mg, 4700mg, 4800mg, 4900mg, 5000mg, 5100mg, 5200mg, 5300mg, 5400mg, 5500mg, 5600mg, 5700mg, 5800mg, 5900mg, 6000mg, 6100mg, 62 00mg, 6300mg, 6400mg, 6500mg, 6600mg, 6700mg, 6800mg, 6900mg, 7000mg, 7100mg, 7200mg, 7300mg, 7400mg, 7500mg, 7600mg, 7700mg, 7800mg, 7900mg, 8000 mg, 8100 mg, 8200 mg, 8300 mg, 8400 mg, 8500 mg, 8600 mg, 8700 mg, 8800 mg, 8900 mg, 9000 mg, 9100 mg, 9200 mg, 9300 mg, 9400 mg, 9500 mg, 9600 mg, 9700 mg, 9800 mg, 9900 mg, 10000 mg, 10100 mg, 10200 mg, 10300 mg, 10400 mg, 10500 mg, 10600 mg, 10700 mg, 10800 mg, 10900 mg, or 11000 mg of an anti-C5 antibody or antigen-binding fragment thereof,In another embodiment, 2700 mg or 3300 mg of an anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to a patient weighing ≥60 to <100 kg. In another embodiment, 2700 mg or 3300 mg of an anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered every two weeks to a patient weighing ≥60 to <100 kg. In another embodiment, 2700 mg or 3300 mg of an anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered every eight weeks to a patient weighing ≥60 to <100 kg.

[0025] In another embodiment, the saturates are 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 960 mg, 980 mg, 990 mg, 1000 mg, 1010 mg, 1020 mg, 1030 mg, 1040 mg, 1050 mg, 1060 mg, 1070 mg, 1080 mg, 1090 mg, 1100 mg, 1110 mg, 1120 mg, 1130 mg, 1140 mg, 1150 mg, 1160 mg, 1170 mg, 1180 mg, 1190 mg, 1200 mg, 1210 mg, 1220 mg, 1230 mg, 1240 mg, 1250 mg, 1260 mg, 1270 mg, 1280 mg, 1290 mg, 1300 mg, 1310 mg, 1320 mg, 1330 mg, 1340 mg, 13 75mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, 1600mg, 1700mg, 1800mg, 1900mg, 2000mg, 2100mg, 2200mg, 2300mg, 2400mg, 2500mg, 2600mg , 2700mg, 2800mg, 2900mg, 3000mg, 3100mg, 3200mg, 3300mg, 3400mg, 3500mg, 3600mg, 3700mg, 3800mg, 3900mg, 4000mg, 4100mg, 4200mg, 4300mg, 4400 mg, 4500mg, 4600mg, 4700mg, 4800mg, 4900mg, 5000mg, 5100mg, 5200mg, 5300mg, 5400mg, 5500mg, 5600mg, 5700mg, 5800mg, 5900mg, 6000mg, 6100mg, 6 200mg, 6300mg, 6400mg, 6500mg, 6600mg, 6700mg, 6800mg, 6900mg, 7000mg, 7100mg, 7200mg, 7300mg, 7400mg, 7500mg, 7600mg, 7700mg, 7800mg, 7900mg , 8000 mg, 8100 mg, 8200 mg, 8300 mg, 8400 mg, 8500 mg, 8600 mg, 8700 mg, 8800 mg, 8900 mg, 9000 mg, 9100 mg, 9200 mg, 9300 mg, 9400 mg, 9500 mg, 9600 mg, 9700 mg, 9800 mg, 9900 mg, 10000 mg, 10100 mg, 10200 mg, 10300 mg, 10400 mg, 10500 mg, 10600 mg, 10700 mg, 10800 mg, 10900 mg, or 11000 mg of an anti-C5 antibody or antigen-binding fragment,In another embodiment, 3000 mg or 3600 mg of an anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab) is administered to a patient weighing ≥ 100 kg.

[0026] In another embodiment, a method of treating a human patient with p-aHUS comprises administering to the patient an anti-C5 antibody, or an antigen-binding fragment thereof (e.g., ravulizumab). (a) Once on day 1, at a dose of 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; (b) On day 15 and every 8 weeks thereafter, at a dose of 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg. The method includes administering

[0027] In another embodiment, a method of treating a human patient with p-aHUS comprises administering an anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab) to a patient weighing ≥ 40 to < 60 kg. (a) at a dose of 2400 mg once on day 1; (b) at a dose of 3000 mg on day 15 and every 8 weeks thereafter Methods of administration are provided.

[0028] In another embodiment, a method of treating a human patient with p-aHUS comprises administering an anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab) to a patient weighing ≥ 60 to < 100 kg. (a) at a dose of 2700 mg once on day 1; (b) on day 15 of the treatment cycle and every 8 weeks thereafter at a dose of 3300 mg Methods of administration are provided.

[0029] In another embodiment, a method of treating a human patient with p-aHUS comprises administering an anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab) to a patient weighing ≥ 100 kg. (a) at a dose of 3000 mg once on day 1; (b) at a dose of 3600 mg on day 15 and every 8 weeks thereafter Methods of administration are provided.

[0030] In another embodiment, a method of treating a human patient with p-aHUS comprises administering to the patient an effective amount of an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody, or antigen-binding fragment thereof, comprises CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, and a variant human Fc region that binds to a human fetal Fc receptor (FcRn), wherein the variant human Fc CH3 region is a variant of a variant human Fc CH3 region that binds to a native human IgG1, each in EU numbering. Methods are provided that include administering an anti-C5 antibody, or antigen-binding fragment thereof, comprising Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434 in the Fc region to a patient: (a) once on day 1 at a dose of 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; or (b) on day 15 and every 8 weeks thereafter at a dose of 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg.

[0031] In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered at a milligram per kilogram (mg / kg) dose. For example, in one embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered at a dose of 0.1 mg / kg, 0.25 mg / kg, 0.5 mg / kg, 0.75 mg / kg, 1.0 mg / kg, 1.25 mg / kg, 1.50 mg / kg, 1.75 mg / kg, 2.0 mg / kg, 2.25 mg / kg, 2.50 mg / kg, 2.75 mg / kg, 3.0 mg / kg, 3.25 mg / kg, 3.50 mg / kg, 3.75 mg / kg, 4.0 mg / kg, 4.25 mg / kg, 4.50 mg / kg, 4.75 mg / kg, 5.0 mg / kg, 5.25mg / kg, 5.50mg / kg, 5.75mg / kg, 6.0mg / kg, 6.25mg / kg, 6.50mg / kg, 6.75mg / kg, 7.0mg / kg, 7.25mg / kg, 7.50mg / kg, 7.75mg / kg, 8.0mg / kg, 8.25mg / kg, 8.50mg / kg, 8.75mg / kg, 9.0mg / kg, 9.25mg / kg, 9.50mg / kg, 9.75mg / kg, 10.0mg / kg, 11.25mg / kg, 11.50mg / kg, 11.75mg / kg, 12.0mg / kg, 12.25mg / kg, 12.50mg / kg, 12.75mg / kg, 13.0mg / kg, 13.25mg / kg, 13.50mg / kg, 13.75mg / kg, 14.0mg / kg, 14.25mg / kg, 14.50mg / kg, 14.75mg / kg, 15.0mg / kg, 15.25mg / kg, 15.50mg / kg, 15.75mg / kg, 16.0mg / kg, 16.25mg / kg, 16.50mg / kg, 16.75mg / kg, 17.0mg / kg, 17.25mg / kg, 17.50 mg / kg, 17.75mg / kg, 18.0mg / kg, 18.25mg / kg, 18.50mg / kg, 18.75mg / kg, 19.0mg / kg, 19.25mg / kg, 19.50mg / kg, 19.75mg / kg, 20.0mg / kg, 20.2 5mg / kg, 20.50mg / kg, 20.75mg / kg, 21.0mg / kg, 21.25mg / kg, 21.50mg / kg, 21.75mg / kg, 22.0mg / kg, 22.25mg / kg, 22.50mg / kg, 22.75mg / kg, 23.The doses are 0 mg / kg, 23.25 mg / kg, 23.50 mg / kg, 23.75 mg / kg, 24.0 mg / kg, 24.25 mg / kg, 24.50 mg / kg, 24.75 mg / kg, or 25.0 mg / kg.

[0032] In one embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or daily. In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered twice a day. In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks, or once every twelve weeks. In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered as a loading dose on day 1, followed by different maintenance doses on day 15 and every eight weeks thereafter.

[0033] In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered shortly after symptoms first appear. In another embodiment, treatment begins 1-20 days after symptoms first appear. In another embodiment, treatment begins 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days after symptoms first appear. In another embodiment, treatment begins 5-15 days after delivery. In another embodiment, treatment begins 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days after delivery.

[0034] In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered in one or more administration cycles. In one embodiment, the administration cycle is 26 weeks. In another embodiment, the treatment includes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 cycles. In another embodiment, the patient is treated for about 1, 2, 3, 4, 5, or 6 months. In another embodiment, the treatment continues for the life of the human patient.

[0035] In some embodiments, the patient has not been previously treated with a complement inhibitor (e.g., the patient is a complement inhibitor treatment-naive patient). In other embodiments, the patient is a complement inhibitor treatment-naive patient who has previously undergone plasma exchange and / or dialysis.

[0036] The anti-C5 antibody or antigen-binding fragment thereof can be administered via any suitable means. In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered intravenously. In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered subcutaneously.

[0037] In another aspect, a method of treating a human patient with p-aHUS is provided, comprising administering to the patient effective amounts of a first anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), followed by a second anti-C5 antibody, or antigen-binding fragment thereof.

[0038] In some embodiments, patients treated according to the methods described herein have been vaccinated against meningococcal infection within three years prior to or at the time of initiating treatment. In one embodiment, patients treated less than two weeks after receiving a meningococcal vaccine are also treated with appropriate prophylactic antibiotics up to two weeks after vaccination. In another embodiment, patients treated according to the methods described herein are vaccinated against meningococcal serogroups A, C, Y, W135, and / or B.

[0039] In another aspect, the described treatment regimen is sufficient to maintain a particular serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof. For example, in one embodiment, treatment is continued for 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 205, 210, 215, 220, 225, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 410, 420, 430, 440, 450, 460, 470, 480, 490, 510, 520, 530, 540, 550, 560, 570, 580, 590, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, The treatment may maintain a serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof, of 245, 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 μg / mL or greater. In one embodiment, the treatment maintains a serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof, of 100 μg / mL or greater. In another embodiment, the treatment maintains a serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof, of 150 μg / mL or greater. In another embodiment, the treatment maintains a serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof, of 200 μg / mL or greater. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody, or antigen-binding fragment thereof, of 250 μg / mL or greater. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody, or antigen-binding fragment thereof, of 300 μg / mL or greater. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody, or antigen-binding fragment thereof, of 100 μg / mL to 200 μg / mL. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody, or antigen-binding fragment thereof, of about 175 μg / mL.

[0040] In another embodiment, to achieve an effective response, the anti-C5 antibody is administered at a concentration of at least 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 105 μg, 110 μg, 115 μg, 120 μg, 125 μg, 130 μg, 135 μg, 140 μg, 145 μg, 150 μg, 15 ... In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain between 0 μg, 155 μg, 160 μg, 165 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg, 195 μg, 200 μg, 205 μg, 210 μg, 215 μg, 220 μg, 225 μg, 230 μg, 235 μg, 240 μg, 245 μg, 250 μg, 255 μg, or 260 μg of antibody per milliliter of blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain between 50 μg and 250 μg of antibody per milliliter of blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain between 100 μg and 200 μg of antibody per milliliter of blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain about 175 μg of antibody per milliliter of blood in the patient.

[0041] In another embodiment, to achieve an effective response, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain a minimum free C5 concentration. For example, in one embodiment, the anti-C5 antibody can be administered to the patient in an amount and frequency to maintain a free C5 concentration of 0.2 μg / mL, 0.3 μg / mL, 0.4 μg / mL, 0.5 μg / mL or less. In another embodiment, the treatment described herein reduces free C5 concentrations by more than 99% over the entire treatment period.

[0042] In another aspect, the methods of treating p-aHUS described herein can be used alone or in combination with one or more additional treatments and / or therapeutic agents. For example, in one embodiment, the method further comprises administering to the patient an anti-inflammatory agent (e.g., prednisone).

[0043] The effectiveness of the treatment methods provided herein can be assessed using any suitable means. In one embodiment, the treatment results in or produces at least one therapeutic effect selected from the group consisting of severe hypertension, proteinuria, uremia, lethargy / fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and a reduction or cessation of renal dysfunction (e.g., acute renal failure) compared to baseline.

[0044] In other embodiments, the treatment results in terminal complement inhibition.

[0045] In other embodiments, treatment results in a shift toward normal levels of hemolysis-related hematological biomarkers selected from the group consisting of free hemoglobin, haptoglobin, reticulocyte count, PNH red blood cell (RBC) clone, and D-dimer compared to baseline.

[0046] In another embodiment, treatment results in a shift toward normal levels of Ba factor, soluble tumor necrosis factor receptor 1 [sTNFR1], soluble vascular adhesion molecule 1 [sVCAM1], thrombomodulin, D-dimer, and cystatin C.

[0047] In another embodiment, treatment results in increased hemoglobin stabilization compared to the patient's pre-treatment baseline. In another embodiment, treatment results in an increase in hemoglobin of ≧20 g / dL.

[0048] In other embodiments, the treatment results in platelet normalization (≧150×10 / L). In other embodiments, the treatment results in platelet normalization (≧150×10 / L) for at least 28 days (e.g., at least 28 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, or 2 years). In other embodiments, the treatment results in platelet normalization 5-12 days after initiation of treatment. For example, in one embodiment, platelet normalization occurs 5, 6, 7, 8, 9, 10, 11, or 12 days after initiation of treatment. In a specific embodiment, platelet normalization occurs 8 days after initiation of treatment.

[0049] In another embodiment, the treatment results in LDH normalization (≦246 U / L). In another embodiment, the treatment results in LDH normalization (≦246 U / L) for at least 28 days (e.g., at least 28 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, or 2 years). In another embodiment, the treatment results in LDH normalization 5-12 days after initiation of treatment. For example, in one embodiment, LDH normalization occurs 5, 6, 7, 8, 9, 10, 11, or 12 days after initiation of treatment. In another embodiment, LDH normalization occurs 8 days after initiation of treatment. In another embodiment, LDH and platelet normalization occurs 8 days after initiation of treatment.

[0050] In other embodiments, treatment results in a ≧25% improvement in serum creatinine from baseline. In other embodiments, treatment results in a ≧25% improvement in serum creatinine from baseline for at least 28 days (e.g., at least 28 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, or 2 years).

[0051] In other embodiments, the treatment results in a complete TMA response (i.e., platelet normalization (≧150×10 / L), LDH normalization (≦246 U / L), and a ≧25% improvement in serum creatinine from baseline). In other embodiments, the treatment results in a complete TMA response for at least 28 days (e.g., at least 28 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, or 2 years). In other embodiments, the treatment confers a complete TMA response in the patient in less than about 57 days (e.g., 56, 55, 54, 53, 52, 51, 50, 49, 48, 48, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 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, 2, or 1 day). In other embodiments, the treatment confers a complete TMA response in the patient in less than about 43 days. In other embodiments, the treatment confers a complete TMA response in the patient in less than about 22 days. In other embodiments, treatment confers a complete TMA response in patients in less than about 15 days. In other embodiments, treatment of p-aHUS patients with an anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab) confers a complete TMA response in about 32 days (range: 8 days to 57 days, 95% CI: 9 days to 46 days).

[0052] In other embodiments, the treatment results in a modified complete TMA response (i.e., platelet normalization (≧150×10 / L), LDH normalization (≦246 U / L), and weaning the patient off dialysis if the patient was on dialysis at baseline, or a ≧25% improvement in serum creatinine from baseline for patients weaned from dialysis at baseline). In other embodiments, the treatment results in a modified complete TMA response for at least 28 days (e.g., at least 28 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, or 2 years).

[0053] In other embodiments, treatment results in hematological normalization, including platelet count normalization (e.g., ≧150×10 / L), lactate dehydrogenase (LDH) normalization (e.g., ≦246 U / L), and preferably both platelet count and LDH normalization over time, and optionally improvement in serum creatinine (e.g., ≧25% improvement) (e.g., two separate assessments separated by ≧28 days).

[0054] In other embodiments, treatment results in a reduction in the need for blood transfusions. In another embodiment, treatment results in a greater than 70% increase in transfusion avoidance.

[0055] In other embodiments, the treatment results in elimination of breakthrough hemolysis during the treatment period. In another embodiment, the treatment results in a reduction in breakthrough hemolysis compared to a pre-treatment baseline amount of breakthrough hemolysis.

[0056] In other embodiments, treatment results in a reduction in major adverse vascular events (MAVEs).

[0057] In other embodiments, treatment improves dialysis requirements compared to baseline, e.g., reduces or completely discontinues dialysis. In one embodiment, treatment results in cessation of dialysis within 15 to 30 days. For example, in other embodiments, dialysis is discontinued 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days after initiation of treatment. In one embodiment, dialysis is discontinued about 21 days after initiation of treatment.

[0058] In other embodiments, treatment results in a change in quality of life from baseline as assessed via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale, Version 4 and the European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 Scale. In one embodiment, treatment results in a change in quality of life from baseline of 1 point or more (e.g., 1, 2, or 3 points) as assessed via the FACIT-Fatigue Scale. In another embodiment, treatment is initiated 150 days or more (e.g., 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 2010, 2011, 2012, 2013, 2014, 2015, 2016, 2017, 2018, 2020, 2021, 2022, 2023, 2024, 2025, 2026, 2027, 2028, 2030, 2031, 2032, 2033, 2034, 2035, 2036, 2037, 2038, 2039, 2040, 2041, 2042, 2043, 2044, 2045, 2046, 2047, 2048, 2049, 2050, 2 produce a 3-point change in quality of life from baseline as assessed via the FACIT-Fatigue scale after 180 days (181 days, 182 days, 183 days, 184 days, 185 days, 186 days, 187 days, 188 days, 189 days, 190 days, 191 days, 192 days, 193 days, 194 days, 195 days, 196 days, 197 days, 198 days, 199 days, 200 days, 205 days, 210 days, 215 days, 220 days, or 225 days).

[0059] In other embodiments, the treatment results in a shift in eGFR toward normal levels (e.g., ≧90). In other embodiments, the treatment improves eGFR status compared to baseline. In other embodiments, the treatment improves eGFR status compared to baseline within 5 to 10 days of initiating treatment. For example, in one embodiment, the treatment improves eGFR status compared to baseline within 5, 6, 7, 8, 9, or 10 days of initiating treatment. In another embodiment, the treatment improves eGFR status compared to baseline within 8 days of initiating treatment.

[0060] In other embodiments, the treatment extends the pregnancy (e.g., by days, weeks, or months). For example, in some embodiments, the treatment extends the pregnancy by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 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, or 60 days. In other embodiments, the treatment extends the pregnancy by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks. In other embodiments, the treatment extends the pregnancy by 1, 2, 3, 4, or 5 months. In other embodiments, the treatment advances the gestational age (e.g., by days, weeks, or months). For example, in some embodiments, treatment advances gestational age by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 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, or 60 days. In other embodiments, treatment advances gestational age by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks. In other embodiments, treatment advances gestational age by 1, 2, 3, 4, or 5 months.

[0061] In other embodiments, the treatment prevents end-stage renal disease (ESRD). In other embodiments, the treatment prolongs the time to ESRD (e.g., by days, weeks, months, or years), for example, by at least 10 months, 20 months, 40 months, 60 months, 80 months, 100 months, or at least 120 months. In some embodiments, the treatment prolongs the time to ESRD after the initial manifestation of thrombotic microangiopathy (TMA).

[0062] In other embodiments, treatment extends the patient's survival (e.g., by days, weeks, months, or years), for example, by at least 10 months, 20 months, 40 months, 60 months, 80 months, 100 months, or at least 120 months.

[0063] Further provided are kits for treating p-aHUS (e.g., postpartum aHUS). In one embodiment, the kit includes: (a) a dose of an anti-C5 antibody, or antigen-binding fragment thereof (e.g., any of those previously described herein); and (b) instructions for using the anti-C5 antibody, or antigen-binding fragment thereof, in a method described herein.

[0064] In one embodiment, a kit for treating p-aHUS (e.g., postpartum aHUS) in a human patient is provided, comprising: (a) a dose of an anti-C5 antibody, or an antigen-binding fragment thereof, comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively; and (b) instructions for using the anti-C5 antibody, or the antigen-binding fragment thereof, in the methods described herein.

[0065] In another embodiment, a kit for treating p-aHUS (e.g., postpartum aHUS) in a human patient is provided, the kit including: (a) a dose of an anti-C5 antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7 and a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 8; and (b) instructions for using the anti-C5 antibody, or antigen-binding fragment thereof, in the methods described herein.

[0066] In another embodiment, a kit for treating p-aHUS (e.g., postpartum aHUS) in a human patient is provided, comprising: (a) a dose of an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 10 and a light chain having the amino acid sequence set forth in SEQ ID NO: 11; and (b) instructions for using the anti-C5 antibody or antigen-binding fragment thereof in the methods described herein.

[0067] In another embodiment, a kit for treating p-aHUS (e.g., postpartum aHUS) in a human patient is provided, the kit including: (a) a dose of eculizumab; and (b) instructions for using eculizumab in the methods described herein.

[0068] In another embodiment, a kit for treating p-aHUS (e.g., postpartum aHUS) in a human patient is provided, comprising: (a) a dose of an anti-C5 antibody, or an antigen-binding fragment thereof, comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively; and (b) instructions for using the anti-C5 antibody, or the antigen-binding fragment thereof, in the methods described herein.

[0069] In another embodiment, a kit for treating p-aHUS (e.g., postpartum aHUS) in a human patient is provided, comprising: (a) a dose of an anti-C5 antibody, or antigen-binding fragment thereof, comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively; the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively; and a variant human Fc region that binds to a human fetal Fc receptor (FcRn), wherein the variant human Fc CH3 region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, of native human IgG Fc region; and (b) instructions for using the anti-C5 antibody, or antigen-binding fragment thereof, in the methods described herein.

[0070] In another embodiment, provided is a kit for treating p-aHUS (e.g., postpartum aHUS) in a human patient, the kit including: (a) a dose of ravulizumab; and (b) instructions for using ravulizumab in the methods described herein. The present invention provides, for example, the following items. (Item 1) 1. A method of treating a human patient with pregnancy-associated atypical hemolytic uremic syndrome (p-aHUS), comprising administering to the patient an effective amount of an anti-C5 antibody, or an antigen-binding fragment thereof; The anti-C5 antibody, or antigen-binding fragment thereof, comprises CDR1, CDR2 and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5 and 6, respectively. (Item 2) 2. The method of item 1, wherein the antibody comprises a variant human Fc region that binds to the human fetal Fc receptor (FcRn), and the variant human Fc CH3 region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, in EU numbering, of a native human IgG Fc region. (Item 3) 3. The method of claim 1, wherein the anti-C5 antibody or antigen-binding fragment thereof comprises a heavy chain variable region set forth in SEQ ID NO: 12 and a light chain variable region set forth in SEQ ID NO: 8. (Item 4) 4. The method according to any one of items 1 to 3, wherein the anti-C5 antibody or antigen-binding fragment thereof further comprises a heavy chain constant region shown in SEQ ID NO: 13. (Item 5) 5. The method according to any one of items 1 to 4, wherein the anti-C5 antibody or antigen-binding fragment thereof comprises a heavy chain set forth in SEQ ID NO: 14 and a light chain set forth in SEQ ID NO: 11. (Item 6) 6. The method of any one of items 1 to 5, wherein the anti-C5 antibody, or antigen-binding fragment thereof, binds to human C5 with an affinity dissociation constant (KD) within the range of 0.1 nM≦KD≦1 nM at pH 7.4 and 25°C. (Item 7) 6. The method according to any one of items 1 to 5, wherein the anti-C5 antibody or antigen-binding fragment thereof binds to human C5 with a KD≧10 nM at pH 6.0 and 25°C. (Item 8) 8. The method of any one of items 1 to 7, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is formulated for intravenous administration. (Item 9) administering the anti-C5 antibody, or antigen-binding fragment thereof, to the patient. (a) Once on day 1, at a dose of 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; (b) On day 15 and every 8 weeks thereafter, at a dose of 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg. 9. The method according to any one of items 1 to 8, wherein the method comprises administering (Item 10) 1. A method of treating a human patient with p-aHUS, comprising administering to said patient an effective amount of an anti-C5 antibody, or antigen-binding fragment thereof; the anti-C5 antibody, or antigen-binding fragment thereof, comprises CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively; and a variant human Fc region that binds to a human fetal Fc receptor (FcRn), wherein the variant human Fc CH3 region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, in EU numbering, of a native human IgG Fc region; administering the anti-C5 antibody, or antigen-binding fragment thereof, to the patient. (a) Once on day 1, at a dose of 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; (b) On day 15 and every 8 weeks thereafter, at a dose of 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg. Method of administration. (Item 11) The anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 40 to < 60 kg. (a) at a dose of 2400 mg once on day 1; (b) at a dose of 3000 mg on day 15 and every 8 weeks thereafter 11. The method according to any one of items 1 to 10, wherein the method comprises administering (Item 12) The anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥60 to <100 kg. (a) at a dose of 2700 mg once on day 1; (b) at a dose of 3300 mg on day 15 and every 8 weeks thereafter 12. The method according to any one of items 1 to 11, wherein the method comprises administering (Item 13) The anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 100 kg. (a) at a dose of 3000 mg once on day 1; (b) at a dose of 3600 mg on day 15 and every 8 weeks thereafter 12. The method according to any one of items 1 to 11, wherein the method comprises administering (Item 14) 14. The method according to any one of items 1 to 13, wherein the treatment maintains a serum trough concentration of the anti-C5 antibody of 100 μg / ml or more during the treatment. (Item 15) 15. The method according to any one of items 1 to 14, wherein the treatment maintains a serum trough concentration of the anti-C5 antibody of 200 μg / ml or more during the treatment. (Item 16) 16. The method of any one of items 1 to 15, wherein the treatment reduces free C5 concentrations by more than 99% over the entire treatment period. (Item 17) 17. The method of any one of items 1 to 16, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is administered at a dose of 3000 mg, 3300 mg, or 3600 mg every 8 weeks for up to 2 years after the treatment. (Item 18) 18. The method of any one of items 1 to 17, wherein the treatment results in terminal complement inhibition. (Item 19) 19. The method of any one of items 1 to 18, wherein the treatment results in a reduction in hemolysis compared to baseline as assessed by lactate dehydrogenase (LDH) levels. (Item 20) 20. The method of any one of items 1 to 19, wherein the treatment results in normalization of LDH levels. (Item 21) 21. The method of any one of items 1 to 20, wherein the treatment results in a shift toward normal levels of a hemolysis-associated hematological biomarker selected from the group consisting of free hemoglobin, haptoglobin, reticulocyte count, PNH red blood cell (RBC) clone, and D-dimer. (Item 22) 22. The method of any one of items 1 to 21, wherein the treatment produces at least one therapeutic effect selected from the group consisting of a reduction or cessation of severe hypertension, proteinuria, uremia, lethargy, fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and renal dysfunction compared to baseline. (Item 23) 23. The method of any one of items 1 to 22, wherein the treatment results in a shift toward normal levels of Ba factor, soluble tumor necrosis factor receptor 1 [sTNFR1], soluble vascular adhesion molecule 1 [sVCAM1], thrombomodulin, D-dimer, and cystatin C. (Item 24) 24. The method of any one of items 1 to 23, wherein the treatment results in increased hemoglobin stabilization compared to baseline. (Item 25) 25. The method of any one of items 1 to 24, wherein the treatment results in a reduction in the need for blood transfusions compared to baseline. (Item 26) 26. The method of any one of items 1 to 25, wherein the treatment results in a reduction in major adverse vascular events (MAVE). (Item 27) 27. The method of any one of items 1 to 26, wherein the treatment results in a change in quality of life from baseline as assessed via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, version 4 and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 scale. (Item 28) 28. The method of any one of items 1 to 27, wherein the treatment results in platelet normalization. (Item 29) 29. The method of any one of items 1 to 28, wherein said treatment results in a ≧25% improvement in serum creatinine from baseline. (Item 30) 30. The method of any one of items 1 to 29, which results in a complete TMA response. (Item 31) 31. The method of any one of items 1 to 30, wherein the treatment results in a modified complete TMA response. (Item 32) 32. The method of any one of items 1 to 31, wherein the treatment results in a shift in eGFR towards normal levels (e.g., ≧90). (Item 33) 33. The method according to any one of items 1 to 32, wherein the treatment results in a reduction or cessation of dialysis. (Item 34) 34. The method of any one of items 1 to 33, wherein the treatment prevents or prolongs the time to end-stage renal disease (ESRD). (Item 35) 35. The method of any one of items 1 to 34, wherein said treatment extends survival of said patient. (Item 36) 36. The method according to any one of items 1 to 35, wherein the p-aHUS is postpartum aHUS. (Item 37) 1. A kit for treating pregnancy-associated atypical hemolytic uremic syndrome (p-aHUS) in a human patient, comprising: (a) a dose of an anti-C5 antibody, or antigen-binding fragment thereof, comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively; and (b) Instructions for using the anti-C5 antibody or its antigen-binding fragment in the method according to any one of items 1 to 32. Kit including: (Item 38) 1. A kit for treating pregnancy-associated atypical hemolytic uremic syndrome (p-aHUS) in a human patient, comprising: (a) a dose of an anti-C5 antibody, or antigen-binding fragment thereof, comprising CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, and a variant human Fc region that binds to a human fetal Fc receptor (FcRn), wherein the variant human Fc CH3 region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, in EU numbering, of a native human IgG Fc region; and (b) Instructions for using the anti-C5 antibody or its antigen-binding fragment in the method according to any one of items 1 to 32. Kit including: (Item 39) Item 37. The kit according to item 35 or 36, wherein the p-aHUS is postpartum aHUS. [Brief explanation of the drawings]

[0071] [Figure 1] Kaplan-Meier graph showing median time to complete TMA response, in days, for eight patients with postpartum aHUS enrolled in a phase 3 multicenter trial ("Study 311"). [Figure 2] Graph showing observed platelet counts over time. Data are shown as mean (error bars, 95% confidence interval). "BL" is baseline. [Figure 3] Graph showing observed lactate dehydrogenase values ​​over time. Data are shown as mean (error bars, 95% confidence interval). "BL" is baseline. [Figure 4] Figure 1 is a graph showing observed eGFR values ​​over time. Data are shown as mean (error bars, 95% confidence interval). "BL" is baseline. "eGFR" is estimated glomerular filtration rate. [Figure 5] 1 is a Kaplan-Meier estimate graph of survival using time to end-stage renal disease (ESRD) after initial TMA manifestation. DETAILED DESCRIPTION OF THE INVENTION

[0072] I. Anti-C5 antibody The 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 noted above, such antibodies also have, for example, improved pharmacokinetic properties compared to other anti-C5 antibodies used therapeutically (e.g., eculizumab).

[0073] The term "antibody" describes a polypeptide comprising at least one antibody-derived antigen-binding site (e.g., a VH / VL region or Fv, or a CDR). Antibodies include known forms of antibodies. For example, an antibody can be a human antibody, a humanized antibody, a bispecific antibody, or a chimeric antibody. An antibody can also be a Fab, Fab'2, ScFv, SMIP, Affibody®, nanobody, or domain antibody. An antibody can also be of any of the following isotypes: IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD, IgE, or a hybrid of any of these isotypes. An antibody can be a naturally occurring antibody or an antibody that has been altered by protein engineering techniques (e.g., by mutation, deletion, substitution, conjugation to a non-antibody moiety). An antibody can contain one or more variant amino acids that, for example, alter the properties (e.g., functional properties) of the antibody (compared to a naturally occurring antibody). Many such modifications are known in the art that affect, for example, the half-life, effector functions, and / or the immune response to the antibody in a patient. The term "antibody" also includes artificial or engineered polypeptide constructs that contain at least one antibody-derived antigen-binding site.

[0074] Anti-C5 antibodies (or VH / VL domains derived therefrom) suitable for use herein can be generated using methods known in the art. Alternatively, art-recognized anti-C5 antibodies can be used. Antibodies that compete with any of these art-recognized antibodies for binding to C5 can also be used.

[0075] Eculizumab (also known as SOLIRIS®) is an anti-C5 antibody comprising heavy chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOS: 1, 2, 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. Eculizumab comprises a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7 and a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 8. The variable regions of eculizumab are described in PCT / US1995 / 005688 and U.S. Patent No. 6,355,245, the teachings of which are incorporated herein by reference in their entireties. Eculizumab comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 10 and a light chain having the amino acid sequence set forth in SEQ ID NO: 11. The complete heavy and light chains of eculizumab are described in PCT / US2007 / 006606, the entire teachings of which are incorporated herein by reference. In some embodiments, eculizumab includes a biosimilar of SOLIRIS®. As used herein, a biosimilar is a product that is highly similar (e.g., in structure, function, or properties) to another already approved biological drug (e.g., a reference drug). Representative examples of SOLIRIS® biosimilars include, for example, monoclonal antibodies ABP959; ELIZARIA; and monoclonal antibody SB12.

[0076] An exemplary anti-C5 antibody is ravulizumab, which comprises heavy and light chains having the sequences set forth in SEQ ID NOs: 14 and 11, respectively, or antigen-binding fragments and variants thereof. Ravulizumab (also known as ULTOMIRIS®) is described in PCT / US2015 / 019225 and U.S. Patent No. 9,079,949, the entire teachings of which are incorporated herein by reference. Ravulizumab selectively binds to the human complement protein C5 and inhibits its cleavage into C5a and C5b during complement activation. This inhibition prevents the release of the proinflammatory 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), which are essential for microbial opsonization and immune complex clearance.

[0077] In other embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of ravulizumab. The antibody may comprise, for example, 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 NOs: 12 and 8, respectively.

[0078] Another exemplary anti-C5 antibody comprises heavy and light chains having the sequences set forth in SEQ ID NOs: 20 and 11, respectively, or antigen-binding fragments and variants thereof. In other embodiments, the antibody may comprise the heavy and light chain CDRs of SEQ ID NOs: 20 and 11. Thus, in one embodiment, the antibody comprises VH CDR1, CDR2, and CDR3 domains having the sequence set forth in SEQ ID NO: 12, and VL region CDR1, CDR2, and CDR3 domains 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.

[0079] The exact boundaries of CDRs have been defined differently according to various methods. In some embodiments, the locations of CDRs or framework regions within a light or heavy chain variable domain may be as defined by Kabat et al. ("Sequences of Proteins of Immunological Interest," NIH Publication No. 91-3242, USDapartment of Health and Human Services, Bethesda, MD, 1991). In such cases, the CDRs may be referred to as "Kabat CDRs" (e.g., "Kabat LCDR2" or "Kabat HCDR1"). In some embodiments, the locations of CDRs in a light or heavy chain variable region may be as defined by Chothia et al. (Nature, 342:877-83, 1989). Accordingly, these regions may be referred to as "Chothia CDRs" (e.g., "Chothia LCDR2" or "Chothia HCDR3"). In some embodiments, the locations of CDRs in light and heavy chain variable regions may be as defined by the Kabat-Chothia combined definition. In such embodiments, these regions can be referred to as "combined Kabat-Chothia CDRs" (Thomas et al., Mol. Immunol., 33:1389-401, 1996).

[0080] 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 set forth in SEQ ID NO: 13. In another embodiment, the antibody comprises a heavy chain polypeptide set forth in SEQ ID NO: 14 and a light chain polypeptide set forth in SEQ ID NO: 11. In another embodiment, the antibody comprises a variant human Fc region that binds to the human fetal Fc receptor (FcRn), wherein the variant human Fc CH3 region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, in EU numbering, of native human IgG Fc region.

[0081] In another embodiment, the antibody comprises the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively; the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively; and a variant human Fc region that binds to the human fetal Fc receptor (FcRn), wherein the variant human Fc CH3 region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, in EU numbering, of native human IgG Fc region.

[0082] In another embodiment, the anti-C5 antibodies described herein comprise a heavy chain CDR1 comprising, or consisting of, the following amino acid sequence: GHIFSNYWIQ (SEQ ID NO: 19). In another embodiment, the anti-C5 antibodies described herein comprise a heavy chain CDR2 comprising, or consisting of, the following amino acid sequence: EILPGSGHTEYTENFKD (SEQ ID NO: 18).

[0083] In another embodiment, the antibody binds to human C5 with an affinity dissociation constant (KD) within the range of 0.1 nM≦KD≦1 nM at pH 7.4 and 25° C. In another embodiment, the antibody binds to human C5 with a KD≧10 nM at pH 6.0 and 25° C. In yet another embodiment, the KD of the antibody or antigen-binding fragment thereof for human C5 at pH 6.0 and 25° C. / (KD of the antibody or antigen-binding fragment thereof for human C5 at pH 7.4 and 25° C.) is greater than 25.

[0084] Another exemplary anti-C5 antibody is as described in U.S. Patent Nos. 8,241,628 and 8,883,158. In one 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 a VH region having the sequence set forth in SEQ ID NO: 27 and a VL region having the sequence set forth in SEQ ID NO: 28.

[0085] Other exemplary anti-C5 antibodies are also described in U.S. Patent Nos. 8,241,628 and 8,883,158. In one 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 a VH region having the sequence set forth in SEQ ID NO: 35 and a VL region having the sequence set forth in SEQ ID NO: 36.

[0086] Another exemplary anti-C5 antibody is described in U.S. Patent Application Publication No. 2016 / 0176954A1. In one 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 a VH region having the sequence set forth in SEQ ID NO: 43 and a VL region having the sequence set forth in SEQ ID NO: 44.

[0087] Another exemplary anti-C5 antibody is described in Fukuzawa T. et al. (Sci. Rep., 7:1080, 2017). In one 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.

[0088] Another exemplary anti-C5 antibody is described in U.S. Patent Application Publication No. 2017 / 0355757. In one embodiment, the antibody comprises a heavy chain variable region comprising SEQ ID NO: 47 and a light chain variable region comprising SEQ ID NO: 48. In another embodiment, the antibody comprises a heavy chain comprising SEQ ID NO: 49 and a light chain comprising SEQ ID NO: 50.

[0089] The antibodies described herein may compete for binding to the same epitope on C5 as any of the antibodies described above and / or may bind to the same epitope on C5. The term "binds to the same epitope" with respect 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 an antibody binds to the "same epitope on C5" as an antibody described herein include, for example, epitope mapping methods, such as X-ray analysis of crystals of antigen:antibody complexes, which provide atomic resolution of the epitope, and hydrogen / deuterium exchange mass spectrometry (HDX-MS). Other methods monitor antibody binding to peptide antigen fragments or variations of the antigen, where loss of binding due to alterations of amino acid residues within the antigen sequence is often considered an indication of epitope content. Additionally, combinatorial computational 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 with the same VH and VL or the same CDR1, CDR2 and CDR3 sequences are predicted to bind to the same epitope.

[0090] The antibodies described herein can have, for example, at least about 90% variable region amino acid sequence identity (e.g., at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% variable region identity) with the antibodies described above.

[0091] In some embodiments, the anti-C5 antibodies described herein may comprise a variant human Fc region that binds to the human fetal Fc receptor (FcRn) with higher affinity than the affinity of the native human Fc region from which the variant human Fc region was derived. The Fc constant region may contain, for example, one or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) amino acid substitutions compared to the native human Fc region from which the variant human Fc region was derived. The substitutions may increase the binding affinity of an IgG antibody containing the variant Fc region for FcRn at pH 6.0 while maintaining the pH dependence of the interaction. Methods for testing whether one or more substitutions in the Fc region of an antibody increase the affinity of the Fc region for FcRn at pH 6.0 (while maintaining the pH dependence of the interaction) are known in the art and are exemplified in the Examples.

[0092] Substitutions that improve the binding affinity of an antibody Fc region to FcRn are known in the art and include, for example, (1) an M252Y / S254T / T256E triple substitution (Dall'Acqua, W. et al., J. Biol. Chem., 281:23514-24, 2006); (2) an M428L or T250Q / M428L substitution (Hinton, P. et al., J. Biol. Chem., 279:6213-6, 2004; Hinton, P. et al., J. Immunol., 176:346-56); and (3) an N434A or T307 / E380A / N434A substitution (Petkova, S. et al., Int. Immunol., 18:1759-69, 2006). Additional substitution pairs, such as P257I / Q311I, P257I / N434H, and D376V / N434H, are described, for example, in Datta-Mannan, A. et al. (J. Biol. Chem., 282:1709-17, 2007), the disclosure of each of which is incorporated herein by reference in its entirety.

[0093] In some embodiments, the constant region may comprise a substitution at EU amino acid residue 255 for valine, a substitution at EU amino acid residue 309 for asparagine, a substitution at EU amino acid residue 312 for isoleucine, and / or a substitution at EU amino acid residue 386.

[0094] The antibodies described herein may comprise a variant Fc region with 30 or fewer (e.g., 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 or fewer) amino acid substitutions, insertions, or deletions relative to the native constant region from which the variant Fc region is derived. In some embodiments, the variant Fc 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 region comprises a methionine at position 428 and an asparagine at position 434, respectively, according to EU numbering. In some embodiments, the variant Fc region comprises a 428L / 434S double substitution, for example, as described in US Pat. No. 8,088,376.

[0095] In some embodiments, the exact location of the substitutions can be shifted from the native human Fc region location as desired for antibody engineering. For example, a 428L / 434S double substitution can correspond to 429L and 435S, such as the M429L and N435S variant found in ravulizumab, when used in an IgG2 / 4 chimeric Fc.

[0096] The antibodies described herein can comprise, for example, a constant region comprising a substitution at one or more amino acid positions 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 a native human constant region. In some embodiments, the substitutions are, all in EU numbering, glycine to methionine at position 237; proline to alanine at position 238; serine to lysine at position 239; lysine to isoleucine at position 248; threonine to alanine, phenylalanine, isoleucine, methionine, glutamine, serine, valine, tryptophan, or tyrosine at position 250; methionine to phenylalanine, tryptophan, or tyrosine at position 252; serine to threonine at position 254; arginine to glutamic acid at position 255; threonine to aspartic acid, glutamic acid, or glutamine at position 256; proline to alanine, glycine, isoleucine, leucine, methionine, asparagine, serine, threonine, or valine at position 257; glutamic acid at position 258; aspartic acid to histidine at position 265; aspartic acid to alanine at position 270; asparagine to alanine or glutamic acid at position 286; threonine to histidine at position 289; asparagine to alanine at position 297; serine to glycine at position 298; valine to alanine at position 303; valine to alanine at position 305; threonine to alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, valine, tryptophan or tyrosine at position 307; valine to alanine, phenylalanine, isoleucine, leucine, methionine, proline, glutamine or threonine at position 308;Leucine or valine to alanine, aspartic acid, glutamic acid, proline, or arginine at position 309; glutamine to alanine, histidine, or isoleucine at position 311; aspartic acid to alanine or histidine at position 312; leucine to lysine or arginine at position 314; asparagine to alanine or histidine at position 315; lysine to alanine at position 317; asparagine to glycine at position 325; isoleucine to valine at position 332; lysine to leucine at position 334; lysine to histidine at position 360; aspartic acid to alanine at position 376; glutamic acid to alanine at position 380; glutamic acid to alanine at position 382; asparagine or serine at position 384 to alanine; glycine to aspartic acid or histidine at position 385; glutamine to proline at position 386; proline to glutamic acid at position 387; asparagine to alanine or serine at position 389; serine to alanine at position 424; methionine to alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, asparagine, proline, glutamine, serine, threonine, valine, tryptophan or tyrosine at position 428; histidine to lysine at position 433; asparagine to alanine, phenylalanine, histidine, serine, tryptophan or tyrosine at position 434; and tyrosine or phenylalanine to histidine at position 436.

[0097] Anti-C5 antibodies suitable 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, 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.

[0098] In one embodiment, the antibody binds to C5 with a KD that is at least 0.1 nM (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, 0.925, 0.95 or 0.975 nM) at pH 7.4 and 25°C (and under otherwise physiological conditions). In some embodiments, the KD of the anti-C5 antibody, or antigen-binding fragment thereof, is 1 nM or less (e.g., 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, or 0.2 nM or less).

[0099] In other embodiments, the KD of the antibody to C5 at pH 6.0 and 25° C. / (KD of the antibody to C5 at pH 7.4 and 25° C.) is greater than 21 (e.g., 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, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4100, 4200, 4300, 440 70, 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 greater than 8000).

[0100] The anti-C5 antibodies described herein may have a serum half-life in humans that is, for example, at least 20 days (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 antibodies described herein have a serum half-life in humans that is at least 40 days. In another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans that is approximately 43 days. In another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans that is 39 to 48 days. Methods for measuring the serum half-life of an antibody are known in the art. In some embodiments, the anti-C5 antibodies, or antigen-binding fragments thereof, described herein have a serum half-life that is at least 20% longer than the serum half-life of eculizumab (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, 500% longer than the serum half-life of eculizumab).

[0101] An antibody that "competes with another antibody for binding to a target" refers to an antibody that inhibits (partially or completely) the binding of the other antibody to a target. Whether two antibodies compete with each other for binding to a target, i.e., whether and to what extent one antibody inhibits the binding of the other antibody to a target, can be determined using known competition experiments. In certain embodiments, an antibody competes with another antibody for binding to a target and inhibits the binding of the other antibody to the target by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. The level of inhibition or competition can vary depending on which antibody is a "blocking antibody." Competing antibodies bind to the same epitope, overlapping epitopes, or adjacent epitopes (e.g., as evidenced by steric hindrance).

[0102] The anti-C5 antibodies or antigen-binding fragments thereof described herein used in the methods described herein can be produced using a variety of art-recognized techniques. Monoclonal antibodies can be obtained by a variety of techniques known to those skilled in the art. Briefly, splenocytes from animals immunized with a desired antigen are immortalized, typically by fusion with myeloma cells (Koehler, G. & Milstein, C., Eur. J. Immunol., 6:511-9, 1976). Alternative 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 the production of antibodies with the desired specificity and affinity for the antigen, and the yield of monoclonal antibodies produced by such cells can be enhanced by various techniques, such as injection into the peritoneal cavity of a vertebrate host. Alternatively, DNA sequences encoding monoclonal antibodies or binding fragments thereof can be isolated by screening a DNA library from human B cells (Huse, W. et al., Science, 246:1275-81, 1989). II. Composition Compositions containing the anti-C5 antibodies or antigen-binding fragments thereof described herein can be formulated as pharmaceutical solutions. Pharmaceutical compositions generally contain a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" refers to any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, including, for example, the following. The compositions may contain, for example, pharmaceutically acceptable salts, such as acid or base addition salts, sugars, carbohydrates, polyols, and / or tonicity modifying agents.

[0103] The compositions described herein can be formulated according to standard methods. Pharmaceutical formulation is a well-established field of technology (Gennaro, "Remington: The Science and Practice of Pharmacy," 20th Edition, Lippincott, Williams & Wilkins (ISBN: 0683306472), 2000; Ansel et al., "Pharmaceutical Dosage Forms and Drug Delivery Systems," 7th Edition, Lippincott Williams & Wilkins Publishers (ISBN: 0683305727), 1999; and Kibbe, "Handbook of Pharmaceutical Excipients American Pharmaceutical Association," 3rd Edition (ISBN: 091733096X), 2000). In some embodiments, the compositions can be formulated, for example, as a buffer solution of a suitable concentration suitable for storage at 2-8°C (e.g., 4°C). In some embodiments, the compositions can be formulated for storage at temperatures below 0°C (e.g., -20°C or -80°C). In some embodiments, the compositions can be formulated for storage at 2-8° C. (e.g., 4° C.) for up to two years (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 1.5 years, or 2 years). Thus, in some embodiments, the compositions described herein are stable upon storage at 2-8° C. (e.g., 4° C.) for at least one year.

[0104] Pharmaceutical compositions can be in a variety of forms. These forms include, for example, 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 compositions intended for systemic or local delivery can be in the form of, for example, injectable or infusible solutions. Thus, the compositions can be formulated for parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection). The terms "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, including, but not limited to, 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.

[0105] In some embodiments, the anti-C5 antibody, or antigen-binding fragment thereof, is formulated as a pharmaceutical solution and administered via subcutaneous injection. Subcutaneous administration can be achieved by a device.

[0106] In some embodiments, the composition comprises ravulizumab for injection. In one embodiment, the injection is a sterile, clear to translucent, slightly whitish, preservative-free solution for intravenous use. In another embodiment, each single-dose vial contains 300 mg of ravulizumab for injection at a concentration of 10 mg / mL at a pH of 7.0. In another embodiment, ravulizumab for injection requires dilution to a final concentration of 5 mg / mL. In another embodiment, each mL further comprises polysorbate 80 (0.2 mg; vegetable origin), sodium chloride (8.77 mg), sodium monohydrogen phosphate (1.78 mg), sodium dihydrogen phosphate (0.46 mg), and water. III. Treatment Methods Provided is a method of treating p-aHUS (e.g., postpartum aHUS) in a human patient, the method comprising administering to the patient an anti-C5 antibody, or an antigen-binding fragment thereof (e.g., ravulizumab). As used herein, the term "subject" or "patient" refers to a human patient (e.g., a patient with p-aHUS).

[0107] Hemolytic uremic syndrome (HUS) is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. HUS is classified as one of two types: diarrhea-associated (D+HUS; also called Shiga toxin-producing Escherichia coli (STEC)-HUS or typical HUS) and non-diarrheal or atypical HUS (aHUS). D+HUS is the most common form, accounting for over 90% of cases, and is caused by a preceding illness with Shiga-like toxin-producing bacteria, such as E. coli O157:H7.

[0108] aHUS can be hereditary, acquired, or idiopathic. Hereditary forms of aHUS can be associated with mutations in multiple human complement components, such as complement factor H (CFH), membrane cofactor protein (MCP), complement factor I (CFI), C4b-binding protein (C4BP), complement factor B (CFB), and complement component 3 (C3) (see, e.g., Caprioli et al. (2006) Blood 108:1267-1279). Certain mutations in the gene encoding CD55, while not yet associated with aHUS, are associated with the severity of aHUS (see, e.g., Esparza-Gordillo et al. (2005) Hum Mol Genet 14:703-712). aHUS can be considered hereditary if two or more (e.g., 3, 4, 5, or 6 or more) members of the same family have the disease at least 6 months apart, excluding exposure to a common precipitating agent, or if one or more aHUS-associated genetic mutations (e.g., one or more mutations in CFH, MCP / CD46, CFB, or CFI) are identified in the subject. For example, a subject may have CFH-associated aHUS, CFB-associated aHUS, CFI-associated aHUS, or MCP-associated aHUS. Up to 30% of hereditary aHUS cases are associated with mutations in CFH, 12% with mutations in MCP, 5-10% with mutations in CFI, and less than 2% with mutations in CFB. Hereditary aHUS can be multiplex (i.e., familial; two or more affected family members) or simplex (i.e., a single occurrence in a family). aHUS can be considered acquired if an underlying environmental factor (e.g., a drug, systemic illness, or a viral or bacterial agent that does not result in Shiga-like exotoxins) or trigger can be identified. aHUS can be considered idiopathic if no trigger (genetic or environmental) is apparent.

[0109] Pregnancy-induced aHUS ("p-aHUS") is a rare and serious systemic disease associated with dysfunction of the alternative complement pathway, occurring in approximately 1 in 25,000 pregnant women. Complement hyperactivation leads to diffuse endothelial injury and subsequent formation of fibrin and platelet microthrombi in blood vessels, which result in hemolysis, thrombocytopenia, and end-organ dysfunction (mainly in the form of acute kidney injury) from ischemia. The majority of p-aHUS cases occur during the postpartum period and are therefore referred to as postpartum aHUS. In some embodiments, patients have severe or early-onset p-aHUS. In such cases, prolonging the pregnancy is necessary to improve perinatal outcomes.

[0110] Laboratory tests can be performed to determine whether a human subject has thrombocytopenia, microangiopathic hemolytic anemia, or acute renal insufficiency. Thrombocytopenia can be diagnosed by a medical professional as one or more of the following: (i) a platelet count of less than 150,000 / mm (e.g., less than 60,000 / mm); (ii) a reduced platelet survival time, reflecting increased platelet destruction in the circulation; and (iii) large platelets observed in a peripheral smear, consistent with secondary activation of thrombopoiesis. Microangiopathic hemolytic anemia can be diagnosed by a healthcare professional as one or more of the following: (i) a hemoglobin concentration of less than 10 mg / dL (e.g., less than 6.5 mg / dL); (ii) an elevated serum lactate dehydrogenase (LDH) concentration (>460 U / L); (iii) hyperbilirubinemia, reticulocytosis, circulating free hemoglobin, and a low or undetectable haptoglobin concentration; and (iv) detection of fragmented red blood cells (schistocytes) with the typical appearance of acanthocytes or helmet cells in a peripheral smear, along with a negative Coombs test. See, for example, Kaplan et al. (1992) "Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura," Informa Health Care (ISBN 0824786637) and Zipfel (2005) "Complement and Kidney Disease," Springer (ISBN 3764371668). Blood levels of C3 and C4 can also be used as a measure of complement activation or dysfunction. Furthermore, a subject's condition can be further characterized by identifying the subject as carrying one or more mutations in genes associated with aHUS, such as CFI, CFB, CFH, or MCP (see above). Suitable methods for detecting mutations in genes include, for example, DNA sequencing and nucleic acid array technology. See, e.g., Breslin et al. (2006) Clin Am Soc Nephrol 1:88-99 and Goicoechea de Jorge et al. (2007) Proc Natl Acad Sci USA 104:240-245.

[0111] In one embodiment, the patient also has preeclampsia (PE) and / or HELLP syndrome. PE is a multisystem, progressive disorder characterized by new-onset hypertension and proteinuria (e.g., >300 mg / 24-hour protein excretion) after 20 weeks of pregnancy or postpartum in previously normotensive women, or hypertension and end-organ dysfunction with or without proteinuria. In pregnant women with PE, delivery of the fetus and placenta is the only curative treatment, which carries the risk of preterm birth and its associated complications. HELLP syndrome is a pregnancy complication characterized by hemolysis, elevated liver enzymes, and low platelet counts. PE / HELLP and p-aHUS share biochemical features, and HELLP and p-aHUS may be part of a continuum. While aHUS is primarily characterized by microangiopathic hemolytic anemia (MAHA) and AKI, PE / HELLP manifests as renal dysfunction, noncardiogenic pulmonary edema, subcapsular hepatic hematomas, and impaired liver function in addition to AKI and MAHA (see, e.g., Elabd et al., BMJ Case Rep. 2019;12). Generally, PE and HELLP syndrome manifest as microvascular disease and share many of the same findings as thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). These disorders typically occur during the third trimester of pregnancy and require delivery of the neonate. Clinicians recommend considering TTP and HUS in patients suspected of preeclampsia or HELLP syndrome if TTP persists after delivery. To this end, plasma exchange and corticosteroid administration can be used to treat TTP; if the patient does not respond, rituximab can be administered. For HUS, supportive care and cobalamin supplementation (hydroxocobalamin, folic acid, and / or betaine) can be provided (Thurman et al., Clin J Am Soc Nephrol 13:933-936, 2018).

[0112] As used herein, "gestational age" (or "menstrual age") refers to the time elapsed between the first day of the last normal menstrual period and the date of delivery. Gestational age is conventionally expressed as the number of completed weeks. Thus, a fetus at 25 weeks and 5 days is considered a 25-week fetus. The term "gestational age" is commonly used instead of "menstrual age" to describe the age of a fetus or newborn. Gestational age is often determined by a "best obstetric estimate," which is based on a combination of the first day of the last menstrual period, maternal physical examination, prenatal ultrasound, and assisted delivery history. A best obstetric estimate is necessary because of gaps in obstetric information and inherent variability (as long as 2 weeks) in methods of gestational age estimation. If the best obstetric estimate is deemed inaccurate, a postnatal physical examination of the infant may be used as a method to determine gestational age.

[0113] As used herein, "chronological age" (or "postnatal" age) refers to the time that has elapsed since birth. It is usually described in days, weeks, months, and / or years. This is distinct from the term "postmenstrual age."

[0114] As used herein, "postmenstrual age" refers to the time elapsed between the first day of the last menstrual period and birth (gestational age) and the time elapsed since birth (chronological age). Postmenstrual age is usually described in weeks and is most frequently applied during the perinatal period beginning after the birth date. Thus, a premature infant born at 33 weeks' gestational age who is now 10 weeks old (chronological age) has a postmenstrual age of 43 weeks.

[0115] As used herein, "corrected age" (or "adjusted age") refers to the term most appropriately used to describe children born prematurely up to the age of 3 years. Corrected age is calculated by subtracting the number of weeks at birth before 40 weeks gestation from the chronological age. Thus, an infant aged 24 months or younger, with a gestational age of 28 weeks, has a corrected age of 21 months according to the following formula: 24 months - [(40 weeks - 28 weeks) x 1 month / 4 weeks]. Corrected age and chronological age are not synonymous in premature infants. Furthermore, the term "corrected age" should be used instead of "adjusted age."

[0116] As used herein, "gestational age" is the time elapsed between the date of conception and the date of delivery. Because assisted birth techniques precisely define the date of conception or implantation, precise gestational age can be determined in pregnancies resulting from such techniques.

[0117] As used herein, "effective treatment" refers to treatment that produces a beneficial effect, e.g., an improvement in at least one symptom of a disease or disorder. The beneficial effect can take the form of an improvement over baseline, i.e., an improvement over measurements or observations made before the start of treatment according to the method. For example, effective treatment can refer to a reduction in one or more symptoms selected from the group consisting of severe hypertension, proteinuria, uremia, lethargy / fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and a reduction or cessation of renal dysfunction (e.g., acute renal failure) compared to baseline.

[0118] The term "effective amount" refers to an amount of an agent that provides a desired biological, therapeutic, and / or prophylactic result. That result can be reduction, amelioration, alleviation, reduction, delay, 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 an amount of an anti-C5 antibody, or antigen-binding fragment thereof, that has been clinically proven to alleviate at least one symptom of aHUS. An effective amount can be administered in one or more administrations.

[0119] As used herein, the phrase "end stage renal disease" (also known as ESRD or renal failure) refers to the final stage of chronic kidney disease in which the kidneys stop functioning adequately, thereby requiring lifelong dialysis or a kidney transplant for survival.

[0120] In one embodiment, a method is provided for treating a human patient with p-aHUS, comprising administering to the patient an effective amount of an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody, or antigen-binding fragment thereof, comprises the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences having the sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively. In another embodiment, a method is provided for treating a human patient with p-aHUS, comprising administering to the patient an effective amount of an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7 and a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 8. In another embodiment, a method of treating a human patient with p-aHUS is provided, comprising administering to the patient an effective amount of an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody, or antigen-binding fragment thereof, comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 10 and a light chain having the amino acid sequence set forth in SEQ ID NO: 11.

[0121] In one embodiment, a method of treating a human patient with p-aHUS is provided, comprising administering to the patient an effective amount of an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody, or antigen-binding fragment thereof, comprises the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively. In another embodiment, the antibody further comprises a variant human Fc constant region that binds to a human fetal 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, respectively, in EU numbering, of the native human IgG Fc constant region.

[0122] In one embodiment, the anti-C5 antibody or antigen-binding fragment is administered as a fixed dose. For example, in one embodiment, the anti-C5 antibody or antigen-binding fragment is administered at a fixed dose of 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 40 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 900 mg, 1000 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 40 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 1000 mg, 1250 mg, 1500 mg, 1750 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 2000 mg, 2100 mg, 225 mg, 250 mg, 275 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, 1600mg, 1700mg, 1800mg, 1900mg, 2000mg, 2 38 00mg,3900mg,4000mg,4100mg,4200mg,4300mg,4400mg,4500mg,4600mg,4700mg,4800mg,4900mg,5000mg,5100mg,5200mg,5300mg,5400mg,550 0mg, 5600mg, 5700mg, 5800mg, 5900mg, 6000mg, 6100mg, 6200mg, 6300mg, 6400mg, 6500mg, 6600mg, 6700mg, 6800mg, 6900mg, 7000mg, 7100mg, 7200 mg, 7300mg, 7400mg, 7500mg, 7600mg, 7700mg, 7800mg, 7900mg, 8000mg, 8100mg, 8200mg, 8300mg, 8400mg, 8500mg, 8600mg, 8700mg, 8800mg, 8900m g.In another embodiment, the anti-C5 antibody or antigen-binding fragment is administered at a sub-therapeutic dose.

[0123] In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab) is administered at a dose of 2400 mg, 2700 mg, 3000 mg, 3300 mg, or 3600 mg.

[0124] In another embodiment, the dose of the anti-C5 antibody or antigen-binding fragment is based on the patient's weight. For example, in one embodiment, the dose is 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 92 5mg, 950mg, 975mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, 1600mg, 1700mg, 1800mg, 1900mg, 2000mg, 2100mg, 2200mg, 2300mg, 2400m g, 2500mg, 2600mg, 2700mg, 2800mg, 2900mg, 3000mg, 3100mg, 3200mg, 3300mg, 3400mg, 3500mg, 3600mg, 3700mg, 3800mg, 3900mg, 4000mg, 4100mg ,4200mg,4300mg,4400mg,4500mg,4600mg,4700mg,4800mg,4900mg,5000mg,5100mg,5200mg,5300mg,5400mg,5500mg,5600mg,5700mg,5800mg , 5900mg, 6000mg, 6100mg, 6200mg, 6300mg, 6400mg, 6500mg, 6600mg, 6700mg, 6800mg, 6900mg, 7000mg, 7100mg, 7200mg, 7300mg, 7400mg, 7500mg, 7600mg, 7700mg, 7800mg, 7900mg, 8000mg, 8100mg, 8200mg, 8300mg, 8400mg, 8500mg, 8600mg, 8700mg, 8800mg, 8900mg, 9000mg, 9100mg, 9200mg, 9 300mg, 9400mg, 9500mg, 9600mg, 9700mg, 9800mg, 9900mg, 10000mg, 10100mg, 10200mg, 10300mg, 10400mg, 10500mg, 10600mg, 10700mg, 10800mg,10,900 mg or 11,000 mg of an anti-C5 antibody or antigen-binding fragment is administered to a patient weighing ≥ 40 kg to < 60 kg. In another embodiment, 2,400 mg or 3,000 mg of an anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to a patient weighing ≥ 40 kg to < 60 kg. In another embodiment, 2,400 mg or 3,000 mg of an anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered every two weeks to a patient weighing ≥ 40 kg to < 60 kg. In another embodiment, 2,400 mg or 3,000 mg of an anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered every eight weeks to a patient weighing ≥ 40 kg to < 60 kg.

[0125] In another embodiment, the saturates are 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 960 mg, 980 mg, 990 mg, 1000 mg, 1010 mg, 1020 mg, 1030 mg, 1040 mg, 1050 mg, 1060 mg, 1070 mg, 1080 mg, 1090 mg, 1100 mg, 1110 mg, 1120 mg, 1130 mg, 1140 mg, 1150 mg, 1160 mg, 1170 mg, 1180 mg, 1190 mg, 1200 mg, 1210 mg, 1220 mg, 1230 mg, 1240 mg, 1250 mg, 1260 mg, 1270 mg, 1280 mg, 1290 mg, 1300 mg, 1310 mg, 1320 mg, 1330 mg, 1340 mg, 13 75mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, 1600mg, 1700mg, 1800mg, 1900mg, 2000mg, 2100mg, 2200mg, 2300mg, 2400mg, 2500mg, 2600mg, 2700mg, 2800mg, 2900mg, 3000mg, 3100mg, 3200mg, 3300mg, 3400mg, 3500mg, 3600mg, 3700mg, 3800mg, 3900mg, 4000mg, 4100mg, 4200mg, 4300mg, 4400m g, 4500mg, 4600mg, 4700mg, 4800mg, 4900mg, 5000mg, 5100mg, 5200mg, 5300mg, 5400mg, 5500mg, 5600mg, 5700mg, 5800mg, 5900mg, 6000mg, 6100mg, 62 00mg, 6300mg, 6400mg, 6500mg, 6600mg, 6700mg, 6800mg, 6900mg, 7000mg, 7100mg, 7200mg, 7300mg, 7400mg, 7500mg, 7600mg, 7700mg, 7800mg, 7900mg, 8000 mg, 8100 mg, 8200 mg, 8300 mg, 8400 mg, 8500 mg, 8600 mg, 8700 mg, 8800 mg, 8900 mg, 9000 mg, 9100 mg, 9200 mg, 9300 mg, 9400 mg, 9500 mg, 9600 mg, 9700 mg, 9800 mg, 9900 mg, 10000 mg, 10100 mg, 10200 mg, 10300 mg, 10400 mg, 10500 mg, 10600 mg, 10700 mg, 10800 mg, 10900 mg, or 11000 mg of an anti-C5 antibody or antigen-binding fragment thereof,In another embodiment, 2700 mg or 3300 mg of a C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to a patient weighing ≥60 to <100 kg. In another embodiment, 2700 mg or 3300 mg of an anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to a patient weighing ≥60 to <100 kg every 8 weeks.

[0126] In another embodiment, the concentrations of 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, 1600mg, 1700mg, 1800mg, 1900mg, 2000mg, 2100mg, 2200mg, 2300mg, 2400mg, 2500mg, 2600m g, 2700mg, 2800mg, 2900mg, 3000mg, 3100mg, 3200mg, 3300mg, 3400mg, 3500mg, 3600mg, 3700mg, 3800mg, 3900mg, 4000mg, 4100mg, 4200mg, 4300mg, 440 0mg, 4500mg, 4600mg, 4700mg, 4800mg, 4900mg, 5000mg, 5100mg, 5200mg, 5300mg, 5400mg, 5500mg, 5600mg, 5700mg, 5800mg, 5900mg, 6000mg, 6100mg, 6200mg, 6300mg, 6400mg, 6500mg, 6600mg, 6700mg, 6800mg, 6900mg, 7000mg, 7100mg, 7200mg, 7300mg, 7400mg, 7500mg, 7600mg, 7700mg, 7800mg, 7900m g, 8000 mg, 8100 mg, 8200 mg, 8300 mg, 8400 mg, 8500 mg, 8600 mg, 8700 mg, 8800 mg, 8900 mg, 9000 mg, 9100 mg, 9200 mg, 9300 mg, 9400 mg, 9500 mg, 9600 mg, 9700 mg, 9800 mg, 9900 mg, 10000 mg, 10100 mg, 10200 mg, 10300 mg, 10400 mg, 10500 mg, 10600 mg, 10700 mg, 10800 mg, 10900 mg, or 11000 mg of an anti-C5 antibody or antigen-binding fragment,In another embodiment, 3000 mg or 3600 mg of an anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab) is administered to a patient weighing ≧100 kg. In another embodiment, 3000 mg or 3600 mg of an anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab) is administered to a patient weighing ≧100 kg every 8 weeks.

[0127] In another embodiment, a method of treating a human patient with p-aHUS is provided, comprising administering to the patient an anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab): (a) once on day 1 at a dose of 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; and (b) on day 15 and every 8 weeks thereafter at a dose of 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg.

[0128] In another embodiment, a method of treating a human patient with m-aHUS is provided, comprising administering an anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab) to a patient weighing ≧40 to <60 kg: (a) once on day 1 at a dose of 2400 mg; (b) once on day 15 and every 8 weeks thereafter at a dose of 3000 mg.

[0129] In another embodiment, a method of treating a human patient with p-aHUS is provided, comprising administering an anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab) to a patient weighing ≥60 to <100 kg: (a) once on day 1 at a dose of 2700 mg; (b) once on day 15 of a dosing cycle and every 8 weeks thereafter at a dose of 3300 mg.

[0130] In another embodiment, a method of treating a human patient with p-aHUS is provided, comprising administering an anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab) to a patient weighing ≧100 kg: (a) once on day 1 at a dose of 3000 mg; (b) once on day 15 and every 8 weeks thereafter at a dose of 3600 mg.

[0131] In another embodiment, a method of treating a human patient with p-aHUS comprises administering to the patient an effective amount of an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody, or antigen-binding fragment thereof, comprises CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, and a variant human Fc region that binds to a human fetal Fc receptor (FcRn), wherein the variant human Fc CH3 region is a variant of a variant human Fc CH3 region that binds to a native human IgG1, each in EU numbering. Methods are provided that include administering an anti-C5 antibody, or antigen-binding fragment thereof, comprising Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434 in the Fc region to a patient: (a) once on day 1 at a dose of 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; or (b) on day 15 and every 8 weeks thereafter at a dose of 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg.

[0132] In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered in a milligram per kilogram (mg / kg) dose. For example, in one embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered at a dose of 0.1 mg / kg, 0.25 mg / kg, 0.5 mg / kg, 0.75 mg / kg, 1.0 mg / kg, 1.25 mg / kg, 1.50 mg / kg, 1.75 mg / kg, 2.0 mg / kg, 2.25 mg / kg, 2.50 mg / kg, 2.75 mg / kg, 3.0 mg / kg, 3.25 mg / kg, 3.50 mg / kg, 3.75 mg / kg, 4.0 mg / kg, 4.25 mg / kg, 4.50 mg / kg, 4.75 mg / kg, 5.0 mg / kg, 5.25mg / kg, 5.50mg / kg, 5.75mg / kg, 6.0mg / kg, 6.25mg / kg, 6.50mg / kg, 6.75mg / kg, 7.0mg / kg, 7.25mg / kg, 7.50mg / kg, 7.75mg / kg, 8.0mg / kg, 8.25mg / kg, 8.50mg / kg, 8.75mg / kg, 9.0mg / kg, 9.25mg / kg, 9.50mg / kg, 9.75mg / kg, 10.0mg / kg, 11.25mg / kg, 11.50mg / kg, 11.75mg / kg, 12.0mg / kg, 12.25mg / kg, 12.50mg / kg, 12.75mg / kg, 13.0mg / kg, 13.25mg / kg, 13.50mg / kg, 13.75mg / kg, 14.0mg / kg, 14.25mg / kg, 14.50mg / kg, 14.75mg / kg, 15.0mg / kg, 15.25mg / kg, 15.50mg / kg, 15.75mg / kg, 16.0mg / kg, 16.25mg / kg, 16.50mg / kg, 16.75mg / kg, 17.0mg / kg, 17.25mg / kg, 17.50 mg / kg, 17.75mg / kg, 18.0mg / kg, 18.25mg / kg, 18.50mg / kg, 18.75mg / kg, 19.0mg / kg, 19.25mg / kg, 19.50mg / kg, 19.75mg / kg, 20.0mg / kg, 20.2 5mg / kg, 20.50mg / kg, 20.75mg / kg, 21.0mg / kg, 21.25mg / kg, 21.50mg / kg, 21.75mg / kg, 22.0mg / kg, 22.25mg / kg, 22.50mg / kg, 22.75mg / kg, 23.The doses are 0 mg / kg, 23.25 mg / kg, 23.50 mg / kg, 23.75 mg / kg, 24.0 mg / kg, 24.25 mg / kg, 24.50 mg / kg, 24.75 mg / kg, or 25.0 mg / kg.

[0133] In one embodiment, the anti-C5 antibody or antigen-binding fragment is administered once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or daily. In another embodiment, the anti-C5 antibody or antigen-binding fragment is administered twice a day. In another embodiment, the anti-C5 antibody or antigen-binding fragment is administered once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks, or once every twelve weeks. In another embodiment, the anti-C5 antibody or antigen-binding fragment is administered as a loading dose on day 1, followed by different maintenance doses on day 15 and every eight weeks thereafter.

[0134] In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered shortly after symptoms first appear. In another embodiment, treatment begins 1-20 days after symptoms first appear. In another embodiment, treatment begins 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days after symptoms first appear. In another embodiment, treatment begins 5-15 days after delivery. In another embodiment, treatment begins 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days after delivery. In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered in one or more administration cycles. In one embodiment, the administration cycle is 26 weeks. In another embodiment, the treatment comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 cycles. In another embodiment, the patient is treated for about 1, 2, 3, 4, 5, or 6 months. In another embodiment, the treatment continues for the life of the human patient.

[0135] In some embodiments, the patient has not been previously treated with a complement inhibitor (e.g., the patient is a complement inhibitor treatment-naive patient). In other embodiments, the patient is a complement inhibitor treatment-naive patient who has previously undergone plasma exchange and / or dialysis.

[0136] The anti-C5 antibody or antigen-binding fragment can be administered via any suitable means. In one embodiment, the anti-C5 antibody or antigen-binding fragment is administered intravenously. In another embodiment, the anti-C5 antibody or antigen-binding fragment is administered subcutaneously.

[0137] In some embodiments, patients treated according to the methods described herein have been vaccinated against meningococcal infection within three years prior to or at the time of initiating treatment. In one embodiment, patients treated less than two weeks after receiving a meningococcal vaccine are also treated with appropriate prophylactic antibiotics up to two weeks after vaccination. In another embodiment, patients treated according to the methods described herein are vaccinated against meningococcal serogroups A, C, Y, W135, and / or B.

[0138] In another aspect, the described treatment regimen is sufficient to maintain a particular serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof. Treatment can be continued for, for example, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 205, 210, 215, 220, 225, 230, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 300, 310, 315, 320, 325, 330, 340, 345, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 510, 520, 530, 540, 550, 560, 570, 580, 590, 610, 620, 630, 640, 650, 660, 670, 680, 690, 710, 720, 730, 740, 750, 760, 770, 78 The treatment may maintain a serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof, of 50, 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 μg / mL or greater. In one embodiment, the treatment maintains a serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof, of 100 μg / mL or greater. In another embodiment, the treatment maintains a serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof, of 150 μg / mL or greater. In another embodiment, the treatment maintains a serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof, of 200 μg / mL or greater. In another embodiment, treatment maintains a serum trough concentration of anti-C5 antibody, or antigen-binding fragment thereof, of 250 μg / mL or greater. In another embodiment, treatment maintains a serum trough concentration of anti-C5 antibody, or antigen-binding fragment thereof, of 300 μg / mL or greater. In another embodiment, treatment maintains a serum trough concentration of anti-C5 antibody, or antigen-binding fragment thereof, of 100 μg / mL to 200 μg / mL. In another embodiment, treatment maintains a serum trough concentration of anti-C5 antibody, or antigen-binding fragment thereof, of about 175 μg / mL.

[0139] In another embodiment, to achieve an effective response, the anti-C5 antibody is administered at a concentration of at least 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 105 μg, 110 μg, 115 μg, 120 μg, 125 μg, 130 μg, 135 μg, 140 μg, 145 μg, 150 μg, 15 ... In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain between 0 μg, 155 μg, 160 μg, 165 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg, 195 μg, 200 μg, 205 μg, 210 μg, 215 μg, 220 μg, 225 μg, 230 μg, 235 μg, 240 μg, 245 μg, 250 μg, 255 μg, or 260 μg of antibody per milliliter of blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain between 50 μg and 250 μg of antibody per milliliter of blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain between 100 μg and 200 μg of antibody per milliliter of blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain about 175 μg of antibody per milliliter of blood in the patient.

[0140] In another embodiment, to achieve an effective response, the anti-C5 antibody is administered to the patient in an amount and frequency sufficient to maintain a minimum free C5 concentration. For example, the anti-C5 antibody can be administered to the patient in an amount and frequency sufficient to maintain a free C5 concentration of 0.2 μg / mL, 0.3 μg / mL, 0.4 μg / mL, 0.5 μg / mL or less. In another embodiment, the treatment described herein reduces free C5 concentrations by greater than 99% over the entire treatment period. In another embodiment, the treatment reduces free C5 concentrations by greater than 99.5% over the entire treatment period.

[0141] In another aspect, the methods of treating p-aHUS described herein can be used alone or in combination with one or more additional treatments and / or therapeutic agents. For example, in one embodiment, the method further comprises administering to the patient an anti-inflammatory agent (e.g., prednisone). IV. Outcomes Provided herein are methods for treating p-aHUS in a patient, the methods comprising administering to the patient an anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab).

[0142] Symptoms of p-aHUS include, but are not limited to, severe hypertension, proteinuria, uremia, lethargy / fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and renal dysfunction (e.g., acute renal failure). Patients treated according to the methods disclosed herein preferably experience improvement in at least one symptom of p-aHUS.

[0143] In other embodiments, the treatment results in terminal complement inhibition.

[0144] In other embodiments, treatment results in a shift toward normal levels of hemolysis-related hematological biomarkers selected from the group consisting of free hemoglobin, haptoglobin, reticulocyte count, PNH red blood cell (RBC) clone, and D-dimer.

[0145] In another embodiment, treatment results in an increase in hemoglobin stabilization from the patient's pre-treatment baseline. In another embodiment, treatment results in an increase in hemoglobin of ≧20 g / dL.

[0146] In other embodiments, the treatment results in platelet normalization (≧150×10 / L). In other embodiments, the treatment results in platelet normalization (≧150×10 / L) for at least 28 days (e.g., at least 28 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, or 2 years). In other embodiments, the treatment results in platelet normalization 5-12 days after initiation of treatment. For example, in one embodiment, platelet normalization occurs 5, 6, 7, 8, 9, 10, 11, or 12 days after initiation of treatment. In a specific embodiment, platelet normalization occurs 8 days after initiation of treatment.

[0147] In other embodiments, treatment results in LDH normalization (≦246 U / L). In other embodiments, treatment results in LDH normalization (≦246 U / L) for at least 28 days (e.g., at least 28 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, or 2 years).

[0148] In other embodiments, treatment results in LDH normalization 5 to 12 days after initiation of treatment. For example, in one embodiment, LDH normalization occurs 5, 6, 7, 8, 9, 10, 11, or 12 days after initiation of treatment. In another embodiment, LDH normalization occurs 8 days after initiation of treatment. In another embodiment, LDH and platelet normalization occurs 8 days after initiation of treatment.

[0149] In other embodiments, treatment results in a ≥ 25% improvement in serum creatinine from baseline. In other embodiments, treatment results in a ≥ 25% improvement in serum creatinine from baseline at two separate assessments ≥ 28 days apart. In other embodiments, treatment results in a ≥ 25% improvement in serum creatinine from baseline for at least 28 days (e.g., at least 28 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, or 2 years).

[0150] In other embodiments, the treatment results in a complete TMA response (i.e., platelet normalization (≧150×10 / L), LDH normalization (≦246 U / L), and a ≧25% improvement in serum creatinine from baseline). In other embodiments, the treatment results in a complete TMA response for at least 28 days (e.g., at least 28 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, or 2 years). In other embodiments, the treatment confers a complete TMA response in the patient in less than about 57 days (e.g., 56, 55, 54, 53, 52, 51, 50, 49, 48, 48, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 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, 2, or 1 day). In other embodiments, the treatment confers a complete TMA response in the patient in less than about 43 days. In other embodiments, the treatment confers a complete TMA response in the patient in less than about 22 days. In other embodiments, treatment confers a complete TMA response in patients in less than about 15 days. In other embodiments, treatment of p-aHUS patients with an anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab) confers a complete TMA response in about 32 days (range: 8 days to 57 days, 95% CI: 9 days to 46 days).

[0151] In other embodiments, the treatment results in a modified complete TMA response (i.e., platelet normalization (≧150×10 / L), LDH normalization (≦246 U / L), and weaning the patient off dialysis if the patient was on dialysis at baseline, or a ≧25% improvement in serum creatinine from baseline for patients weaned from dialysis at baseline). In other embodiments, the treatment results in a modified complete TMA response for at least 28 days (e.g., at least 28 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, or 2 years).

[0152] In other embodiments, treatment results in hematological normalization, including platelet count normalization (e.g., ≧150×10 / L), lactate dehydrogenase (LDH) normalization (e.g., ≦246 U / L), and preferably both platelet count and LDH normalization over time, and optionally improvement in serum creatinine (e.g., ≧25% improvement) (e.g., two separate assessments separated by ≧28 days).

[0153] In other embodiments, treatment results in a reduction in the need for blood transfusions. In another embodiment, treatment results in a greater than 70% increase in transfusion avoidance.

[0154] In other embodiments, treatment improves dialysis requirements compared to baseline, e.g., reduces or completely discontinues dialysis. In one embodiment, treatment results in cessation of dialysis within 15 to 30 days. For example, in other embodiments, dialysis is discontinued 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days after initiation of treatment. In one embodiment, dialysis is discontinued about 21 days after initiation of treatment.

[0155] In other embodiments, treatment results in a reduction in major adverse vascular events (MAVEs).

[0156] In other embodiments, treatment results in a change in quality of life from baseline as assessed via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, version 4 and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 scale. In one embodiment, treatment results in a change in quality of life from baseline of 1 point or more (e.g., 1, 2, or 3 points) as assessed via the FACIT-Fatigue scale. In another embodiment, treatment is initiated 150 days or more (e.g., 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 2010, 2011, 2012, 2013, 2014, 2015, 2016, 2017, 2018, 2020, 2021, 2022, 2023, 2024, 2025, 2026, 2027, 2028, 2030, 2031, 2032, 2033, 2034, 2035, 2036, 2037, 2038, 2039, 2040, 2041, 2042, 2043, 2044, 2045, 2046, 2047, 2048, 2049, 2050, 2 produce a 3-point change in quality of life from baseline as assessed via the FACIT-Fatigue scale after 180 days (181 days, 182 days, 183 days, 184 days, 185 days, 186 days, 187 days, 188 days, 189 days, 190 days, 191 days, 192 days, 193 days, 194 days, 195 days, 196 days, 197 days, 198 days, 199 days, 200 days, 205 days, 210 days, 215 days, 220 days, or 225 days).

[0157] In another embodiment, the treatment results in a shift in eGFR toward normal levels (e.g., ≧90). In another embodiment, the treatment improves eGFR status compared to baseline. In another embodiment, the treatment improves eGFR status compared to baseline within 5 to 10 days of initiating treatment. For example, in one embodiment, the treatment improves eGFR status compared to baseline within 5, 6, 7, 8, 9, or 10 days of initiating treatment. In another embodiment, the treatment improves eGFR status compared to baseline within 8 days of initiating treatment.

[0158] In other embodiments, the treatment extends the pregnancy (e.g., by days, weeks, or months). For example, in some embodiments, the treatment extends the pregnancy by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 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, or 60 days. In other embodiments, the treatment extends the pregnancy by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks. In other embodiments, the treatment extends the pregnancy by 1, 2, 3, 4, or 5 months. In other embodiments, the treatment advances the gestational age (e.g., by days, weeks, or months). For example, in some embodiments, treatment advances gestational age by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 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, or 60 days. In other embodiments, treatment advances gestational age by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks. In other embodiments, treatment advances gestational age by 1, 2, 3, 4, or 5 months.

[0159] In other embodiments, the treatment prevents end-stage renal disease (ESRD). In other embodiments, the treatment prolongs the time to ESRD (e.g., by days, weeks, months, or years), e.g., by at least 10 months, at least 20 months, at least 40 months, at least 60 months, at least 80 months, at least 100 months, or at least 120 months. In some embodiments, the treatment prolongs the time to ESRD after the initial manifestation of thrombotic microangiopathy (TMA). TMA manifestation can be analyzed using routine methods, such as (A) the occurrence of ≥2 laboratory changes selected from (1) a ≥25% decrease in platelet count and <lower limit of normal (LLN); (2) a ≥25% increase in serum creatinine (SCr) and >upper limit of normal (ULN) and (3) a ≥25% increase in LDH and >ULN; (B) clinical signs / symptoms selected from (1) thrombosis; (2) stroke; (3) decreased renal function; (4) proteinuria; (5) hematuria; (6) increased hemolytic anemia; (7) biopsy-confirmed TMA; or (8) extrarenal manifestations of TMA (e.g., confusion, cardiovascular abnormalities, pericarditis, gastrointestinal symptoms / diarrhea); or (C) requirement for compensation, e.g., plasma exchange / plasma infusion (PE / PI); dialysis; blood transfusion; or kidney transplant.

[0160] In other embodiments, treatment extends the survival of the patient (eg, by days, weeks, months, or years). V. Kits and Unit Dosage Forms Also provided herein are kits containing a pharmaceutical composition containing an anti-C5 antibody, or antigen-binding fragment thereof (e.g., any of those already described herein), in a therapeutically effective amount adapted for use in the methods described herein and a pharmaceutically acceptable carrier. The kit may also optionally contain instructions, including, for example, an administration schedule, to enable a practitioner (e.g., a doctor, a nurse, or a patient) to administer the composition contained therein to a patient with p-aHUS. The kit may also include a syringe.

[0161] Optionally, the kit includes multiple packages of single-dose pharmaceutical compositions, each containing an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof, for single administration according to the methods provided above. The kit can also include an apparatus or device necessary for administering the pharmaceutical composition(s). For example, the kit can provide one or more pre-filled syringes containing a certain amount of an anti-C5 antibody or an antigen-binding fragment thereof.

[0162] In one embodiment, a kit for treating p-aHUS (e.g., postpartum aHUS) in a human patient is provided, comprising: (a) a dose of an anti-C5 antibody, or an antigen-binding fragment thereof, comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively; and (b) instructions for using the anti-C5 antibody, or the antigen-binding fragment thereof, in the methods described herein.

[0163] In another embodiment, a kit for treating p-aHUS (e.g., postpartum aHUS) in a human patient is provided, the kit including: (a) a dose of an anti-C5 antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7 and a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 8; and (b) instructions for using the anti-C5 antibody, or antigen-binding fragment thereof, in the methods described herein.

[0164] In another embodiment, a kit for treating p-aHUS (e.g., postpartum aHUS) in a human patient is provided, comprising: (a) a dose of an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 10 and a light chain having the amino acid sequence set forth in SEQ ID NO: 11; and (b) instructions for using the anti-C5 antibody or antigen-binding fragment thereof in the methods described herein.

[0165] In another embodiment, a kit for treating p-aHUS (e.g., postpartum aHUS) in a human patient is provided, the kit including: (a) a dose of eculizumab; and (b) instructions for using eculizumab in the methods described herein.

[0166] In another embodiment, a kit for treating p-aHUS (e.g., postpartum aHUS) in a human patient is provided, comprising: (a) a dose of an anti-C5 antibody, or an antigen-binding fragment thereof, comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively; and (b) instructions for using the anti-C5 antibody, or the antigen-binding fragment thereof, in the methods described herein.

[0167] In another embodiment, a kit for treating p-aHUS (e.g., postpartum aHUS) in a human patient is provided, comprising: (a) a dose of an anti-C5 antibody, or antigen-binding fragment thereof, comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, and a variant human Fc region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, of native human IgG Fc region; and (b) instructions for using the anti-C5 antibody, or antigen-binding fragment thereof, in the methods described herein.

[0168] In another embodiment, provided is a kit for treating p-aHUS (e.g., postpartum aHUS) in a human patient, the kit including: (a) a dose of ravulizumab; and (b) instructions for using ravulizumab in the methods described herein.

[0169] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials for use in this disclosure are described; other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries (e.g., PUBMED, NCBI, or UNIPROT accession numbers), and other references mentioned herein are incorporated by reference in their entirety. [Example]

[0170] Example 1: Efficacy and safety of ravulizumab in patients with postpartum atypical hemolytic uremic syndrome A. Study Oversight and Study Design Clinical Trial 311 (NCT02949128) is a phase 3, single-arm, multicenter study designed to evaluate the efficacy and safety of ULTOMIRIS® (ravulizumab) administered by intravenous (IV) infusion to complement inhibitor-naive adults with aHUS. Patients included in this analysis were ≥18 years old, weighed ≥40 kg, and had evidence of active TMA (thrombocytopenia, hemolysis, and renal insufficiency) postpartum and TMA persisting for ≥3 days postpartum. Patients could meet platelet and lactate dehydrogenase (LDH) criteria (<150 × 109 and ≥1.5 × upper limit of normal, respectively) based on results from local laboratories; however, serum creatinine (≥ upper limit of normal) had to be confirmed by a central laboratory at baseline.

[0171] The study consisted of a 183-day initial evaluation period. As described in Table 1, ULTOMIRIS® (ravulizumab) was administered to postpartum aHUS patients at an initial loading dose, followed two weeks later by maintenance doses every eight weeks based on the patient's weight. Specifically, ULTOMIRIS® (ravulizumab) was administered via intravenous (IV) loading doses of 2400 mg, 2700 mg, and 3000 mg on Day 1 in patients weighing ≥40 to <60 kg, ≥60 to <100 kg, and ≥100 kg, respectively. Maintenance doses of 3000 mg, 3300 mg, and 3600 mg, respectively, were administered on Day 15, then every eight weeks thereafter. Baseline was defined as the period of screening prior to the time of the first study drug infusion and included Day 1.

[0172] [Table 1]

[0173] Patients had to have received meningococcal vaccination according to local and national guidelines at the start of treatment and were also required to receive antibiotic prophylaxis from the first dose of ULTOMIRIS® (ULTOMIRIS) until at least 2 weeks after vaccination.

[0174] Patients were excluded if they had ADAMTS13 deficiency (activity <5%), Shiga toxin-producing Escherichia coli-HUS, hematopoietic stem cell transplantation within 6 months prior to screening, or a history of malignancy within 5 years of screening. Patients receiving complement inhibitors, immunosuppressive therapy (excluding kidney transplant regimens), steroids, tranexamic acid within 7 days, or chronic dialysis were also excluded. Plasma exchange / infusion (PE / PI) was permitted until the first dose of ULTOMIRIS® (ravulizumab), but was not permitted thereafter. However, patients were excluded if treatment exceeded 28 days.

[0175] The protocol was approved by the institutional review board or independent ethics committee at each participating institution, and the study was conducted in accordance with the Declaration of Helsinki and the Council for International Organizations of Medical Sciences International Ethical Guidelines. B. Efficacy and Safety Endpoints The primary efficacy endpoint was complete TMA response throughout the 183-day initial evaluation period. Criteria for complete TMA response were platelet count normalization (≥ 150 × 109 / L), LDH normalization (≤ 246 U / L), and a ≥ 25% improvement in serum creatinine from baseline, simultaneously met on two separate assessments of any measurement, separated by ≥ 28 days. If patients were on dialysis at baseline, the first valid baseline value was the first assessment ≥ 6 days after dialysis. Patients were considered to be on dialysis at baseline if dialysis was performed within 5 days prior to starting ULTOMIRIS® (ravulizumab).

[0176] Secondary objectives of the included studies were: time to complete TMA response; changes in hematological variables (platelets, LDH, and hemoglobin); changes in estimated glomerular filtration rate (eGFR); and dialysis requirement status. Exploratory genetic analysis by whole exome sequencing was performed on patients in the original studies. Additional genetic analysis performed at the centers treating individual patients included in this analysis was also included. Safety and tolerability of ULTOMIRIS® (ravulizumab) were assessed by clinical and laboratory evaluations and the frequency of adverse events (AEs) and serious AEs (SAEs). C. Results i. Patient characteristics Eight postpartum patients were identified with a median age of 37.7 years (range, 22.1-45.2 years) and were diagnosed within 12 days of delivery. These patients met the inclusion criteria and were enrolled. They received at least one dose of ULTOMIRIS® (ULTOMIRIS). Seven patients were Caucasian (one was Asian). Six patients (75%) had undergone plasma exchange before ULTOMIRIS® (ULTOMIRIS) treatment. Five patients (63%) were on dialysis before ULTOMIRIS® (ULTOMIRIS) treatment. No patients were reported to be breastfeeding during the study. Baseline demographics and disease characteristics are shown in Table 2.

[0177] At baseline and before any ULTOMIRIS® (ravulizumab) administration, all patients experienced acute serious medical emergencies related to pregnancy or labor, such as intrauterine death, hemorrhage, and the need for blood transfusion. All patients had labor complications and presented postpartum. Five of the eight patients had emergency labors, four of which were cesarean sections and had serious postoperative complications. The fifth patient had a planned cesarean section and also had serious postpartum complications. Preeclampsia and hypertension were reported in two patients each, and renal failure and gastrointestinal diabetes were reported in one patient each. Two patients suffered placental abruption, resulting in prenatal fetal death in one of these cases. Five patients underwent emergency cesarean sections, with complications in four, hemorrhage in two, secondary hysterectomies in two (one hemorrhage), and fetal death in one. Additional data regarding pre-TMA events are detailed in Table 3.

[0178] All patients completed the 183-day initial evaluation period without study or drug discontinuation.

[0179] [Table 2-1]

[0180] [Table 2-2]

[0181] [Table 3-1]

[0182] [Table 3-2]

[0183] ii. Primary endpoint During the initial evaluation period, seven of eight patients (87.5%) met the primary endpoint of complete TMA response (Figure 1). The patient who did not achieve a complete TMA response had a rapid response to ULTOMIRIS® (ravulizumab) treatment, with normalization of both platelets and LDH by Day 8. The female patient had a dialysis session five days before the first dose, and her baseline creatinine was the value obtained on Day 8 (≥6 days after the last dialysis session as defined by the protocol). On Day 8, the patient's serum creatinine level had already improved to 51 μmol / L, and she did not achieve the additional 25% improvement in serum creatinine from this value required to meet the complete TMA response criterion. iii. Secondary endpoints The median time to complete TMA response (95% CI) was 31.5 (9.0, 46.0) days (Figure 1). Hematological normalization, platelet count, and LDH normalization were observed in all patients (100%). Both platelet count and LDH values ​​rapidly improved (Figures 2 and 3). Overall, eGFR showed rapid improvement within 8 days and continued to improve throughout the initial evaluation period (Figure 4). All patients on dialysis at baseline were able to discontinue dialysis within 21 days of initiating treatment with ULTOMIRIS® (ravulizumab). By Day 183, all five patients on dialysis at baseline had discontinued dialysis, and all eight patients had improved eGFR status from baseline to Day 183. iv. Safety Adverse events after the initiation of treatment were recorded in all eight patients included in the analysis (see Table 4). The most common adverse events reported in at least two patients were headache and fever (each occurring in three patients). Other adverse events reported in two patients each included constipation, urinary tract infection, nasopharyngitis, alopecia, hypertension, arthralgia, increased alanine aminotransferase, and increased aspartate aminotransferase. Three possible non-serious treatment-related adverse events (as determined by the investigator) were recorded in two patients (arthralgia and nasopharyngitis; urinary tract infection). Both patients recovered from these events. One serious adverse event was reported. This event was a routine kidney biopsy unrelated to treatment with ULTOMIRIS® (ravulizumab). No deaths or meningococcal infections occurred.

[0184] [Table 4]

[0185] D. Discussion This is the largest prospective interventional study to evaluate the efficacy and safety of a C5 inhibitor in patients with aHUS manifesting after delivery. All patients analyzed presented with serious medical emergencies and postpartum complications immediately after delivery. Patients responded rapidly to treatment with ULTOMIRIS® (ravulizumab), with 7 / 8 (84.5%) patients achieving the primary endpoint of complete TMA response by day 43 (median time 31.5 days). No safety concerns were identified.

[0186] Data from this study demonstrate that a higher proportion of patients presenting postpartum achieved TMA resolution with ULTOMIRIS® (ULTOMIRIS) treatment compared with the full cohort of patients with aHUS in Study 311. While patients in this analysis received treatment shortly after initial symptoms (range: 2-18 days), the time to treatment in Study 311 was more variable, with patients receiving their first dose of ULTOMIRIS® (ULTOMIRIS) as early as symptom onset or as late as 215 months after initial symptoms of aHUS, highlighting the importance of early treatment. Furthermore, the median time to complete TMA response in this subgroup of patients was rapid at 31.5 days (38.2 days for patients on dialysis) compared with 86 days for the full cohort in Study 311. Previous clinical trial data have demonstrated that renal outcomes are better in patients who initiate complement inhibitor treatment within 7 days of disease manifestation compared with patients who initiate treatment 7 days later. One patient did not achieve a complete TMA response by study criteria; however, this patient responded to treatment with ULTOMIRIS® (ravulizumab) with improvement in all clinical parameters, including serum creatinine levels, platelets, and LDH normalization by day 8, and complete recovery of renal function at last follow-up.

[0187] As previously described, patients presented with severe illness: 62.5% of patients required dialysis at baseline, and 87.5% required intensive care unit-level care, similar to other reports detailing patients with pregnancy-induced aHUS.

[0188] Regarding pathogenic variants, no association was found between the identification of complement abnormalities and response to ULTOMIRIS® (ravulizumab) (one patient had a complement factor B (CFB) variant and one patient had anti-complement factor H (CFH) antibodies). A subgroup of patients analyzed here had labor complications with significant bleeding, which, as suggested in other studies, could induce the syndrome. One patient with a severe predisposing factor (CFB pathogenic variant) had a normal labor, while some patients without identified pathogenic variants had severe bleeding complications, hypertension, and preeclampsia, resulting in more severe clinical findings. In this study, five patients underwent emergency labor, four of which were by cesarean section (the fifth patient also had a previously scheduled cesarean section with postoperative complications). Based on the observations in this subgroup, only two patients tested positive for pathogenic variants in our study, we hypothesize that patients with a severe genetic predisposition do not necessarily require a severe trigger to develop aHUS, while patients with more severe triggers may not require a known strong pathogenic variant to develop the disease.

[0189] The rate of treatment-related AEs in the full 311 cohort was similar to that in the subgroup of patients in this analysis (34.5% and 37.5%, respectively), and no additional safety concerns were identified here. In the full 311 cohort, the most common AEs were headache, diarrhea, and vomiting, while headache and fever were most common in this subgroup. No patients died or suffered from meningococcal infections. E. Conclusion In this first prospective interventional study evaluating the efficacy and safety of the long-acting C5 inhibitor ULTOMIRIS® (ravulizumab), aHUS-induced TMA rapidly resolved in postpartum patients, with continued improvement over time and an acceptable safety profile. Furthermore, treatment with ULTOMIRIS® (ravulizumab) at an 8-week dosing interval resulted in rapidly improved hematologic and renal endpoints in patients with postpartum aHUS. The results from this study support the use of ULTOMIRIS® (ravulizumab) in women with postpartum aHUS. Example 2: Global aHUS Registry Analysis: Characteristics and Outcomes of Pregnancy-Induced Atypical Hemolytic Uremic Syndrome (aHUS) Pregnancy-induced aHUS (p-aHUS) accounts for 10-20% of aHUS diagnoses. Complement-mediated thrombotic microangiopathy (CM-TMA) can be associated with high maternal and fetal morbidity and mortality, including end-stage renal disease (ESRD). We described the clinical features and survival probability of p-aHUS in patients treated with the complement C5 inhibitor eculizumab using the largest collection of p-aHUS data available in a single study. A. Method Patients with a clinical diagnosis of aHUS were included in the Global aHUS Registry (NCT01522183). Patients with p-aHUS were identified as those with a first TMA manifestation during pregnancy or within 60 days postpartum. Patients with other triggers of aHUS were excluded. Survival time based on time to ESRD was calculated using the Kaplan-Meier method. B. Results In the registry, 51 / 1029 female patients were diagnosed with p-aHUS, and 27 received eculizumab. The mean ± SD age at onset of pregnancy was 30.7 ± 5.9 years. p-aHUS occurred during pregnancy in 28 (54.9%) patients, and the remainder occurred postpartum. A diagnosis of preeclampsia or HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome was reported in 28 (54.9%) and 17 (33.3%) patients, respectively. Complement pathogenic variants were identified in 23 (45.1%) patients, of whom 3 (8.3%) also tested positive for anti-complement factor H antibodies. The mean ± SD duration of eculizumab treatment was 1.8 ± 1.8 years. Survival rates were higher in eculizumab-treated patients compared with those not receiving eculizumab (see Figure 5). C. Consideration Survival probability was lower in patients diagnosed when eculizumab was not available compared with patients who received eculizumab. Successful treatment with eculizumab, along with nearly half of patients with complement pathogenic variants, supports the appropriate classification of P-aHUS as CM-TMA.

[0190] [Table 5]

[0191] [Table 6]

[0192] [Table 7]

[0193] [Table 8]

[0194] [Table 9]

[0195]

Table 10

[0196]

Table 11

Claims

1. 1. A composition for use in a method of treating a human patient with pregnancy-associated atypical hemolytic uremic syndrome (p-aHUS), comprising an anti-C5 antibody, or an antigen-binding fragment thereof; The anti-C5 antibody, or antigen-binding fragment thereof, comprises the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, and the anti-C5 antibody, or antigen-binding fragment thereof, comprises the heavy chain set forth in SEQ ID NO: 14 and the light chain set forth in SEQ ID NO:

11.

2. The anti-C5 antibody, or antigen-binding fragment thereof, is administered to the patient. (a) once on day 1 at a dose of 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; (b) on day 15 and every 8 weeks thereafter, at a dose of 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg The composition of claim 1 , wherein the composition is administered intravenously.

3. The treatment comprises: (i) maintaining a serum trough concentration of the anti-C5 antibody of 100 μg / ml or greater; or maintain a serum trough concentration of the anti-C5 antibody of 200 μg / ml or greater; and / or (ii) reducing free C5 concentrations by more than 99%; The composition according to claim 1 or 2.

4. 3. The composition of claim 2, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is administered in (b) at a dose of 3000 mg, 3300 mg, or 3600 mg every 8 weeks for up to 2 years.

5. The treatment comprises: (i) results in terminal complement inhibition; (ii) results in a reduction in hemolysis compared to baseline as assessed by lactate dehydrogenase (LDH) levels; (iii) resulting in normalization of LDH levels; and / or (iv) producing a shift toward normal levels of hemolysis-related hematological biomarkers selected from the group consisting of free hemoglobin, haptoglobin, reticulocyte count, PNH red blood cell (RBC) clones, and D-dimers; The composition according to any one of claims 1 to 4.

6. The treatment comprises: (i) produces at least one therapeutic effect selected from the group consisting of a reduction or cessation of severe hypertension, proteinuria, uremia, lethargy, fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and renal dysfunction compared to baseline; (ii) causes a shift toward normal levels of factor Ba, soluble tumor necrosis factor receptor 1 [sTNFR1], soluble vascular adhesion molecule 1 [sVCAM1], thrombomodulin, D-dimer, and cystatin C; (iii) produces an increase in hemoglobin stabilization compared to baseline; (iv) resulting in a reduction in the need for blood transfusions compared to baseline; (v) producing a reduction in major adverse vascular events (MAVE); (vi) produce change in quality of life from baseline assessed via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, version 4 and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 scale; (vii) resulting in platelet normalization; (viii) results in a ≥ 25% improvement in serum creatinine from baseline; (ix) result in a complete TMA response; (x) results in a modified complete TMA response; and / or (xi) resulting in a shift in eGFR towards normal levels (e.g., ≧90); The composition according to any one of claims 1 to 5.

7. The treatment comprises: (i) resulting in a reduction or cessation of dialysis; (ii) preventing or prolonging the time to end-stage renal disease (ESRD); and / or (iii) prolonging the survival of said patient; The composition according to any one of claims 1 to 6.

8. (i) the anti-C5 antibody, or antigen-binding fragment thereof, binds to human C5 with an affinity dissociation constant (KD) within the range of 0.1 nM≦KD≦1 nM at pH 7.4 and 25°C; (ii) the anti-C5 antibody, or antigen-binding fragment thereof, binds to human C5 with a K≥10 nM at pH 6.0 and 25°C; or (iii) the antibody has a [(KD of the antibody or antigen-binding fragment thereof against human C5 at pH 6.0 and 25°C) / (KD of the antibody or antigen-binding fragment thereof against human C5 at pH 7.4 and 25°C)] ratio of greater than 25; The composition according to any one of claims 1 to 7.

9. The composition of any one of claims 1 to 8, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is formulated for intravenous administration.

10. The composition of any one of claims 1 to 9, wherein the p-aHUS is postpartum aHUS.

11. The method of claim 10, wherein treatment begins 1 to 20 days, optionally 5 to 15 days, after delivery.

12. A composition described in any one of claims 1 to 11, wherein the anti-C5 antibody is ravulizumab.

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