Supplemental dosing and administration of anti-C5 antibodies to treat hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA)

Abstract

Provided herein are methods for treating HSCT-TMA in specific patient subpopulations (e.g., HSCT-TMA patients weighing ≥ 30 kg who received a transfusion (e.g., a platelet or red blood cell (RBC) transfusion) within 4 weeks after a maintenance dose), comprising administering to the patient an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is administered (or is for administration) according to a specific clinical dosing regimen (e.g., at specific loading, maintenance, and supplemental doses, and according to a specific schedule).

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 404,061, filed September 6, 2022, and U.S. Provisional Application No. 63 / 440,984, filed January 25, 2023, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Thrombotic microangiopathy (TMA) is a post-transplant complication of hematopoietic stem cell transplantation (HSCT) that can affect 10%–35% of HSCT recipients (Dvorak et al., Front Pediatr. 2019;7:133; Jodele et al., Blood Rev. 2015;29(3):191–204; Seaby et al., Pediatr Nephrol. 2018;33(9):1489–1500). It manifests through endothelial injury and affects the kidneys and other organs. It is estimated that 30% of patients with HSCT TMA will develop severe disease (Rosenthal et al., J. Blood Med. 2016;7:181-186). In these cases, patients with HSCT-TMA develop kidney damage, serositis, pulmonary hypertension, and systemic vascular injury manifested in multiple organ failure. The 1-year survival rate for patients with HSCT-TMA has been reported to range from 18% to 40% (Wanchoo et al., Am. J. Kidney Dis. 2018;72(6):857-865). Severe HSCT-TMA is associated with long-term morbidity and mortality of approximately 80%. Studies have shown that the majority of patients die within six months (Cho et al., Bone Marrow Transplant. 2008;41(9):813-820; Cho et al., Transplantation. 2010;90(8):918-926; Oran, 2007). Another study showed a 9% overall survival rate for patients with severe HSCT-TMA who did not receive TMA-targeted therapy, with all deaths occurring within 10 months of TMA diagnosis (Jodele, et al., Blood. 2014b;124(4):645-653).

[0003] In pediatric patients, HSCT-TMA typically occurs early after allogeneic HSCT, with a median diagnosis of 35–47 days after HSCT, with 88%–92% occurring before day +100. However, cases have been reported up to 2 years after HSCT. Autologous recipients may develop HSCT TMA even earlier, at a median of 18 days after HSCT (Dvorak et al., Front Pediatr. 2019;7:133).

[0004] Endothelial injury is fundamental to the pathogenesis of HSCT-TMA, and dysregulated complement activation is likely a consequence of endothelial injury. Risk factors associated with the development of HSCT-TMA that also initiate endothelial injury include calcineurin inhibitors (CNIs), infections, and conditioning regimens (high-dose chemotherapy or total-body irradiation) (Khosla, et al., Bone Marrow Transplant. 2018;53(2):129-137; Masias, et al., Blood. 2017;129(21):2857-2863). Currently, there are no approved therapies for the treatment of HSCT-TMA. The primary intervention for HSCT-TMA is withdrawal of the causative agent (e.g., CNI) and / or treatment of any precipitating conditions (e.g., treatment of infection) (Dvorak, et al., Front Pediatr. 2019;7:133; Seaby et al., Pediatr. Nephrol. 2018;33(9):1489-1500). In some patients, withdrawal of the causative agent and / or treatment of any associated precipitating conditions does not reverse HSCT-TMA. Therefore, an object of the present disclosure is to provide improved methods for treating patients with HSCT-TMA. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Dvorak et al., Front Pediatr. 2019;7:133 [Non-Patent Document 2] Jodele et al., Blood Rev. 2015;29(3):191-204 [Non-Patent Document 3] Seaby et al., Pediatr Nephrol. 2018;33(9):1489-1500 [Non-Patent Document 4] Rosenthal et al., J. Blood Med. 2016;7:181-186 [Non-Patent Document 5] Wanchoo et al., Am. J. Kidney Dis. 2018;72(6):857-865 [Non-Patent Document 6] Cho et al., Bone Marrow Transplant. 2008;41(9):813-820 [Non-Patent Document 7] Cho et al., Transplantation. 2010;90(8):918-926 [Non-Patent Document 8] Jodele, et al., Blood. 2014b;124(4):645-653 [Non-Patent Document 9] Khosla, et al., Bone Marrow Transplant. 2018;53(2):129-137 [Non-Patent Document 10] Masias, et al., Blood. 2017;129(21):2857-2863 [Summary of the Invention]

[0006] In accordance with the present invention, it has been discovered that HSCT-TMA patients treated with ravulizumab according to a particular clinical dosing regimen (e.g., at particular loading and maintenance doses and according to a particular dosing schedule) and who received one or more transfusions, e.g., platelet transfusions or red blood cell (RBC) transfusions, experienced faster clearance (e.g., compared with non-transfused patients), thereby providing significant clinical benefit when treated with supplemental doses of ravulizumab in transfused cohorts of HSCT-TMA patients. Specifically, using a supplemental dosing simulation model, the inventors determined that delivery of supplemental doses of ravulizumab to achieve mean (standard deviation) minimum and maximum plasma concentrations of ravulizumab during the dosing interval of 474 (200) μg / mL to 1350 (430) μg / mL, respectively, provided more effective treatment for HSCT-TMA patients who received transfusions, e.g., RBC transfusions, during treatment. In particular, as illustrated in the non-limiting examples, HSCT patients weighing ≥ 30 kg who received any RBC transfusions (e.g., one, two, three, or more) within four weeks after the maintenance dose were administered a supplemental dose of ravulizumab four weeks after the maintenance dose. The supplemental ravulizumab administration regimen achieved immediate, complete, and sustained terminal complement inhibition. A supplemental dosing scheme was also applied to effectively treat HSCT-TMA patients in cohorts with lower body weights (e.g., < 30 kg), particularly very low body weights (e.g., < 20 kg, particularly < 10 kg).

[0007] In other embodiments, as illustrated in the non-limiting examples, HSCT patients weighing <30 kg who received any (e.g., one, two, three, or more) RBC transfusions within a specified time frame after the maintenance dose (e.g., two weeks for patients weighing <20 kg and four weeks for patients weighing ≥20 kg (e.g., 20 kg < 30 kg, 30 kg < 40 kg, 40 kg < 60 kg, 60 kg < 100 kg, or ≥ 100 kg)) received a supplemental dose of ravulizumab within a specified time frame after the maintenance dose. The supplemental ravulizumab administration regimen achieved immediate, complete, and sustained terminal complement inhibition.

[0008] Thus, provided herein are methods for treating HSCT-TMA in specific patient subpopulations (e.g., HSCT-TMA patients weighing ≥ 30 kg who received a transfusion (e.g., a platelet or RBC transfusion) within 4 weeks after a maintenance dose), comprising administering to the patient an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is administered (or is for administration) according to a specific clinical dosing regimen (e.g., at specific loading, maintenance, and one or more supplemental doses, and according to a specific schedule). Also provided herein is a method for treating HSCT-TMA in specific patient subpopulations, e.g., HSCT-TMA patients weighing <30 kg who received a transfusion (e.g., a platelet or RBC transfusion) within 2 weeks (<20 kg) or 4 weeks (≥20 kg-30 kg) after a maintenance dose, comprising administering to the patient an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is administered (or is for administration) according to a specific clinical dosing regimen (e.g., at specific loading, maintenance, and one or more supplemental doses, and according to a specific schedule).

[0009] An exemplary anti-C5 antibody is ravulizumab (ULTOMIRIS®), 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 neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of native human IgG Fc constant region, respectively, according to EU numbering rules.

[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, and 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 neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, of native human IgG Fc constant region, according to EU numbering rules.

[0012] In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the BNJ421 antibody (described in WO2015134894 and U.S. Patent No. 9,079,949). In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the 7086 antibody (see U.S. Patent Nos. 8,241,628 and 8,883,158). In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the 8110 antibody (see U.S. Patent Nos. 8,241,628 and 8,883,158). In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the 305LO5 antibody (see U.S. Patent No. 9,765,135). In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the SKY59 antibody. In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the REGN3918 antibody.

[0013] In another embodiment, the anti-C5 antibody is a biosimilar of eculizumab (SOLIRIS®). For example, in one embodiment, the anti-C5 antibody is, for example, ABP 959 antibody (manufactured by Amgen Inc., USA), ELIZARIA® (manufactured by Generium JNC, Russia), SB12 (manufactured by Samsung Bioepis, Incheon, South Korea), ISU305 (eculizumab biosimilar from ISU Abxis, South Korea), ABLYZE® (eculizumab biosimilar from CinnaGen, Iran), BCD 148 (eculizumab biosimilar from Biocad Medical, Quebec, Canada), tesidolumab (manufactured by Novartis), crovalimab (manufactured by Roche), CAN106 (manufactured by CanBridge Pharmaceuticals, China), or pozelimab (manufactured by Regeneron).

[0014] In another embodiment, the antibody competes for binding to and / or binds to the same epitope on C5 as any of the above-mentioned antibodies, hi another embodiment, the antibody has at least about 90% variable region amino acid sequence identity with any of the above-mentioned antibodies (e.g., at least about 90%, 95%, or 99% variable region identity with SEQ ID NO: 12 or SEQ ID NO: 8).

[0015] In another embodiment, the antibody has a K D Affinity dissociation constants (K) in the range of ≦1 nM D In another embodiment, the antibody binds to human C5 with an affinity dissociation constant (K) of about 0.5 nM at pH 7.4 and 25°C. D In another embodiment, the antibody binds to human C5 at a K D In another embodiment, the antibody binds to human C5 with a K of about 22 nM at pH 6.0 and 25° C. D In yet another embodiment, the K of the antibody or antigen-binding fragment thereof against human C5 at pH 6.0 and 25°C is D ) / (K of an antibody or antigen-binding fragment thereof against human C5 at pH 7.4 and 25°C D )] is over 25.

[0016] In certain embodiments, the dosing regimens described herein provide an optimal desired response (e.g., effective treatment). In some embodiments, effective treatment includes achieving immediate, complete, and sustained terminal complement inhibition in patients with HSCT-TMA.

[0017] According to the present disclosure, there is provided a method for treating HSCT-TMA in a patient who has received a blood transfusion (e.g., a platelet or RBC transfusion), in which an anti-C5 antibody (or antigen-binding fragment) of the present disclosure is administered in a dosing cycle including stepwise dosing, followed by maintenance dosing, and supplemental dosing. In embodiments, the anti-C5 antibody, or antigen-binding fragment thereof, is administered as follows: a loading dose on day 1 (e.g., of the dosing cycle), a loading dose on day 5 (e.g., of the dosing cycle), a loading dose on day 10 (e.g., of the dosing cycle), and maintenance doses every 8 weeks thereafter starting on day 15. In another embodiment, a maintenance dose of the anti-C5 antibody or antigen-binding fragment thereof is administered every 8 weeks after treatment (e.g., the dosing cycle) for an extended period of up to 2 years.

[0018] In embodiments, the anti-C5 antibody, or antigen-binding fragment thereof, is administered once on day 1 (e.g., of a dosing cycle) as a loading dose, once on day 5 (e.g., of a dosing cycle) as a loading dose, once on day 10 (e.g., of a dosing cycle) as a loading dose, and once every 8 weeks thereafter as a maintenance dose starting on day 15, along with supplemental doses. In embodiments, the supplemental dose is administered to a patient who receives a red blood cell (RBC) transfusion within 4 weeks of the maintenance dose, and the supplemental dose is administered 4 weeks after the maintenance dose. In another embodiment, a supplemental dose is administered to patients weighing ≧30 kg who receive an RBC transfusion within 4 weeks of the maintenance dose, and a supplemental dose is administered 4 weeks after the maintenance dose at a dose of 2700 mg for patients weighing ≧30 kg to <40 kg, 3000 mg for patients weighing ≧40 kg to <60 kg, 3300 mg for patients weighing ≧60 kg to <100 kg, or 3600 mg for patients weighing ≧100 kg.

[0019] In another embodiment, a method of treating a human patient having HSCT-TMA, preferably an RBC-transfused HSCT-TMA patient, is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody or antigen-binding fragment thereof is (a) A loading dose of 600 mg for patients weighing 5 kg to <10 kg, 600 mg for patients weighing 10 kg to <20 kg, 900 mg for patients weighing 20 kg to <30 kg, 1200 mg for patients weighing ≥30 kg to <40 kg, 2400 mg for patients weighing ≥40 kg to <60 kg, 2700 mg for patients weighing ≥60 kg to <100 kg, or 3000 mg for patients weighing ≥100 kg, once on day 1; (b) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg once on day 5; (c) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg, once on day 10; and (d) 15th day and (i) every 4 weeks thereafter at a maintenance dose of 300 mg or 400 mg for patients weighing 5 kg to <10 kg or 600 mg or 800 mg for patients weighing 10 kg to <20 kg; or (ii) every 8 weeks thereafter at a maintenance dose of 2100 mg for patients weighing 20 kg to <30 kg, 2700 mg for patients weighing ≥30 kg to <40 kg, 3000 mg for patients weighing ≥40 kg to <60 kg, 3300 mg for patients weighing ≥60 kg to <100 kg, or 3600 mg for patients weighing ≥100 kg; The supplemental dose is (i) administered to patients weighing <30 kg who receive a red blood cell (RBC) transfusion within the specified time frame of the maintenance dose, and the supplemental dose is administered within the specified time frame after the maintenance dose; a. Administered at a dose of 300 mg or 400 mg to patients weighing 5 kg to < 10 kg, and the time frame specified above is 2 weeks, or b. Administered at a dose of 600 mg or 800 mg to patients weighing 10 kg to <20 kg, and the time frame specified above is 2 weeks; or c. Administered at a dose of 2100 mg to patients weighing 20 kg to <30 kg and the time frame specified above is 4 weeks, or (ii) administered to patients weighing ≥ 30 kg who receive a red blood cell (RBC) transfusion within 4 weeks of a maintenance dose, and the supplemental dose is administered 4 weeks after the maintenance dose; a. 2700 mg dose for patients weighing ≥ 30 kg to < 40 kg b. 3000 mg dose for patients weighing ≥ 40 kg to < 60 kg c. A dose of 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d. Administered at a dose of 3600 mg to patients weighing ≥ 100 kg.

[0020] In another embodiment, there is provided a method of treating a human patient having HSCT-TMA, preferably an RBC-transfused HSCT-TMA patient, the method comprising administering to the patient an effective amount of an anti-C5 antibody 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 a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, according to EU numbering rules, and wherein the anti-C5 antibody (a) A loading dose of 600 mg for patients weighing 5 kg to <10 kg, 600 mg for patients weighing 10 kg to <20 kg, 900 mg for patients weighing 20 kg to <30 kg, 1200 mg for patients weighing ≥30 kg to <40 kg, 2400 mg for patients weighing ≥40 kg to <60 kg, 2700 mg for patients weighing ≥60 kg to <100 kg, or 3000 mg for patients weighing ≥100 kg, once on day 1; (b) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg once on day 5; (c) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg, once on day 10; and (d) 15th day and (i) every 4 weeks thereafter at a maintenance dose of 300 mg or 400 mg for patients weighing 5 kg to <10 kg or 600 mg or 800 mg for patients weighing 10 kg to <20 kg; or (ii) every 8 weeks thereafter at a maintenance dose of 2100 mg for patients weighing 20 kg to <30 kg, 2700 mg for patients weighing ≥30 kg to <40 kg, 3000 mg for patients weighing ≥40 kg to <60 kg, 3300 mg for patients weighing ≥60 kg to <100 kg, or 3600 mg for patients weighing ≥100 kg; The supplemental dose is (i) administered to patients weighing <30 kg who receive a red blood cell (RBC) transfusion within the specified time frame of the maintenance dose, and the supplemental dose is administered within the specified time frame after the maintenance dose; a. Administered at a dose of 300 mg or 400 mg to patients weighing 5 kg to < 10 kg, and the time frame specified above is 2 weeks, or b. Administered at a dose of 600 mg or 800 mg to patients weighing 10 kg to <20 kg, and the time frame specified above is 2 weeks; or c. Administered at a dose of 2100 mg to patients weighing 20 kg to <30 kg and the time frame specified above is 4 weeks, or (ii) administered to patients weighing ≥ 30 kg who receive a red blood cell (RBC) transfusion within 4 weeks of a maintenance dose, and the supplemental dose is administered 4 weeks after the maintenance dose; a. 2700 mg dose for patients weighing ≥ 30 kg to < 40 kg b. 3000 mg dose for patients weighing ≥ 40 kg to < 60 kg c. A dose of 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d. Administered at a dose of 3600 mg to patients weighing ≥ 100 kg.

[0021] In another embodiment, a method of treating a human patient with HSCT-TMA, preferably an RBC-transfused HSCT-TMA patient, is provided, the method comprising administering to the patient an effective amount of ravulizumab, wherein the ravulizumab: (a) A loading dose of 600 mg for patients weighing 5 kg to <10 kg, 600 mg for patients weighing 10 kg to <20 kg, 900 mg for patients weighing 20 kg to <30 kg, 1200 mg for patients weighing ≥30 kg to <40 kg, 2400 mg for patients weighing ≥40 kg to <60 kg, 2700 mg for patients weighing ≥60 kg to <100 kg, or 3000 mg for patients weighing ≥100 kg, once on day 1; (b) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg once on day 5; (c) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg, once on day 10; and (d) 15th day and (i) every 4 weeks thereafter at a maintenance dose of 300 mg or 400 mg for patients weighing 5 kg to <10 kg or 600 mg or 800 mg for patients weighing 10 kg to <20 kg; or (ii) every 8 weeks thereafter at a maintenance dose of 2100 mg for patients weighing 20 kg to <30 kg, 2700 mg for patients weighing ≥30 kg to <40 kg, 3000 mg for patients weighing ≥40 kg to <60 kg, 3300 mg for patients weighing ≥60 kg to <100 kg, or 3600 mg for patients weighing ≥100 kg; The supplemental dose is (i) administered to patients weighing <30 kg who receive a red blood cell (RBC) transfusion within the specified time frame of the maintenance dose, and the supplemental dose is administered within the specified time frame after the maintenance dose; a. Administered at a dose of 300 mg or 400 mg to patients weighing 5 kg to < 10 kg, and the time frame specified above is 2 weeks, or b. Administered at a dose of 600 mg or 800 mg to patients weighing 10 kg to <20 kg, and the time frame specified above is 2 weeks; or c. Administered at a dose of 2100 mg to patients weighing 20 kg to <30 kg with a specified time frame of 4 weeks, or (ii) administered to patients weighing ≥ 30 kg who receive a red blood cell (RBC) transfusion within 4 weeks of a maintenance dose, and the supplemental dose is administered 4 weeks after the maintenance dose; a. 2700 mg dose for patients weighing ≥ 30 kg to < 40 kg b. 3000 mg dose for patients weighing ≥ 40 kg to < 60 kg c. A dose of 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d. Administered at a dose of 3600 mg to patients weighing ≥ 100 kg. and the treatment results in a reduction of LDH levels to within normal levels or within 50% of what is considered the ULN level (e.g., within 105 to 333 IU / L (international units per liter)), a serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof of at least 175 μg / mL, and / or a free C5 concentration of 0.5 μg / mL or less (e.g., 0.4 μg / mL, 0.3 μg / mL, 0.2 μg / mL, or 0.1 μg / mL or less).

[0022] In another embodiment, a method of treating a human patient with HSCT-TMA, preferably an RBC-transfused HSCT-TMA patient, is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing 5 kg to <10 kg. (a) 600 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 300 mg on day 15 and every 4 weeks thereafter; and (e) A supplemental dose of 300 mg is administered to patients who receive an RBC transfusion within the specified time frame of the maintenance dose, and this supplemental dose is administered within a specified time frame after the maintenance dose, the specified time frame being 2 weeks.

[0023] In another embodiment, a method of treating a human patient with HSCT-TMA, preferably an RBC-transfused HSCT-TMA patient, is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing 5 kg to <10 kg. (a) 600 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 400 mg on day 15 and every 4 weeks thereafter; and (e) A supplemental dose of 400 mg is administered to patients who receive an RBC transfusion within the specified time frame of the maintenance dose, and this supplemental dose is administered within a specified time frame after the maintenance dose, the specified time frame being 2 weeks.

[0024] In another embodiment, a method of treating a human patient with HSCT-TMA, preferably an RBC-transfused HSCT-TMA patient, is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing 10 kg to <20 kg. (a) 600 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 600 mg on day 15 and every 4 weeks thereafter; and (e) A supplemental dose of 600 mg is administered to patients who receive an RBC transfusion within the specified time frame of the maintenance dose, and this supplemental dose is administered within a specified time frame after the maintenance dose, the specified time frame being 2 weeks.

[0025] In another embodiment, a method of treating a human patient with HSCT-TMA, preferably an RBC-transfused HSCT-TMA patient, is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing 10 kg to <20 kg. (a) 600 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 800 mg on day 15 and every 4 weeks thereafter; and (e) A supplemental dose of 800 mg is administered to patients who receive an RBC transfusion within the specified time frame of the maintenance dose, and this supplemental dose is administered within a specified time frame after the maintenance dose, the specified time frame being 2 weeks.

[0026] In another embodiment, a method of treating a human patient with HSCT-TMA, preferably an RBC-transfused HSCT-TMA patient, is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing 20 kg to <30 kg. (a) 900 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 2100 mg on day 15 and every 8 weeks thereafter; and (e) A supplemental dose of 2100 mg is administered to patients who receive an RBC transfusion within the specified time frame of the maintenance dose, and this supplemental dose is administered within a specified time frame after the maintenance dose, the specified time frame being 4 weeks.

[0027] In some embodiments, the supplemental doses are administered when warranted by the clinical algorithm set forth in Figure 3. In some embodiments, the supplemental doses are administered when warranted by the clinical algorithm set forth in Table 7.

[0028] In another embodiment, a method of treating a human patient with HSCT-TMA, preferably an RBC-transfused HSCT-TMA patient, is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing ≥ 30 kg to < 40 kg. (a) 1200 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; and (d) a maintenance dose of 2700 mg on day 15 and every 8 weeks thereafter; The patient receives an RBC transfusion within 4 weeks of the maintenance dose, then receives a supplemental dose of 2700 mg 4 weeks after the maintenance dose.

[0029] In another embodiment, a method of treating a human patient with HSCT-TMA, preferably an RBC-transfused HSCT-TMA patient, is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing ≥ 30 kg to < 40 kg. (a) 1200 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; and (d) a maintenance dose of 2700 mg on day 15 and every 8 weeks thereafter; If the patient receives an RBC transfusion within 4 weeks of the maintenance dose and then receives a supplemental dose of 2700 mg 4 weeks after the maintenance dose, the treatment results in immediate, complete, and sustained terminal complement inhibition.

[0030] In another embodiment, a method of treating a human patient with HSCT-TMA, preferably an RBC-transfused HSCT-TMA patient, is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing ≥ 40 kg to < 60 kg. (a) 2400 mg loading dose once on day 1; (b) a loading dose of 600 mg once on day 5; (c) a loading dose of 600 mg once on day 10; and (d) a maintenance dose of 3000 mg on day 15 and every 8 weeks thereafter; The patient receives an RBC transfusion within 4 weeks of the maintenance dose, then receives a supplemental dose of 3000 mg 4 weeks after the maintenance dose.

[0031] In another embodiment, a method of treating a human patient with HSCT-TMA, preferably an RBC-transfused HSCT-TMA patient, is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing ≥ 40 kg to < 60 kg. (a) 2400 mg loading dose once on day 1; (b) a loading dose of 600 mg once on day 5; (c) a loading dose of 600 mg once on day 10; and (d) a maintenance dose of 3000 mg on day 15 and every 8 weeks thereafter; If the patient receives an RBC transfusion within 4 weeks of the maintenance dose and then receives a supplemental dose of 3000 mg 4 weeks after the maintenance dose, the treatment results in immediate, complete, and sustained terminal complement inhibition.

[0032] In another embodiment, a method of treating a human patient with HSCT-TMA, preferably an RBC-transfused HSCT-TMA patient, is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing ≥ 60 kg to < 100 kg. (a) 2700 mg loading dose once on day 1; (b) a loading dose of 900 mg once on day 5; (c) a loading dose of 900 mg once on day 10; and (d) a maintenance dose of 3300 mg on day 15 and every 8 weeks thereafter; The patient receives an RBC transfusion within 4 weeks of the maintenance dose, then receives a supplemental dose of 3300 mg 4 weeks after the maintenance dose.

[0033] In another embodiment, a method of treating a human patient with HSCT-TMA, preferably an RBC-transfused HSCT-TMA patient, is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing ≥ 60 kg to < 100 kg. (a) 2700 mg loading dose once on day 1; (b) a loading dose of 900 mg once on day 5; (c) a loading dose of 900 mg once on day 10; and (d) a maintenance dose of 3300 mg on day 15 and every 8 weeks thereafter; If the patient receives an RBC transfusion within 4 weeks of the maintenance dose and then receives a supplemental dose of 3300 mg 4 weeks after the maintenance dose, the treatment results in immediate, complete, and sustained terminal complement inhibition.

[0034] In another embodiment, a method of treating a human patient with HSCT-TMA, preferably an RBC-transfused HSCT-TMA patient, is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing ≧100 kg. (a) 3000 mg loading dose once on day 1; (b) a loading dose of 900 mg once on day 5; (c) a loading dose of 900 mg once on day 10; and (d) a maintenance dose of 3600 mg on day 15 and every 8 weeks thereafter; The patient receives an RBC transfusion within 4 weeks of the maintenance dose, then receives a supplemental dose of 3600 mg 4 weeks after the maintenance dose.

[0035] In another embodiment, a method of treating a human patient with HSCT-TMA, preferably an RBC-transfused HSCT-TMA patient, is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing ≧100 kg. (a) 3000 mg loading dose once on day 1; (b) a loading dose of 900 mg once on day 5; (c) a loading dose of 900 mg once on day 10; and (d) a maintenance dose of 3600 mg on day 15 and every 8 weeks thereafter; If the patient receives an RBC transfusion within 4 weeks of the maintenance dose and then receives a supplemental dose of 3600 mg 4 weeks after the maintenance dose, the treatment results in immediate, complete, and sustained terminal complement inhibition.

[0036] In some embodiments in which the patient receives an RBC transfusion within two weeks after the first maintenance dose, the patient receives a single post-transfusion supplemental dose of an anti-C5 antibody (e.g., ravulizumab) only midway between the two maintenance doses. Because the maintenance dose is administered every four weeks (Q4W) for certain lower weight cohorts (e.g., <20 kg; see Table 8), the anti-C5 antibody (e.g., ravulizumab) is administered after the second week, e.g., 14 days after the maintenance dose.

[0037] In some embodiments, in which a patient receives an RBC transfusion within four weeks after the first maintenance dose, the patient receives a single post-transfusion supplemental dose of an anti-C5 antibody (e.g., ravulizumab) only at the midpoint between the two maintenance doses. Because the maintenance doses are administered every eight weeks (Q8W), the anti-C5 antibody (e.g., ravulizumab) is administered four weeks later, for example, 28 days after the maintenance dose. In such embodiments, if the patient does not receive any transfusions during the second maintenance dosing period, no supplemental dose is required during this maintenance dosing cycle. Similarly, if the patient receives an RBC transfusion during the second half of the second maintenance dosing period, no supplemental dose is required during this maintenance dosing cycle. In other words, if the first RBC transfusion occurs more than four weeks after the preceding maintenance dose, no post-transfusion supplemental dose is required. In addition, if the patient receives a transfusion during the loading dose period, no supplemental dose is administered.

[0038] In some embodiments of the treatment methods of the present disclosure, the supplemental dosing regimen is continued following a given maintenance dose for a period of two weeks for participants weighing <20 kg or for a period of four weeks for participants weighing ≥20 kg until transfusion-free.

[0039] According to the treatment methods described herein, if any amount of RBC transfusion is provided to an HSCT-TMA patient within two weeks or four weeks after the last maintenance dose, a single post-transfusion supplemental dose of an anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab) is administered to the HSCT-TMA patient, for example, only two weeks (for patients <20 kg) or only four weeks (for patients ≥20 kg) after the last maintenance dose.

[0040] In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered over one or more administration cycles, hi one embodiment, the treatment (e.g., administration cycle) is for at least 26 weeks, at least 52 weeks, at least 1.5 years, or at least 2 years.

[0041] In another embodiment, immediate, complete, and sustained terminal complement inhibition is achieved after administration of a supplemental dose of an anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab).

[0042] In one embodiment, the methods of treatment disclosed herein further comprise administering best supportive care (BSC) measures, including but not limited to transfusion support, corticosteroids, dialysis, and antihypertensive drugs.

[0043] In one embodiment, the patient has not been previously treated with eculizumab. In another embodiment, the patient has been previously treated with eculizumab. In another embodiment, the patient has been previously treated with eculizumab and day 1 (e.g., of a dosing cycle) is 2 weeks or more after the patient's last dose of eculizumab.

[0044] 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. In one embodiment, for example, the treatment regimen is sufficient to maintain a particular serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof. 15, 220, 225, 230, 240, 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, 400, 405 , 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 5 maintains serum trough concentrations of the anti-C5 antibody or antigen-binding fragment thereof of 80, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700 μg / mL or greater. In one embodiment, the treatment regimen maintains serum trough concentrations of the anti-C5 antibody or antigen-binding fragment thereof of ≥100 μg / mL, ≥150 μg / mL, ≥200 μg / mL, ≥250 μg / mL, ≥300 μg / mL, ≥350 μg / mL, ≥400 μg / mL, or ≥450 μg / mL. In another embodiment, treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof between 100 μg / mL and 700 μg / mL; preferably between 300 μg / mL and 600 μg / mL. In another embodiment, treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof between about 475 μg / mL.In one embodiment, the treatment regimen comprises about 1800, 1780, 1760, 1740, 1720, 1700, 1680, 1660, 1640, 1620, 1600, 1580, 1560, 1540, 1520, 1500, 1480, 1460, 1440, 1420, 1400, 1380, 1360, 1340, 1320, 1 The peak serum concentration of the anti-C5 antibody or antigen-binding fragment thereof is maintained at or below 300, 1280, 1260, 1240, 1220, 1200, 1180, 1160, 1140, 1120, 1100, 1080, 1060, 1040, 1020, 1000, 980, 960, 940, 920, or 900 μg / mL. In embodiments, treatment maintains a peak serum concentration of the anti-C5 antibody or antigen-binding fragment thereof between 900 μg / mL and 1800 μg / mL; preferably between 1050 μg / mL and 1550 μg / mL. In another embodiment, treatment maintains a peak serum concentration of the anti-C5 antibody or antigen-binding fragment thereof at about 1350 μg / mL.

[0045] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the patient 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, 155 μg, 160 μg, 165 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg, 200 μg, 210 μg, 220 μg, 230 μg, 240 μg, 250 μg, 260 μg, 270 μg, 280 μg, 290 μg, 300 μg, 310 μg, 320 μg, 330 μg, 340 μg, 350 μg, 360 μg, 370 μg, 380 μg, 390 μg, 400 μg, 410 μg, 420 μg, 430 μg, 440 μg, 450 μg, 460 μg, 470 μg, 480 μg, 490 μg, 500 μg, 510 μg, 520 μg, 530 μg, 540 μg, 550 μg, 560 μg, 570 μg, 580 μg, 590 μg, 600 μg, 610 μg, μg, 140μg, 145μg, 150μg, 155μg, 160μg, 165μg, 170μg, 175μg, 180μg, 185μg, 190μg, 195μg g, 200μg, 205μg, 210μg, 215μg, 220μg, 225μg, 230μg, 235μg, 240μg, 245μg, 250μg, 255μg , 260μg, 270μg, 280μg, 290μg, 300μg, 320μg, 340μg, 360μg, 380μg, 400μg, 420μg, 440μg , 460μg, 480μg, 500μg, 550μg, 600μg, 650μg, 700μg, 750μg, 800μg, 850μg, 900μg, 950μg, It is administered in an amount and frequency to maintain 1000 μg, 1050 μg, 1100 μg, 1150 μg, 1200 μg, 1250 μg, 1300 μg, 1350 μg, 1400 μg, 1450 μg, 1500 μg, 1550 μg, 1600 μg, 1650 μg, 1700 μg, 1750 μg or more, for example, 1800 μg of antibody.

[0046] In embodiments, to obtain an effective response, the anti-C5 antibody (e.g., ravulizumab) is administered to the patient in an amount and frequency to maintain minimum and maximum plasma concentrations (±standard deviation) of the anti-C5 antibody (e.g., ravulizumab) during the dosing interval, which are preferably between 474 (±200) μg / mL and 1350 (±430) μg / mL, respectively.

[0047] In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency sufficient to maintain a minimum free C5 concentration to obtain an effective response. For example, in one embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency sufficient to maintain a free C5 concentration of 0.5 μg / mL or less (e.g., 0.4 μg / mL, 0.3 μg / mL, 0.2 μg / mL, or 0.1 μg / mL or less).

[0048] The anti-C5 antibody or antigen-binding fragment thereof can be administered to the patient by any suitable means. In one embodiment, the antibody is formulated for intravenous administration.

[0049] The efficacy of the therapeutic methods provided herein can be assessed using any suitable means. In one embodiment, for HSCT-TMA patients, the treatment results in at least one therapeutic effect selected from the group consisting of a reduction or cessation of microangiopathic hemolytic anemia, thrombocytopenia, endothelial damage, renal damage, renal failure, serositis, pulmonary hypertension, and multiple organ failure compared to baseline.

[0050] In another embodiment, treatment comprises (a) a platelet count of ≥ 50,000 / mm without transfusion support in the past 7 days. 3 , (b) LDH < 1.5 x ULN, and (c) absence of schistocytes (if schistocytes were present at baseline).

[0051] In another embodiment, treatment comprises (a) a platelet count of ≥ 50,000 / mm without transfusion support in the past 7 days. 3 (b) LDH<1.5×ULN, (c) absence of schistocytes (if schistocytes were present at baseline), and (d) at least a 50% reduction in proteinuria from baseline. In one embodiment, proteinuria is a protein / creatinine ratio of ≧0.5 mg / mg.

[0052] In another embodiment, the treatment results in a favorable hematological response.

[0053] In another embodiment, treatment results in normalization of LDH, elimination of the need for red blood cell and platelet transfusions, and elimination of schistocytes.

[0054] In another embodiment, the treatment results in the patient's ability to maintain hemoglobin > 8 g / dL without transfusion support. In another embodiment, the treatment results in hemoglobin > 8 g / dL without transfusion support.

[0055] In another embodiment, treatment results in a decrease in LDH, an increase in platelets, and / or an increase in hemoglobin compared to baseline.

[0056] In another embodiment, treatment results in normal levels of serum creatinine compared to baseline.

[0057] In another embodiment, treatment results in an improvement in TMA-associated organ dysfunction in the renal, cardiovascular, pulmonary, CNS, and / or GI systems compared to baseline.

[0058] In another embodiment, the treatment results in terminal complement inhibition.

[0059] In another embodiment, treatment results in a reduction in adverse events.

[0060] In another embodiment, treatment results in a shift to normal levels of biomarkers associated with vascular inflammation (e.g., shed tumor necrosis factor receptor 1 (TNF-R1)), endothelial injury and / or activation (e.g., thrombomodulin and shed vascular cell adhesion molecule 1 (VCAM-1)), renal injury (e.g., cystatin C), and / or complement proteins and complement activation pathway products. In another embodiment, treatment results in a shift to normal levels of thrombomodulin (TM) and / or syndecan-1 (SYND1). In another embodiment, treatment results in a shift to normal levels of complement factor Ba.

[0061] In another embodiment, treatment results in a change from baseline in quality of life as assessed via a quality of life assessment (e.g., the Quality of Life Inventory (PedsQL) scale or the EQ-5D-5L questionnaire).

[0062] In another embodiment, treatment results in a reduction in hemolysis as assessed by lactate dehydrogenase (LDH) levels compared to baseline. In one embodiment, a patient treated according to the disclosed methods experiences a decrease in LDH levels to near normal levels or within 10% or 20% of what is considered normal (e.g., within 10-333 IU / L (International Units per Liter)). In another embodiment, the patient's LDH levels normalize throughout the maintenance period of treatment. In another embodiment, the treated patient's LDH levels normalize at least at least 95% of the time during the maintenance period of treatment. In another embodiment, the treated patient's LDH levels normalize at least at least 90%, 85%, or 80% of the time during the maintenance period of treatment. In one embodiment, the patient's LDH levels are ≥ 1.5 times the upper limit of normal (LDH ≥ 1.5 x ULN) before initiating treatment.

[0063] In one embodiment, a patient treated according to the disclosed methods experiences a decrease in LDH levels to within 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%, or within 50% (e.g., within 105-333 IU / L (International Units per Liter)) of the normal level range, or within what is considered the ULN level. In one embodiment, the patient's LDH level is ≧1.5 times the ULN (LDH≧1.5×ULN) before initiating treatment.

[0064] In one embodiment, a patient treated according to the disclosed methods experiences a 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% LDH percent change compared to baseline.

[0065] Also provided are kits comprising a pharmaceutical composition containing a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment thereof, e.g., ravulizumab, suitable for use in the methods described herein, e.g., for the effective treatment of an HSCT-TMA patient who has received at least one transfusion, e.g., a platelet or RBC transfusion, and a pharmaceutically acceptable carrier. In one embodiment, the kit comprises (a) a dose of an anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 12 and CDR1, CDR2, and CDR3 domains of a light chain variable region having the 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, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 5 kg to <10 kg, (a) 600 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 300 mg on day 15 and every 4 weeks thereafter; and (e) Administered in a supplemental dose of 300 mg with the indication that the supplemental dose is administered to patients receiving a red blood cell (RBC) transfusion within 2 weeks of the maintenance dose, with this supplemental dose being administered 2 weeks after the maintenance dose.

[0067] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 5 kg to <10 kg, (a) 600 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 400 mg on day 15 and every 4 weeks thereafter; and (e) Administered in a supplemental dose of 400 mg with instructions that the supplemental dose be administered to patients receiving an RBC transfusion within 2 weeks of the maintenance dose, with this supplemental dose being administered 2 weeks after the maintenance dose.

[0068] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 10 kg to <20 kg. (a) 600 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 600 mg on day 15 and every 4 weeks thereafter; and (e) Administered in a supplemental dose of 600 mg with instructions that the supplemental dose be administered to patients receiving an RBC transfusion within 2 weeks of the maintenance dose, with this supplemental dose being administered 2 weeks after the maintenance dose.

[0069] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 10 kg to <20 kg. (a) 600 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 800 mg on day 15 and every 4 weeks thereafter; and (e) Administered in a supplemental dose of 800 mg with instructions that the supplemental dose be administered to patients receiving an RBC transfusion within 2 weeks of the maintenance dose, with this supplemental dose being administered 2 weeks after the maintenance dose.

[0070] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 20 kg to <30 kg. (a) 900 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 2100 mg on day 15 and every 8 weeks thereafter; and (e) Administered at a supplemental dose of 2100 mg with instructions that the supplemental dose be administered to patients receiving an RBC transfusion within 4 weeks of the maintenance dose, with this supplemental dose being administered 4 weeks after the maintenance dose.

[0071] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 30 kg to < 40 kg. (a) 1200 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 2700 mg on day 15 and every 8 weeks thereafter; and (e) administered at a supplemental dose of 2700 mg according to instructions that the supplemental dose be administered to a patient receiving an RBC transfusion within 4 weeks of the maintenance dose, with the supplemental dose being administered 4 weeks after the maintenance dose.

[0072] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 40 kg to < 60 kg. (a) 2400 mg loading dose once on day 1; (b) a loading dose of 600 mg once on day 5; (c) a loading dose of 600 mg once on day 10; (d) a maintenance dose of 3000 mg on day 15 and every 8 weeks thereafter; and (e) administered at a supplemental dose of 3000 mg according to instructions that the supplemental dose be administered to a patient receiving an RBC transfusion within 4 weeks of the maintenance dose, with the supplemental dose being administered 4 weeks after the maintenance dose.

[0073] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 60 kg to < 100 kg. (a) 2700 mg loading dose once on day 1; (b) a loading dose of 900 mg once on day 5; (c) a loading dose of 900 mg once on day 10; (d) a maintenance dose of 3300 mg on day 15 and every 8 weeks thereafter; and (e) administered at a supplemental dose of 3300 mg according to instructions that the supplemental dose be administered to a patient receiving an RBC transfusion within 4 weeks of the maintenance dose, with the supplemental dose being administered 4 weeks after the maintenance dose.

[0074] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 100 kg, (a) 3000 mg loading dose once on day 1; (b) a loading dose of 900 mg once on day 5; (c) a loading dose of 900 mg once on day 10; (d) a maintenance dose of 3600 mg on day 15 and every 8 weeks thereafter; and (e) administered at a supplemental dose of 3600 mg according to instructions that the supplemental dose be administered to a patient receiving an RBC transfusion within 4 weeks of the maintenance dose, with the supplemental dose being administered 4 weeks after the maintenance dose.

[0075] In another aspect, an anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab (ULTOMIRIS®)), is provided for use in treating HSCT-TMA patients who received an RBC transfusion during the first half of the maintenance phase of treatment, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is (a) A loading dose of 600 mg for patients weighing 5 kg to <10 kg, 600 mg for patients weighing 10 kg to <20 kg, 900 mg for patients weighing 20 kg to <30 kg, 1200 mg for patients weighing ≥30 kg to <40 kg, 2400 mg for patients weighing ≥40 kg to <60 kg, 2700 mg for patients weighing ≥60 kg to <100 kg, or 3000 mg for patients weighing ≥100 kg, once on day 1; (b) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg once on day 5; (c) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg, once on day 10; and (d) 15th day and (i) every 4 weeks thereafter at a maintenance dose of 300 mg or 400 mg for patients weighing 5 kg to <10 kg or 600 mg or 800 mg for patients weighing 10 kg to <20 kg; or (ii) every 8 weeks thereafter at a maintenance dose of 2100 mg for patients weighing 20 kg to <30 kg, 2700 mg for patients weighing ≥30 kg to <40 kg, 3000 mg for patients weighing ≥40 kg to <60 kg, 3300 mg for patients weighing ≥60 kg to <100 kg, or 3600 mg for patients weighing ≥100 kg; The supplemental dose is (i) administered to patients weighing <30 kg who receive an RBC transfusion within the specified time frame of the maintenance dose, and the supplemental dose is administered within the specified time frame after the maintenance dose; a. Administered at a dose of 300 mg or 400 mg to patients weighing 5 kg to < 10 kg, and the time frame specified above is 2 weeks, or b. Administered at a dose of 600 mg or 800 mg to patients weighing 10 kg to <20 kg, and the time frame specified above is 2 weeks; or c. Administered at a dose of 2100 mg to patients weighing 20 kg to <30 kg with a specified time frame of 4 weeks, or (ii) administered to patients weighing ≥ 30 kg who receive a red blood cell (RBC) transfusion within 4 weeks of a maintenance dose, and the supplemental dose is administered 4 weeks after the maintenance dose; a. 2700 mg dose for patients weighing ≥ 30 kg to < 40 kg b. 3000 mg dose for patients weighing ≥ 40 kg to < 60 kg c. A dose of 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d. Administered at a dose of 3600 mg to patients weighing ≥ 100 kg.

[0076] Further provided herein is the use of an anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab (ULTOMIRIS®)), for the treatment of HSCT-TMA patients who received an RBC transfusion during the first half of the maintenance phase of treatment, wherein the anti-C5 antibody, or antigen-binding fragment thereof: (a) A loading dose of 600 mg for patients weighing 5 kg to <10 kg, 600 mg for patients weighing 10 kg to <20 kg, 900 mg for patients weighing 20 kg to <30 kg, 1200 mg for patients weighing ≥30 kg to <40 kg, 2400 mg for patients weighing ≥40 kg to <60 kg, 2700 mg for patients weighing ≥60 kg to <100 kg, or 3000 mg for patients weighing ≥100 kg, once on day 1; (b) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg once on day 5; (c) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg, once on day 10; and (d) 15th day and (i) every 4 weeks thereafter at a maintenance dose of 300 mg or 400 mg for patients weighing 5 kg to <10 kg or 600 mg or 800 mg for patients weighing 10 kg to <20 kg; or (ii) every 8 weeks thereafter at a maintenance dose of 2100 mg for patients weighing 20 kg to <30 kg, 2700 mg for patients weighing ≥30 kg to <40 kg, 3000 mg for patients weighing ≥40 kg to <60 kg, 3300 mg for patients weighing ≥60 kg to <100 kg, or 3600 mg for patients weighing ≥100 kg; The supplemental dose is (i) Administered to patients weighing <30 kg who receive an RBC transfusion within the specified time frame of the maintenance dose, and a supplemental dose within a specified time frame after the maintenance dose; a. Two weeks after the maintenance dose, at a dose of 300 mg or 400 mg for patients weighing 5 kg to < 10 kg, b. 2 weeks after the maintenance dose, at a dose of 600 mg or 800 mg for patients weighing 10 kg to <20 kg, or c. 4 weeks after the maintenance dose, administered at a dose of 2100 mg to patients weighing 20 to <30 kg; or (ii) administered to patients weighing ≥ 30 kg who receive a red blood cell (RBC) transfusion within 4 weeks of the maintenance dose, and a supplemental dose is administered 4 weeks after the maintenance dose; a. 2700 mg dose for patients weighing ≥ 30 kg to < 40 kg b. 3000 mg dose for patients weighing ≥ 40 kg to < 60 kg c. A dose of 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d. Use in patients weighing ≥ 100 kg, administered at a dose of 3600 mg. [Brief explanation of the drawings]

[0077] [Figure 1] Graphs depicting the ravulizumab pharmacokinetic (PK) profile for each patient. On days 5 and 10, ravulizumab concentrations were maintained above the 175 μg / mL threshold (dashed line). [Figure 2] Graph showing the free C5 concentration-time profile (i.e., pharmacodynamic (PD) profile) for each patient. All patients exhibited free C5 concentrations below the 0.5 μg / mL threshold (dashed line). [Figure 3] FIG. 1 is a schematic diagram showing a clinical algorithm for assessing post-RBC supplemental medication. DETAILED DESCRIPTION OF THE INVENTION

[0078] I. Definition As used herein, the term "subject" or "patient" refers to a human patient (e.g., a patient with hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA)).

[0079] As used herein, the term "pediatric" patient is a human patient classified by a physician or caregiver as belonging to a non-adult category and may include, for example, newborns (both preterm and full-term), infants, children, and adolescents. Typically, a pediatric patient is a patient under the age of 18 (<18 years).

[0080] As used herein, the term "adult" patient is a human patient who has been classified as such by a physician or caregiver, e.g., a person who is not a neonate, infant, child, or adolescent, e.g., based on age, developmental status, physiological characteristics, etc. Typically, an adult patient is a patient who is 18 years of age or older (≧18 years of age).

[0081] HSCT-TMA is a multifactorial disorder caused by systemic vascular endothelial injury that can be triggered by several mechanisms during the transplant process. It manifests through endothelial damage, affecting the kidneys and other organs. It is estimated that 30% of patients with HSCT TMA will present with severe disease (Rosenthal et al., J. Blood Med. 2016;7:181-186). In these cases, patients with HSCT-TMA develop systemic vascular injury manifested in kidney damage, serositis, pulmonary hypertension, and multiorgan failure. In one embodiment, TMA diagnosis is based on all of the following simultaneous criteria: (a) de novo thrombocytopenia or platelet transfusion refractoriness, where de novo thrombocytopenia is ≦50,000 / mm 3 Transfusion refractoriness was defined as a new decrease in platelet count to 10 × 10 after at least two platelet transfusions, a platelet increase 10–60 minutes after transfusion not exceeding the transfusion trigger, or a platelet count of 10 × 10 after 20–24 hours after transfusion. 9(b) new anemia (defined as a new decrease in hemoglobin to ≤8 g / dL) or increased transfusion requirements (defined as the need to administer more frequent transfusions to maintain hemoglobin ≥8 g / dL); (c) any one of the following markers of hemolysis: LDH >1.5 × ULN or the presence of schistocytes in ≥2 high-power fields (HPF) on a peripheral blood smear; (d) proteinuria on a spot urine test, defined as a protein / creatinine ratio ≥0.5 mg / mg. The presence of proteinuria should be confirmed by a second measurement (at least 4 hours apart); and (e) the presence of hypertension, defined as the presence of any one of the following three conditions: systolic blood pressure ≥139 mmHg or diastolic blood pressure >80 mmHg on two consecutive measurements at least 1 hour apart.

[0082] As used herein, "effective treatment" refers to treatment that results in 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, e.g., an improvement over a measurement or observation made before initiation of treatment according to the method. Effective treatment can refer to the alleviation of at least one symptom of HSCT-TMA (e.g., microangiopathic hemolytic anemia, thrombocytopenia, endothelial damage, renal damage, renal failure, serositis, pulmonary hypertension, and multiple organ failure).

[0083] The term "effective amount" refers to the amount of an agent that provides a desired biological, therapeutic, and / or prophylactic result. The result can be a reduction, amelioration, alleviation, mitigation, delay, and / or amelioration 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 HSCT-TMA (e.g., microangiopathic hemolytic anemia, thrombocytopenia, endothelial damage, kidney damage, kidney failure, serositis, pulmonary hypertension, and multiple organ failure). An effective amount can be administered in one or more administrations.

[0084] As used herein, the term "loading dose" refers to the first dose administered during a dosing cycle (e.g., on days 1, 5, and 10).

[0085] As used herein, the terms "maintenance" and "maintenance phase" are used interchangeably and refer to the second phase of treatment (e.g., doses administered every 8 weeks starting on day 15). In certain embodiments, treatment is continued as long as clinical benefit is observed or until unmanageable toxicity or disease progression occurs.

[0086] As used herein, the term "supplemental dose" refers to an additional dose administered to an HSCT-TMA patient (e.g., having a body weight ≥ 30 kg) who has received an RBC transfusion within 4 weeks after the maintenance dose.

[0087] As used herein, the term "blood transfusion" refers to a procedure in which whole blood or a portion of blood is placed into a patient's bloodstream, for example, through a vein. The blood may be donated by another person, or may be withdrawn from the patient and stored until needed.

[0088] As used herein, the term "red blood cell (RBC) transfusion" refers to the transfusion of red blood cells, i.e., donated whole blood or packed red blood cells obtained by donor apheresis, that enter a patient's bloodstream, e.g., via a vein. The majority of RBC transfusions are by infusion of packed RBCs, which are prepared by removing plasma from a whole blood collection or by apheresis, and subsequently stored with additives to enhance cell viability and storage.

[0089] As used herein, the term "serum trough level" refers to the lowest level at which a drug (e.g., an anti-C5 antibody, or an antigen-binding fragment thereof) or pharmaceutical agent is present in the serum. In contrast, "peak serum level" refers to the highest level of a drug in the serum. "Mean serum level" refers to the average level of a drug in the serum over time.

[0090] 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 single-domain antibody. An antibody can also be any of the following isotypes: IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD, IgE, or a combination thereof. An antibody can be a naturally occurring antibody or an antibody modified 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 (compared to a naturally occurring antibody) that, for example, alters the properties (e.g., functional properties) of the 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.

[0091] II. Anti-C5 antibody The anti-C5 antibodies described herein bind to complement component C5 (e.g., human C5) and inhibit cleavage of C5 into fragments C5a and C5b. As noted above, such antibodies also have improved pharmacokinetic properties compared to, for example, other anti-C5 antibodies used for therapeutic purposes (e.g., eculizumab).

[0092] Anti-C5 antibodies (or VH / VL domains derived therefrom) suitable for use in the methods described herein can be generated using methods known in the art. Alternatively, art-recognized anti-C5 antibodies can be used. Antibodies that compete with any of these art-recognized antibodies or the antibodies described herein for binding to C5 can also be used.

[0093] An exemplary anti-C5 antibody is ravulizumab, or an antigen-binding fragment or variant thereof, comprising heavy and light chains having the sequences set forth in SEQ ID NOs: 14 and 11, respectively. Ravulizumab (also known as ULTOMIRIS®, BNJ441, and ALXN1210) is described in WO 2015134894 and U.S. Patent No. 9,079,949, the entire teachings of which are incorporated herein by reference. The terms ravulizumab, BNJ441, and ALXN1210 may be used interchangeably throughout this specification and all refer to the same antibody. Ravulizumab selectively binds to 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) essential for microbial opsonization and immune complex clearance.

[0094] The polypeptide sequence of ravulizumab registered in the KEGG DRUG database (https: / / www.kegg.jp / entry / D11054) provides that the N-terminal amino acid of the variable heavy chain is "X," but the database does not state what X is. The Chemical Abstracts (CAS) for ravulizumab (CAS 1803171-55-2) also specifies that the N-terminal X is pyroglutamic acid (designated "chain 1 pyroglutamic acid-1" in the CAS report). This information may appear to be different from the VH sequence of ravulizumab, e.g., a heavy chain variable region polypeptide comprising the amino acids set forth in SEQ ID NO: 12 and / or a heavy chain polypeptide comprising the amino acids set forth in SEQ ID NO: 14, but may be different from the VH sequence of ravulizumab, e.g., a heavy chain variable region polypeptide comprising the amino acids set forth in SEQ ID NO: 14, where the N-terminal Q in the polypeptide and / or antibody sequence cyclizes during process development to form the VH sequence of ravulizumab, e.g., a heavy chain variable region polypeptide comprising the amino acids set forth in SEQ ID NO: 12 and / or a heavy chain polypeptide comprising the amino acids set forth in SEQ ID NO: 14, as described by Liu et al. (J Pharm Sci. 2019 Oct;108(10):3194-3200) https: / / pubmed.ncbi.nlm.nih.gov / 31145921 / and Nguyen et al. (Int. J. Mol. Sci. 2017 Jul 20;18(7):1575) As disclosed in https: / / www.researchgate.net / figure / Cyclization-reactions-of-N-terminal-glutamine-and-glutamate-residues-in-a-polypeptide_fig4_318926365, alignments exist between the patented sequence and drug database / CAS sequences as it was recognized in the art to result in nearly 100% drug product conversion to pyroglutamate (Pryo-Q).Further information is provided on page 7 and Table 4 of Xu et al. (MAbs, 2019 Feb / Mar;11(2):239-264), as well as the following referenced publications: (1) Yu et al., "Investigation of N-terminal glutamate cyclization of recombinant monoclonal antibody in formulation development," J. Pharm. Biomed. Anal., 2006, 42, 455-463, and Dicket et al., "Determination of the origin of the N-terminal pyro-glutamate variation in monoclonal antibodies using model peptides," Biotechnol. Bioeng., 2007, 97, 544-553, the disclosures of which are incorporated by reference in their entireties.

[0095] In other embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of ravulizumab. Thus, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of ravulizumab having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of the VL region of ravulizumab having the sequence set forth in SEQ ID NO: 8. In another embodiment, the antibody comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO: 8, respectively.

[0096] Another exemplary anti-C5 antibody is antibody BNJ421, or antigen-binding fragments and variants thereof, comprising heavy and light chains having the sequences set forth in SEQ ID NOs: 20 and 11, respectively. BNJ421 (also known as ALXN1211) is described in WO2015134894 and U.S. Pat. No. 9,079,949, the teachings of which are incorporated herein by reference in their entireties.

[0097] In other embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of BNJ421. Thus, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of BNJ421 having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of the VL region of BNJ421 having the sequence set forth in SEQ ID NO: 8. In another embodiment, the antibody comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO: 8, respectively.

[0098] The exact boundaries of CDRs are defined differently according to different methods. In some embodiments, the locations of CDRs or framework regions within a light or heavy chain variable domain are as defined by Kabat et al. [(1991) "Sequences of Proteins of Immunological Interest", NIH Publication No. 91-3242, USDapartment of Health and Human Services, Bethesda, MD]. 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 the CDRs of a light chain variable region or a heavy chain variable region are 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 the CDRs of light and heavy chain variable regions may be defined by the combined Kabat-Chothia definition. In such embodiments, these regions may be referred to as “Kabat-Chothia composite CDRs.” Thomas, C. et al. (Mol. Immunol., 33:1389-401, 1996) exemplifies the identification of CDR boundaries according to the Kabat and Chothia numbering scheme.

[0099] Another exemplary anti-C5 antibody is the 7086 antibody, described in U.S. Patent Nos. 8,241,628 and 8,883,158. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 7086 antibody (see U.S. Patent Nos. 8,241,628 and 8,883,158). In another embodiment, the antibody, or antigen-binding fragment thereof, comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 21, 22, and 23, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 24, 25, and 26, respectively. In another embodiment, the antibody, or antigen-binding fragment thereof, comprises the VH region of the 7086 antibody having the sequence set forth in SEQ ID NO: 27 and the VL region of the 7086 antibody having the sequence set forth in SEQ ID NO: 28.

[0100] Another exemplary anti-C5 antibody is the 8110 antibody, which is also described in U.S. Patent Nos. 8,241,628 and 8,883,158. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 8110 antibody. In another embodiment, the antibody, or antigen-binding fragment thereof, comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 29, 30, and 31, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 32, 33, and 34, respectively. In another embodiment, the antibody comprises the VH region of the 8110 antibody having the sequence set forth in SEQ ID NO: 35 and the VL region of the 8110 antibody having the sequence set forth in SEQ ID NO: 36.

[0101] Another exemplary anti-C5 antibody is the 305LO5 antibody described in U.S. Patent No. 9,765,135. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 305LO5 antibody. In another embodiment, the antibody, or antigen-binding fragment thereof, comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 37, 38, and 39, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 40, 41, and 42, respectively. In another embodiment, the antibody comprises the VH region of the 305LO5 antibody having the sequence set forth in SEQ ID NO: 43 and the VL region of the 305LO5 antibody having the sequence set forth in SEQ ID NO: 44.

[0102] Another exemplary anti-C5 antibody is the SKY59 antibody (Fukuzawa, T. et al., Sci. Rep., 7:1080, 2017). In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the SKY59 antibody. In some aspects, 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.

[0103] In some embodiments, the anti-C5 antibody comprises the heavy and light chain variable regions or heavy and light chains of the REGN3918 antibody (see U.S. Patent No. 10,633,434). In some embodiments, the anti-C5 antibody, or antigen-binding fragment thereof, comprises the heavy chain variable region sequence set forth in SEQ ID NO: 47 and the light chain variable region comprising the sequence set forth in SEQ ID NO: 48. In some embodiments, the anti-C5 antibody, or antigen-binding fragment thereof, comprises the heavy chain sequence set forth in SEQ ID NO: 49 and the light chain sequence set forth in SEQ ID NO: 50.

[0104] In another embodiment, the anti-C5 antibody is a biosimilar to eculizumab (SOLIRIS®). For example, in one embodiment, the anti-C5 antibody is, for example, ABP 959 antibody (eculizumab biosimilar from Amgen Inc., USA), ELIZARIA® (eculizumab biosimilar from Generium JNC, Russia), SB12 (eculizumab biosimilar from Samsung Bioepis, Incheon, South Korea), ISU305 (eculizumab biosimilar from ISU Abxis, South Korea), ABLYZE® (eculizumab biosimilar from CinnaGen, Iran), BCD 148 (eculizumab biosimilar from Biocad Medical, Quebec, Canada), tesidolumab (from Novartis), Crovalimab (from Roche), CAN106 (from CanBridge Pharmaceuticals, China), or Pozelimab (from Regeneron).

[0105] In some embodiments, 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 some embodiments, 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). In some embodiments, the anti-C5 antibodies described herein comprise a heavy chain variable region comprising the following amino acid sequence:

[0106] [Table 9]

[0107] In some embodiments, the anti-C5 antibodies described herein comprise a light chain variable region comprising the following amino acid sequence:

[0108] [Table 10]

[0109] In some embodiments, the anti-C5 antibodies described herein can comprise a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn) with higher affinity than the affinity of the native human Fc constant region from which the variant human Fc constant region is derived. The Fc constant region can comprise one or more (e.g., two, three, four, five, six, seven, or eight or more) amino acid substitutions, for example, compared to the native human Fc constant region from which the variant human Fc constant region is derived. The substitutions can increase the binding affinity of an IgG antibody containing the variant Fc constant 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 constant region of an antibody increase the affinity of the Fc constant 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. See, for example, WO 2015134894 and U.S. Pat. No. 9,079,949, the disclosures of each of which are incorporated herein by reference in their entireties.

[0110] Substitutions that enhance the binding affinity of antibody Fc constant regions to FcRn are known in the art, and include, for example, (1) M252Y / S254T / T256E triple substitutions (Dall'Acqua, W. et al., J. Biol. Chem., 281:23514-24, 2006); (2) M428L or T250Q / M428L substitutions (Hinton, P. et al., J. Biol. Chem., 279:6213-6, 2004; Hinton, P. et al., J. Immunol., 176:346-56, 2006); and (3) N434A or T307 / E380A / N434A substitutions (Petkova, S. et al., J. Immunol., 176:346-56, 2006). al., Int. Immunol., 18:1759-69, 2006). Additional substitution pairings include P257I / Q311I, P257I / N434H, and D376V / N434H (Datta-Mannan, A. et al., J. Biol. Chem., 282:1709-17, 2007), the disclosures of each of which are incorporated herein by reference in their entirety.

[0111] In some embodiments, the variant constant region has a substitution at EU amino acid position 255 for valine. In some embodiments, the variant constant region has a substitution at EU amino acid position 309 for asparagine. In some embodiments, the variant constant region has a substitution at EU amino acid position 312 for isoleucine. In some embodiments, the variant constant region has a substitution at EU amino acid position 386.

[0112] In some embodiments, the variant Fc constant region comprises no more than 30 (e.g., no more than 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2) amino acid substitutions, insertions, or deletions compared to the native constant region from which it is derived. In some embodiments, the variant Fc constant region comprises one or more amino acid substitutions selected from the group consisting of M252Y, S254T, T256E, N434S, M428L, V259I, T250I, and V308F. In some embodiments, the variant human Fc constant region comprises a methionine at position 428 and an asparagine at position 434 of the native human IgG Fc constant region, each in EU numbering. In some embodiments, the variant Fc constant region comprises a 428L / 434S double substitution, for example, as described in US Pat. No. 8,088,376.

[0113] In some embodiments, the exact locations of these mutations may be shifted from those of the native human Fc constant region by antibody engineering. For example, the 428L / 434S double substitution, when used in an IgG2 / 4 chimeric Fc, can correspond to 429L and 435S as in the M429L and N435S variant found in ravulizumab and described in U.S. Patent No. 9,079,949, the disclosure of which is incorporated herein by reference in its entirety.

[0114] In some embodiments, the variant constant region comprises a substitution at amino acid position 237, 238, 239, 248, 250, 252, 254, 255, 256, 257, 258, 265, 270, 286, 289, 297, 298, 303, 305, 307, 308, 309, 311, 312, 314, 315, 317, 325, 332, 334, 360, 376, 380, 382, ​​384, 385, 386, 387, 389, 424, 428, 433, 434 or 436 (EU numbering) compared to a native human Fc constant region. In some embodiments, the substitutions are: methionine for glycine at position 237; alanine for proline at position 238; lysine for serine at position 239; isoleucine for lysine at position 248; alanine, phenylalanine, isoleucine, methionine, glutamine, serine, valine, tryptophan, or tyrosine for threonine at position 250; phenylalanine, tryptophan, or tyrosine for methionine at position 252; threonine for serine at position 254; glutamic acid for arginine at position 255; aspartic acid, glutamic acid, or glutamine for threonine at position 256; alanine, glycine, isoleucine, leucine, methionine, asparagine, serine, threonine, or valine for proline at position 257; alanine for aspartic acid at position 265; phenylalanine for aspartic acid at position 270; alanine or glutamic acid for asparagine at position 286; histidine for threonine at position 289; alanine for asparagine at position 297; glycine for serine at position 298; alanine for valine at position 303; alanine for valine at position 305; alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, valine, tryptophan, or tyrosine for threonine at position 307; alanine, phenylalanine, isoleucine, leucine, methionine, proline, glutamine, or threonine for valine at position 308;alanine, aspartic acid, glutamic acid, proline, or arginine for leucine or valine at position 309; alanine, histidine, or isoleucine for glutamine at position 311; alanine or histidine for aspartic acid at position 312; lysine or arginine for leucine at position 314; alanine or histidine for asparagine at position 315; alanine for lysine at position 317; glycine for asparagine at position 325; valine for isoleucine at position 332; leucine for lysine at position 334; histidine for lysine at position 360; alanine for aspartic acid at position 376; alanine for glutamic acid at position 380; alanine for glutamic acid at position 382; alanine for asparagine or serine at position 384; aspartic acid or histidine in place of glycine at position 385; proline in place of glutamine at position 386; glutamic acid in place of proline at position 387; alanine or serine in place of asparagine at position 389; alanine in place of serine at position 424; alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, asparagine, proline, glutamine, serine, threonine, valine, tryptophan, or tyrosine in place of methionine at position 428; lysine in place of histidine at position 433; alanine, phenylalanine, histidine, serine, tryptophan, or tyrosine in place of asparagine at position 434; and histidine in place of tyrosine or phenylalanine at position 436 (all according to EU numbering).

[0115] Suitable anti-C5 antibodies for use in the methods described herein, in some embodiments, comprise a heavy chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 14 and / or a light chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 11. Alternatively, suitable anti-C5 antibodies for use in the methods described herein, in some embodiments, comprise a heavy chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 20 and / or a light chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 11.

[0116] In one embodiment, the antibody has an affinity dissociation constant (K) of at least 0.1 (e.g., at least 0.15, 0.175, 0.2, 0.25, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775, 0.8, 0.825, 0.85, 0.875, 0.9, 0.925, 0.95, or 0.975) nM. D ) and binds to C5 at pH 7.4 and 25°C (and otherwise under physiological conditions). In one embodiment, the antibody has an affinity dissociation constant (K) of about 0.5 nM at pH 7.4 and 25°C (and otherwise under physiological conditions). D In some embodiments, the K of an anti-C5 antibody, or antigen-binding fragment thereof, D 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). In some embodiments, the antibody has a K of about 22 nM at pH 6.0 and 25°C (and otherwise under physiological conditions). D binds to C5.

[0117] In another embodiment, the K of an antibody against C5 at pH 6.0 and 25°C D ) / (K of antibody against C5 at pH 7.4 and 25°C D )] 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, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 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, 860, 870, 880, 890, 900, 910 (greater than 0, 250, 260, 270, 280, 290, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, or 8000).

[0118] Methods for determining whether an antibody binds to a protein antigen and / or the affinity of an antibody for a protein antigen are known in the art. Binding of antibodies to protein antigens can be detected and / or quantified using a variety of techniques, including, but not limited to, Western blot, dot blot, surface plasmon resonance (SPR) detection (e.g., BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ), or enzyme-linked immunosorbent assay (ELISA; Benny KC Lo (2004) "Antibody Engineering: Methods and Protocols", Humana Press (ISBN: 1588290921); Johne, B. et al., J. Immunol. Meth., 160:191-8, 1993; Jonsson, U. et al., Ann. Biol. Clin., 51:19-26, 1993; Jonsson, U. et al., Biotechniques, 11:620-7, 1991). Further methods for measuring affinity (eg, dissociation and binding constants) are described in the Examples.

[0119] As used herein, "k a The term "k" refers to the rate constant for the association of an antibody to an antigen. d The term "K" refers to the rate constant for dissociation of an antibody from the antibody / antigen complex. D The term "antibody-antigen interaction" refers to the equilibrium dissociation constant of the antibody-antigen interaction. The equilibrium dissociation constant is the ratio of the kinetic rate constants, K D =k a / k d Such determinations can be made, for example, at 25°C or 37°C (see Examples). The kinetics of antibody binding to human C5 can be determined, for example, by SPR on a BIAcore 3000 instrument at pH 8.0, 7.4, 7.0, 6.5, and 6.0 using an anti-Fc capture method to immobilize the antibody.

[0120] In one embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, blocks the cleavage of C5 into C5a and C5b, which inhibits, for example, the pro-inflammatory effects of C5a and the generation of the C5b-9 membrane attack complex (MAC) at the cell surface.

[0121] Methods for determining whether a particular antibody described herein inhibits C5 cleavage are known in the art. Inhibition of human complement component C5 can reduce the cytolytic ability of complement in a subject's body fluid. Such a reduction in the lytic ability of cellular complement present in the body fluid can be measured, for example, by a conventional hemolytic assay, such as a hemolytic assay (Kabat and Mayer (eds.), "Experimental Immunochemistry, 2002, Vol. 1, No. 1, pp. 111-114, 2002). nd Edition," 135-240, Springfield, IL, CC Thomas (1961), pp. 135-139), or conventional modifications of that assay, such as the chicken erythrocyte hemolysis assay (Hillmen, P. et al., N. Engl. J. Med., 350:552-9, 2004). Methods for determining whether a candidate compound inhibits the cleavage of human C5 into C5a and C5b forms are known in the art (Evans, M. et al., Mol. Immunol., 32:1183-95, 1995). The concentrations and / or biological activities of C5a and C5b in body fluids can be measured, for example, by methods known in the art. For C5b, a hemolytic assay or the assay for soluble C5b-9 discussed herein can be used. Other assays known in the art can also be used. These or other suitable types of assays can be used to screen candidate agents capable of inhibiting human complement component C5.

[0122] Immunological techniques, such as, but not limited to, ELISA, can be used to measure protein concentrations of C5 and / or its degradation products to determine the ability of an anti-C5 antibody, or antigen-binding fragment thereof, to inhibit the conversion of C5 to biologically active products. In some embodiments, C5a production is measured. In some embodiments, a C5b-9 neoepitope-specific antibody is used to detect MAC formation.

[0123] A hemolytic assay can be used to determine the inhibitory activity of an anti-C5 antibody or its antigen-binding fragment on complement activation. To determine the effect of an anti-C5 antibody or its antigen-binding fragment on classical complement pathway-mediated hemolysis in an in vitro serum test solution, for example, sheep red blood cells coated with hemolysin or chicken red blood cells sensitized with anti-chicken red blood cell antibody are used as target cells. The percentage of lysis is normalized by considering 100% lysis to be equal to the lysis occurring in the absence of an inhibitor. In some embodiments, the classical complement pathway is activated by a human IgM antibody, such as that used in the Wieslab® Classical Pathway Complement Kit (Wieslab® COMPL CP310, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with an anti-C5 antibody or its antigen-binding fragment in the presence of a human IgM antibody. The amount of C5b-9 produced is measured by contacting the mixture with an enzyme-conjugated anti-C5b-9 antibody and a fluorogenic substrate and measuring absorbance at an appropriate wavelength. As a control, test serum is incubated in the absence of anti-C5 antibody, or an antigen-binding fragment thereof. In some embodiments, the test serum is C5-deficient serum reconstituted with C5 polypeptide.

[0124] To determine the effect of anti-C5 antibodies, or antigen-binding fragments thereof, on alternative pathway-mediated hemolysis, naive rabbit or guinea pig red blood cells can be used as target cells. In some embodiments, the serum test solution is C5-deficient serum reconstituted with C5 polypeptide. The percentage of lysis is normalized by considering 100% lysis to be equal to the lysis occurring in the absence of inhibitors. In some embodiments, the alternative complement pathway is activated by lipopolysaccharide molecules, such as those utilized in the Wieslab® Alternative Pathway Complement Kit (Wieslab® COMPL AP330, Euro-Diagnostica, Sweden). Briefly, test serum is incubated with anti-C5 antibodies, or antigen-binding fragments thereof, in the presence of lipopolysaccharide. The amount of C5b-9 produced is measured by contacting the mixture with an enzyme-conjugated anti-C5b-9 antibody and a fluorogenic substrate and measuring fluorescence at an appropriate wavelength. As a control, test sera are incubated in the absence of anti-C5 antibody, or antigen-binding fragment thereof.

[0125] In some embodiments, C5 activity or its inhibition is quantified using a CH50eq assay. The CH50eq assay is a method for measuring total classical complement activity in serum. This test is a lytic assay that uses antibody-sensitized red blood cells as an activator of the classical complement pathway and various dilutions of test serum to determine the amount required to give 50% lysis (CH50). Percent hemolysis can be determined, for example, using a spectrophotometer. The CH50eq assay provides an indirect measure of terminal complement complex (TCC) formation, since TCC itself is directly involved in the hemolysis measured. The assay is known and commonly performed by those skilled in the art. Briefly, to activate the classical complement pathway, an undiluted serum sample (e.g., a reconstituted human serum sample) is added to a microassay well containing antibody-sensitized red blood cells, thereby generating TCC. The activated serum is then diluted in a microassay well coated with a capture reagent (e.g., an antibody that binds to one or more components of TCC). TCC present in the activated sample binds to the monoclonal antibody coating the surface of the microassay wells. The wells are washed, and a detectably labeled detection reagent that recognizes the bound TCC is added to each well. The detectable label can be, for example, a fluorescent label or an enzyme label. Assay results are expressed in CH50 unit equivalents per milliliter (CH50 U Eq / mL).

[0126] Inhibition, e.g., as it relates to terminal complement activity, includes at least a 5% (e.g., at least 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60%) decrease in terminal complement activity, e.g., in a hemolytic assay or CH50eq assay, compared to the effect of a control antibody (or antigen-binding fragment thereof) under similar conditions and at an equimolar concentration. Substantial inhibition, as used herein, refers to at least 40% (e.g., at least 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% or more) inhibition of a given activity (e.g., terminal complement activity). In some embodiments, the anti-C5 antibodies described herein contain one or more amino acid substitutions compared to the CDRs of eculizumab (i.e., SEQ ID NOS: 1-6), but retain at least 30% (e.g., at least 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95%) of the complement inhibitory activity of eculizumab in a hemolytic assay or a CH50eq assay.

[0127] The anti-C5 antibodies described herein have a serum half-life in humans of 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 of at least 40 days. In another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans of approximately 43 days. In another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans of 39-48 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% (e.g., at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250, 300, 400, or 500%) greater than the serum half-life of eculizumab, e.g., as measured in one of the mouse model systems described in the Examples (e.g., a C5-deficient / NOD / scid mouse or an hFcRn transgenic mouse model system).

[0128] In one embodiment, the antibody competes for binding to and / or binds to the same epitope on C5 as the antibodies described herein. 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 the antibodies described herein include, for example, x-ray analysis of a crystal of the antigen:antibody complex and epitope mapping methods such as hydrogen / deuterium exchange mass spectrometry (HDX-MS). Antibodies with the same VH and VL or the same CDR1, CDR2, and CDR3 sequences are expected to bind to the same epitope.

[0129] 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 the binding of another antibody to a target and inhibits it 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 the "blocking antibody," i.e., the antibody that is first incubated with the target. Competing antibodies can, for example, bind to the same epitope, overlapping epitopes, or adjacent epitopes (e.g., as evidenced by steric hindrance).

[0130] The anti-C5 antibodies described herein, or antigen-binding fragments thereof, 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 well known to those skilled in the art. Briefly, spleen cells from an animal immunized with a desired antigen are immortalized, typically by fusion with myeloma cells (Kohler, G. & Milstein, C., Eur. J. Immunol., 6:511-9, 1976). Methods of immortalization include transformation with Epstein-Barr virus, oncogenes, or retroviruses, or other methods known in the art. Colonies arising from single immortalized cells are screened for the production of antibodies of the desired specificity and affinity to the antigen, and the yield of monoclonal antibodies produced by such cells can be enhanced by various techniques, including intraperitoneal injection of a vertebrate host. Alternatively, DNA sequences encoding monoclonal antibodies or binding fragments thereof can be isolated by screening a DNA library derived from human B cells (Huse, W. et al., Science, 246:1275-81, 1989).

[0131] III. Composition Also provided herein are compositions comprising an anti-C5 antibody, or an antigen-binding fragment thereof. In one embodiment, the composition comprises an anti-C5 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 8. In another embodiment, the anti-C5 antibody comprises heavy and light chains having the sequences set forth in SEQ ID NOs: 14 and 11, respectively. In another embodiment, the anti-C5 antibody comprises heavy and light chains having the sequences set forth in SEQ ID NOs: 20 and 11, respectively.

[0132] The composition can be formulated as a pharmaceutical solution for administration to a subject, for example, for the treatment of HSCT-TMA. Pharmaceutical compositions generally contain a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" refers to and includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. that are physiologically compatible. The composition can include pharmaceutically acceptable salts, such as acid addition salts or base addition salts, sugars, carbohydrates, polyols, and / or tonicity adjusting agents.

[0133] Compositions can be formulated according to standard methods. Pharmaceutical formulation is an established art (see, e.g., Gennaro (2000) "Remington: The Science and Practice of Pharmacy", 20 th Edition, Lippincott, Williams & Wilkins (ISBN:0683306472); Ansel et al. (1999) "Pharmaceutical Dosage Forms and Drug Delivery Systems", 7 thEdition, Lippincott Williams & Wilkins Publishers (ISBN:0683305727); and Kibbe (2000) “Handbook of Pharmaceutical Excipients American Pharmaceutical Association”, 3 rd (See, for example, the "Issue of the Invention" Edition (ISBN: 091733096X)). In some embodiments, the compositions can be formulated, for example, as a buffer solution at a suitable concentration and 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 2 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 1 year. Pharmaceutical compositions can be in various 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, for example, in the form of an injectable or infusible solution. Thus, the composition can be formulated for parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection). As used herein, "parenteral administration," "parenterally administered," and other grammatically equivalent phrases 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.

[0134] IV. Method Provided herein are methods for treating HSCT-TMA in specific patient subpopulations (e.g., HSCT-TMA patients weighing <30 kg or weighing ≥30 kg who received a transfusion (e.g., a platelet or RBC transfusion) within 4 weeks after a maintenance dose), the methods comprising administering to the patient an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is administered (or is for administration) according to a specific clinical dosing regimen (e.g., at specific loading, maintenance, and one or more supplemental doses, and according to a specific schedule).

[0135] In one embodiment, the dose of the anti-C5 antibody or antigen-binding fragment thereof is based on the patient's weight. For example, in one embodiment, a loading dose of 300 mg or 600 mg of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 5 kg to < 10 kg. In another embodiment, a maintenance dose of 400 mg of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 5 kg to < 10 kg. In another embodiment, supplemental doses of 400 mg of the anti-C5 antibody or antigen-binding fragment thereof are administered to a patient weighing ≥ 5 kg to < 10 kg. In some embodiments, a loading dose of 300 mg or 600 mg of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 10 kg to < 20 kg. In another embodiment, a maintenance dose of 800 mg of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 10 kg to < 20 kg. In another embodiment, a supplemental dose of 800 mg of an anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 10 kg to < 20 kg. In some embodiments, a loading dose of 300 mg or 900 mg of an anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 20 kg to < 30 kg. In another embodiment, a maintenance dose of 2100 mg of an anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 20 kg to < 30 kg. In another embodiment, a supplemental dose of 2100 mg of an anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 20 kg to < 30 kg.

[0136] For example, in one embodiment, a loading dose of 300 mg or 1200 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 30 kg to < 40 kg. In another embodiment, a maintenance dose of 2700 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 30 kg to < 40 kg. In another embodiment, a supplemental dose of 2700 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 30 kg to < 40 kg.

[0137] In another embodiment, a loading dose of 600 mg or 2400 mg of an anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 40 kg to < 60 kg. In another embodiment, a maintenance dose of 3000 mg of an anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 40 kg to < 60 kg. In another embodiment, a supplemental dose of 3000 mg of an anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 40 kg to < 60 kg.

[0138] In another embodiment, a loading dose of 900 mg or 2700 mg of an anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 60 kg to < 100 kg. In another embodiment, a maintenance dose of 3300 mg of an anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 60 kg to < 100 kg. In another embodiment, supplemental doses of 3300 mg of an anti-C5 antibody, or antigen-binding fragment thereof, are administered to a patient weighing ≥ 60 kg to < 100 kg.

[0139] In another embodiment, a loading dose of 900 mg or 3000 mg of an anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≧100 kg. In another embodiment, a maintenance dose of 3600 mg of an anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≧100 kg. In another embodiment, a supplemental dose of 3600 mg of an anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≧100 kg.

[0140] In certain embodiments, dosage regimens are adjusted to provide the optimum desired response (eg, an efficacious response).

[0141] In some embodiments in which a patient receives an RBC transfusion within four weeks after the first maintenance dose, the patient receives a single post-transfusion supplemental dose of an anti-C5 antibody (e.g., ravulizumab) only at the midpoint between the two maintenance doses. Because the maintenance doses are administered every four weeks (Q4W) for patients with a lower (e.g., <20 kg) weight class and every eight weeks (Q8W) for patients with a higher (e.g., ≥20 kg) weight class, the supplemental dose of the anti-C5 antibody (e.g., ravulizumab) is administered two weeks later (for patients <20 kg) and four weeks later (for patients ≥20 kg), e.g., 14 or 28 days after the maintenance dose. In such embodiments, if the patient does not receive any transfusions during the second maintenance dosing period, no supplemental dose is required during this maintenance dosing cycle. Similarly, if the patient receives an RBC transfusion during the second half of the second maintenance dosing period, no supplemental dose is required during this maintenance dosing cycle. In other words, if the first RBC transfusion occurs more than four weeks after the preceding maintenance dose, no post-transfusion supplemental dose is required. In addition, if the patient receives a transfusion during the loading dose phase, no supplemental medication is administered.

[0142] According to the treatment methods described herein, if any amount of RBC transfusion is provided to the HSCT-TMA patient within four weeks after the last maintenance dose, a single post-transfusion supplemental dose of an anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab) is administered to the HSCT-TMA patient only four weeks after the last maintenance dose.

[0143] In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered over one or more administration cycles. In one embodiment, the treatment (e.g., administration cycle) is for 26 weeks. In one embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered as a loading dose once on day 1 (e.g., of the administration cycle), once on day 5 (e.g., of the administration cycle), and once on day 10 (e.g., of the administration cycle). In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered as a loading dose once on day 1 (e.g., of the administration cycle), once on day 5 (e.g., of the administration cycle), once on day 10 (e.g., of the administration cycle), and maintenance doses administered every 8 weeks thereafter starting on day 15. In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered every 8 weeks after treatment (e.g., administration cycle) for an extended period of up to 2 years (e.g., at a dose of 300 mg, 600 mg, 900 mg, 1200 mg, 2100 mg, 2400 mg, 2700 mg, 3000 mg, 3300 mg, or 3600 mg).

[0144] In another embodiment, the supplemental dose is administered to a patient who receives a transfusion (e.g., a platelet or RBC transfusion) within two weeks or four weeks of the maintenance dose, and the supplemental dose is administered two weeks or four weeks after the maintenance dose. In an embodiment, the supplemental dose is administered to a patient weighing <20 kg who receives an RBC transfusion within two weeks of the maintenance dose, and the supplemental dose is administered two weeks after the maintenance dose at a dose of 400 mg for patients weighing ≥5 to <10 kg and 800 mg for patients weighing ≥10 to <20 kg. In an embodiment, the supplemental dose is administered to a patient weighing ≥20 <30 kg who receives an RBC transfusion within four weeks of the maintenance dose, and the replacement dose is administered four weeks after the maintenance dose at a dose of 2100 mg for patients weighing ≥20 <30 kg.

[0145] In another embodiment, a supplemental dose is administered to patients weighing ≧30 kg who receive an RBC transfusion within 4 weeks of the maintenance dose, and a supplemental dose is administered 4 weeks after the maintenance dose at a dose of 2700 mg for patients weighing ≧30 kg to <40 kg, 3000 mg for patients weighing ≧40 kg to <60 kg, 3300 mg for patients weighing ≧60 kg to <100 kg, or 3600 mg for patients weighing ≧100 kg.

[0146] In one embodiment, a method of treating a human patient having HSCT-TMA is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody or antigen-binding fragment thereof is (a) A loading dose of 600 mg for patients weighing 5 kg to <10 kg, 600 mg for patients weighing 10 kg to <20 kg, 900 mg for patients weighing 20 kg to <30 kg, 1200 mg for patients weighing ≥30 kg to <40 kg, 2400 mg for patients weighing ≥40 kg to <60 kg, 2700 mg for patients weighing ≥60 kg to <100 kg, or 3000 mg for patients weighing ≥100 kg, once on day 1; (b) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg once on day 5; (c) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg, once on day 10; and (d) 15th day and (i) every 4 weeks thereafter at a maintenance dose of 300 mg or 400 mg for patients weighing 5 kg to <10 kg or 600 mg or 800 mg for patients weighing 10 kg to <20 kg; or (ii) every 8 weeks thereafter at a maintenance dose of 2100 mg for patients weighing 20 kg to <30 kg, 2700 mg for patients weighing ≥30 kg to <40 kg, 3000 mg for patients weighing ≥40 kg to <60 kg, 3300 mg for patients weighing ≥60 kg to <100 kg, or 3600 mg for patients weighing ≥100 kg; The supplemental dose is (i) administered to patients weighing <30 kg who receive an RBC transfusion within the specified time frame of the maintenance dose, and the supplemental dose is administered within the specified time frame after the maintenance dose; a. Administered at a dose of 300 mg or 400 mg to patients weighing 5 kg to < 10 kg, and the time frame specified above is 2 weeks, or b. Administered at a dose of 600 mg or 800 mg to patients weighing 10 kg to <20 kg, and the time frame specified above is 2 weeks; or c. Administered at a dose of 2100 mg to patients weighing 20 kg to <30 kg and the time frame specified above is 4 weeks, or (ii) administered to patients weighing ≥ 30 kg who receive a red blood cell (RBC) transfusion within 4 weeks of a maintenance dose, and the supplemental dose is administered 4 weeks after the maintenance dose; a. 2700 mg dose for patients weighing ≥ 30 kg to < 40 kg b. 3000 mg dose for patients weighing ≥ 40 kg to < 60 kg c. A dose of 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d. Administered at a dose of 3600 mg to patients weighing ≥ 100 kg.

[0147] In another embodiment, a method of treating a human patient having HSCT-TMA is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody 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 a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, according to EU numbering rules, and wherein the anti-C5 antibody (a) A loading dose of 600 mg for patients weighing 5 kg to <10 kg, 600 mg for patients weighing 10 kg to <20 kg, 900 mg for patients weighing 20 kg to <30 kg, 1200 mg for patients weighing ≥30 kg to <40 kg, 2400 mg for patients weighing ≥40 kg to <60 kg, 2700 mg for patients weighing ≥60 kg to <100 kg, or 3000 mg for patients weighing ≥100 kg, once on day 1; (b) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg once on day 5; (c) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg, once on day 10; and (d) 15th day and (i) every 4 weeks thereafter at a maintenance dose of 300 mg or 400 mg for patients weighing 5 kg to <10 kg or 600 mg or 800 mg for patients weighing 10 kg to <20 kg; or (ii) every 8 weeks thereafter at a maintenance dose of 2100 mg for patients weighing 20 kg to <30 kg, 2700 mg for patients weighing ≥30 kg to <40 kg, 3000 mg for patients weighing ≥40 kg to <60 kg, 3300 mg for patients weighing ≥60 kg to <100 kg, or 3600 mg for patients weighing ≥100 kg; The supplemental dose is (i) administered to patients weighing <30 kg who receive an RBC transfusion within the specified time frame of the maintenance dose, and the supplemental dose is administered within the specified time frame after the maintenance dose; a. Administered at a dose of 300 mg or 400 mg to patients weighing 5 kg to < 10 kg, and the time frame specified above is 2 weeks, or b. Administered at a dose of 600 mg or 800 mg to patients weighing 10 kg to <20 kg, and the time frame specified above is 2 weeks; or c. Administered at a dose of 2100 mg to patients weighing 20 kg to <30 kg and the time frame specified above is 4 weeks, or (ii) administered to patients weighing ≥ 30 kg who receive a red blood cell (RBC) transfusion within 4 weeks of a maintenance dose, and the supplemental dose is administered 4 weeks after the maintenance dose; a. 2700 mg dose for patients weighing ≥ 30 kg to < 40 kg b. 3000 mg dose for patients weighing ≥ 40 kg to < 60 kg c. A dose of 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d. Administered at a dose of 3600 mg to patients weighing ≥ 100 kg.

[0148] In another embodiment, a method of treating a human patient having HSCT-TMA is provided, the method comprising administering to the patient an effective amount of ravulizumab, wherein the ravulizumab: (a) A loading dose of 600 mg for patients weighing 5 kg to <10 kg, 600 mg for patients weighing 10 kg to <20 kg, 900 mg for patients weighing 20 kg to <30 kg, 1200 mg for patients weighing ≥30 kg to <40 kg, 2400 mg for patients weighing ≥40 kg to <60 kg, 2700 mg for patients weighing ≥60 kg to <100 kg, or 3000 mg for patients weighing ≥100 kg, once on day 1; (b) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg once on day 5; (c) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg, once on day 10; and (d) 15th day and (i) every 4 weeks thereafter at a maintenance dose of 300 mg or 400 mg for patients weighing 5 kg to <10 kg or 600 mg or 800 mg for patients weighing 10 kg to <20 kg; or (ii) every 8 weeks thereafter at a maintenance dose of 2100 mg for patients weighing 20 kg to <30 kg, 2700 mg for patients weighing ≥30 kg to <40 kg, 3000 mg for patients weighing ≥40 kg to <60 kg, 3300 mg for patients weighing ≥60 kg to <100 kg, or 3600 mg for patients weighing ≥100 kg; The supplemental dose is (i) administered to patients weighing <30 kg who receive an RBC transfusion within the specified time frame of the maintenance dose, and the supplemental dose is administered within the specified time frame after the maintenance dose; a. Administered at a dose of 300 mg or 400 mg to patients weighing 5 kg to < 10 kg, and the time frame specified above is 2 weeks, or b. Administered at a dose of 600 mg or 800 mg to patients weighing 10 kg to <20 kg, and the time frame specified above is 2 weeks; or c. Administered at a dose of 2100 mg to patients weighing 20 kg to <30 kg and the time frame specified above is 4 weeks, or (ii) administered to patients weighing ≥ 30 kg who receive a red blood cell (RBC) transfusion within 4 weeks of a maintenance dose, and the supplemental dose is administered 4 weeks after the maintenance dose; a. 2700 mg dose for patients weighing ≥ 30 kg to < 40 kg b. 3000 mg dose for patients weighing ≥ 40 kg to < 60 kg c. A dose of 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d. Administered at a dose of 3600 mg to patients weighing ≥ 100 kg.

[0149] In another embodiment, a method of treating a human patient having HSCT-TMA is provided, the method comprising administering to the patient an effective amount of ravulizumab, wherein the ravulizumab: (a) A loading dose of 600 mg for patients weighing 5 kg to <10 kg, 600 mg for patients weighing 10 kg to <20 kg, 900 mg for patients weighing 20 kg to <30 kg, 1200 mg for patients weighing ≥30 kg to <40 kg, 2400 mg for patients weighing ≥40 kg to <60 kg, 2700 mg for patients weighing ≥60 kg to <100 kg, or 3000 mg for patients weighing ≥100 kg, once on day 1; (b) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg once on day 5; (c) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg, once on day 10; and (d) 15th day and (i) every 4 weeks thereafter at a maintenance dose of 300 mg or 400 mg for patients weighing 5 kg to <10 kg or 600 mg or 800 mg for patients weighing 10 kg to <20 kg; or (ii) every 8 weeks thereafter at a maintenance dose of 2100 mg for patients weighing 20 kg to <30 kg, 2700 mg for patients weighing ≥30 kg to <40 kg, 3000 mg for patients weighing ≥40 kg to <60 kg, 3300 mg for patients weighing ≥60 kg to <100 kg, or 3600 mg for patients weighing ≥100 kg; The supplemental dose is (i) administered to patients weighing <30 kg who receive an RBC transfusion within the specified time frame of the maintenance dose, and the supplemental dose is administered within the specified time frame after the maintenance dose; a. Administered at a dose of 300 mg or 400 mg to patients weighing 5 kg to < 10 kg, and the time frame specified above is 2 weeks, or b. Administered at a dose of 600 mg or 800 mg to patients weighing 10 kg to <20 kg, and the time frame specified above is 2 weeks; or c. Administered at a dose of 2100 mg to patients weighing 20 kg to <30 kg and the time frame specified above is 4 weeks, or (ii) administered to patients weighing ≥ 30 kg who receive a red blood cell (RBC) transfusion within 4 weeks of a maintenance dose, and the supplemental dose is administered 4 weeks after the maintenance dose; a. 2700 mg dose for patients weighing ≥ 30 kg to < 40 kg b. 3000 mg dose for patients weighing ≥ 40 kg to < 60 kg c. A dose of 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d. Administered at a dose of 3600 mg to patients weighing ≥ 100 kg. and The treatment results in a reduction of LDH levels to within normal levels or within 50% of what is considered the ULN level (e.g., within 105-333 IU / L (International Units per Liter)), a serum trough concentration of anti-C5 antibody or antigen-binding fragment thereof of at least 175 μg / mL, and / or a free C5 concentration of 0.5 μg / mL or less (e.g., 0.4 μg / mL, 0.3 μg / mL, 0.2 μg / mL, or 0.1 μg / mL or less).

[0150] In another embodiment, a method of treating a human patient having HSCT-TMA is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing 5 kg to <10 kg. (a) 600 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 300 mg on day 15 and every 4 weeks thereafter; and (e) A supplemental dose of 300 mg is administered to patients who receive an RBC transfusion within 2 weeks of the maintenance dose, with this supplemental dose being administered 2 weeks after the maintenance dose.

[0151] In another embodiment, a method of treating a human patient having HSCT-TMA is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing 5 kg to <10 kg. (a) 600 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 400 mg on day 15 and every 4 weeks thereafter; and (e) A supplemental dose of 400 mg is administered to patients who receive an RBC transfusion within 2 weeks of the maintenance dose, with this supplemental dose being administered 2 weeks after the maintenance dose.

[0152] In another embodiment, a method of treating a human patient having HSCT-TMA is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing 10 kg to <20 kg. (a) 600 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 600 mg on day 15 and every 4 weeks thereafter; and (e) A supplemental dose of 600 mg is administered to patients who receive an RBC transfusion within 2 weeks of the maintenance dose, with this supplemental dose being administered 2 weeks after the maintenance dose.

[0153] In another embodiment, a method of treating a human patient having HSCT-TMA is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing 10 kg to <20 kg. (a) 600 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 800 mg on day 15 and every 4 weeks thereafter; and (e) A supplemental dose of 800 mg is administered to patients who receive an RBC transfusion within 2 weeks of the maintenance dose, with this supplemental dose being administered 2 weeks after the maintenance dose.

[0154] In another embodiment, a method of treating a human patient having HSCT-TMA is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing 20 kg to <30 kg. (a) 900 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 2100 mg on day 15 and every 8 weeks thereafter; and (e) A supplemental dose of 2100 mg is administered to patients who receive an RBC transfusion within 2 weeks of the maintenance dose, with this supplemental dose being administered 4 weeks after the maintenance dose.

[0155] In some embodiments, the supplemental doses are administered when warranted by the clinical algorithm set forth in Figure 3. In some embodiments, the supplemental doses are administered when warranted by the clinical algorithm set forth in Table 7.

[0156] In another embodiment, a method of treating a human patient having HSCT-TMA is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing ≥ 30 kg to < 40 kg. (a) 1200 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; and (d) a maintenance dose of 2700 mg on day 15 and every 8 weeks thereafter; The patient receives an RBC transfusion within 4 weeks of the maintenance dose, then receives a supplemental dose of 2700 mg 4 weeks after the maintenance dose.

[0157] In another embodiment, a method of treating a human patient having HSCT-TMA is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing ≥ 40 kg to < 60 kg. (a) 2400 mg loading dose once on day 1; (b) a loading dose of 600 mg once on day 5; (c) a loading dose of 600 mg once on day 10; and (d) a maintenance dose of 3000 mg on day 15 and every 8 weeks thereafter; The patient receives an RBC transfusion within 4 weeks of the maintenance dose, then receives a supplemental dose of 3000 mg 4 weeks after the maintenance dose.

[0158] In another embodiment, a method of treating a human patient having HSCT-TMA is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing ≥ 60 kg to < 100 kg. (a) 2700 mg loading dose once on day 1; (b) a loading dose of 900 mg once on day 5; (c) a loading dose of 900 mg once on day 10; and (d) a maintenance dose of 3300 mg on day 15 and every 8 weeks thereafter; The patient receives an RBC transfusion within 4 weeks of the maintenance dose, then receives a supplemental dose of 3300 mg 4 weeks after the maintenance dose.

[0159] In another embodiment, a method of treating a human patient having HSCT-TMA is provided, the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing ≧100 kg. (a) 3000 mg loading dose once on day 1; (b) a loading dose of 900 mg once on day 5; (c) a loading dose of 900 mg once on day 10; and (d) a maintenance dose of 3600 mg on day 15 and every 8 weeks thereafter; The patient receives an RBC transfusion within 4 weeks of the maintenance dose, then receives a supplemental dose of 3600 mg 4 weeks after the maintenance dose.

[0160] In another embodiment, immediate, complete, and sustained terminal complement inhibition is achieved after administration of a supplemental dose of an anti-C5 antibody, or antigen-binding fragment thereof (e.g., ravulizumab).

[0161] In one embodiment, the methods of treatment disclosed herein further comprise administering best supportive care (BSC) measures, including, but not limited to, transfusion support, corticosteroids, dialysis, and antihypertensive drugs.

[0162] In one embodiment, the patient has not been previously treated with eculizumab. In another embodiment, the patient has been previously treated with eculizumab. In another embodiment, the patient has been previously treated with eculizumab and day 1 (e.g., of a dosing cycle) is 2 weeks or more after the patient's last dose of eculizumab.

[0163] V. Results Provided herein are methods for treating HSCT-TMA in a patient, comprising administering an anti-C5 antibody to the patient. Symptoms of HSCT-TMA include, but are not limited to, microangiopathic hemolytic anemia, thrombocytopenia, endothelial injury, renal injury, renal failure, serositis, pulmonary hypertension, and multiple organ failure.

[0164] Patients treated according to the methods disclosed herein experience an improvement in at least one symptom of HSCT-TMA. Treatment may result in, for example, a reduction or cessation of at least one therapeutic effect selected from the group consisting of microangiopathic hemolytic anemia, thrombocytopenia, endothelial damage, renal damage, renal failure, serositis, pulmonary hypertension, and multiple organ failure compared to baseline.

[0165] In another embodiment, treatment comprises (a) a platelet count of ≥ 50,000 / mm without transfusion support in the past 7 days. 3 , (b) LDH < 1.5 x ULN, and (c) absence of schistocytes (if schistocytes were present at baseline).

[0166] In another embodiment, treatment comprises (a) a platelet count of ≥ 50,000 / mm without transfusion support in the past 7 days. 3 (b) LDH<1.5×ULN, (c) absence of schistocytes (if schistocytes were present at baseline), and (d) at least a 50% reduction in proteinuria from baseline. In one embodiment, proteinuria is a protein / creatinine ratio of ≧0.5 mg / mg.

[0167] In another embodiment, the treatment results in a favorable hematological response.

[0168] In another embodiment, treatment results in normalization of LDH, elimination of the need for red blood cell and platelet transfusions, and elimination of schistocytes.

[0169] In another embodiment, the treatment results in the patient's ability to maintain hemoglobin > 8 g / dL without transfusion support. In another embodiment, the treatment results in hemoglobin > 8 g / dL without transfusion support.

[0170] In another embodiment, treatment results in a decrease in LDH, an increase in platelets, and / or an increase in hemoglobin compared to baseline.

[0171] In another embodiment, treatment results in normal levels of serum creatinine compared to baseline.

[0172] In another embodiment, treatment results in an improvement in TMA-associated organ dysfunction in the renal, cardiovascular, pulmonary, CNS, and / or GI systems compared to baseline.

[0173] In another embodiment, the treatment results in terminal complement inhibition.

[0174] In another embodiment, treatment results in a reduction in adverse events.

[0175] In another embodiment, treatment results in a shift to normal levels of biomarkers associated with vascular inflammation (e.g., shed tumor necrosis factor receptor 1 [TNF-R1]), biomarkers associated with endothelial injury and / or activation (e.g., thrombomodulin and shed vascular cell adhesion molecule 1 [VCAM-1]), biomarkers associated with renal injury (e.g., cystatin C), and / or complement proteins and complement activation pathway products. In another embodiment, treatment results in a shift to normal levels of thrombomodulin (TM) and / or syndecan-1 (SYND1). In another embodiment, treatment results in a shift to normal levels of complement factor Ba.

[0176] In another embodiment, treatment results in a change from baseline in quality of life as assessed via a quality of life assessment (e.g., the Quality of Life Inventory (PedsQL) scale or the EQ-5D-5L questionnaire). The PedsQL 4.0 Generic Core Scales are a multidimensional pediatric self-report and parent-proxy-report standardized instrument for measuring health-related quality of life (QoL) in children and adolescents aged 2-18 years.

[0177] In another embodiment, lactate dehydrogenase (LDH) levels can be used to assess response to treatment. LDH is a marker of intravascular hemolysis (Hill, A. et al., Br. J. Haematol., 149:414-25, 2010; Hillmen, P. et al., N. Engl. J. Med., 350:552-9, 2004; Parker, C. et al., Blood, 106:3699-709, 2005). Erythrocytes contain large amounts of LDH, and a correlation between cell-free hemoglobin and LDH concentrations has been reported in vitro (Van Lente, F. et al., Clin. Chem., 27:1453-5, 1981) and in vivo (Kato, G. et al., Blood, 107:2279-85, 2006). Hemolytic outcomes are independent of anemia (Hill, A. et al., Hematologica, 93(s1):359 Abs.0903, 2008; Kanakura, Y. et al., Int. J. Hematol., 93:36-46, 2011). LDH concentrations obtained at baseline and then serially throughout the treatment period are important measures of hemolysis. Normal LDH values ​​range from 105 to 333 IU / L (International Units per Liter).

[0178] LDH levels can be measured using any suitable test or assay, such as those described by Ferri FF, ed. Ferri's Clinical Advisor 2014. Philadelphia: PA: Elsevier Mosby; 2014: Section IV - Laboratory tests and interpretation of results. LDH concentrations can be measured in various samples obtained from patients, particularly serum samples. As used herein, the term "sample" refers to biological material from a subject. While serum LDH concentrations are of interest, samples can be derived from other sources, including single cells, multiple cells, tissues, tumors, biological fluids, biological molecules, or supernatants or extracts of any of the foregoing. Examples include tissue removed for biopsy, tissue removed during resection, blood, urine, lymphatic tissue, lymphatic fluid, cerebrospinal fluid, mucus, and fecal samples. The sample used can vary based on the assay format, detection method, and the nature of the tumor, tissue, cells, or extract being assayed. Methods for preparing samples are known in the art and can be readily adapted to obtain a sample that is compatible with the method utilized.

[0179] In one embodiment, a patient treated according to the disclosed methods experiences a decrease in LDH levels to normal levels or within 10% or 20% of what is considered normal (e.g., within 10-333 IU / L). For example, patients treated according to the disclosed methods experience a decrease in LDH levels to within 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%, or within 50% (e.g., within 105-333 IU / L (International Units per Liter)) of the normal level range, or within what is considered the ULN level. In one embodiment, the patient's LDH level is ≧1.5 times the ULN (LDH≧1.5×ULN) before initiating treatment.

[0180] In one embodiment, a patient treated according to the disclosed methods experiences a 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% LDH percent change compared to baseline.

[0181] 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. In one embodiment, for example, the treatment regimen is sufficient to maintain a particular serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof. 15, 220, 225, 230, 240, 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, 400, 405 , 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 5 maintains serum trough concentrations of the anti-C5 antibody or antigen-binding fragment thereof of 80, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700 μg / mL or greater. In one embodiment, the treatment regimen maintains serum trough concentrations of the anti-C5 antibody or antigen-binding fragment thereof of ≥100 μg / mL, ≥150 μg / mL, ≥200 μg / mL, ≥250 μg / mL, ≥300 μg / mL, ≥350 μg / mL, ≥400 μg / mL, or ≥450 μg / mL. In another embodiment, treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof between 100 μg / mL and 700 μg / mL; preferably between 300 μg / mL and 600 μg / mL. In another embodiment, treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof between about 475 μg / mL.In one embodiment, the treatment regimen comprises about 1800, 1780, 1760, 1740, 1720, 1700, 1680, 1660, 1640, 1620, 1600, 1580, 1560, 1540, 1520, 1500, 1480, 1460, 1440, 1420, 1400, 1380, 1360, 1340, 1320, 1 The peak serum concentration of the anti-C5 antibody or antigen-binding fragment thereof is maintained at or below 300, 1280, 1260, 1240, 1220, 1200, 1180, 1160, 1140, 1120, 1100, 1080, 1060, 1040, 1020, 1000, 980, 960, 940, 920, or 900 μg / mL. In embodiments, treatment maintains a peak serum concentration of the anti-C5 antibody or antigen-binding fragment thereof between 900 μg / mL and 1800 μg / mL; preferably between 1050 μg / mL and 1550 μg / mL. In another embodiment, treatment maintains a peak serum concentration of the anti-C5 antibody or antigen-binding fragment thereof at about 1350 μg / mL.

[0182] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the patient 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, 155 μg, 160 μg, 165 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg, 200 μg, 210 μg, 220 μg, 230 μg, 240 μg, 250 μg, 260 μg, 270 μg, 280 μg, 290 μg, 300 μg, 310 μg, 320 μg, 330 μg, 340 μg, 350 μg, 360 μg, 370 μg, 380 μg, 390 μg, 400 μg, 410 μg, 420 μg, 430 μg, 440 μg, 450 μg, 460 μg, 470 μg, 480 μg, 490 μg, 500 μg, 510 μg, 520 μg, 530 μg, 540 μg, 550 μg, 560 μg, 570 μg, 580 μg, 590 μg, 600 μg, 610 μg, μg, 140μg, 145μg, 150μg, 155μg, 160μg, 165μg, 170μg, 175μg, 180μg, 185μg, 190μg, 195μg g, 200μg, 205μg, 210μg, 215μg, 220μg, 225μg, 230μg, 235μg, 240μg, 245μg, 250μg, 255μg , 260μg, 270μg, 280μg, 290μg, 300μg, 320μg, 340μg, 360μg, 380μg, 400μg, 420μg, 440μg , 460μg, 480μg, 500μg, 550μg, 600μg, 650μg, 700μg, 750μg, 800μg, 850μg, 900μg, 950μg, It is administered in an amount and frequency to maintain 1000 μg, 1050 μg, 1100 μg, 1150 μg, 1200 μg, 1250 μg, 1300 μg, 1350 μg, 1400 μg, 1450 μg, 1500 μg, 1550 μg, 1600 μg, 1650 μg, 1700 μg, 1750 μg or more, for example, 1800 μg of antibody.

[0183] In embodiments, to obtain an effective response, the anti-C5 antibody (e.g., ravulizumab) is administered to the patient in an amount and frequency to maintain minimum and maximum plasma concentrations (±standard deviation) of the anti-C5 antibody (e.g., ravulizumab) during the dosing interval, which are preferably between 474 (±200) μg / mL and 1350 (±430) μg / mL, respectively.

[0184] In one embodiment, a patient treated according to the disclosed methods has a free C5 concentration of 0.5 μg / mL or less (e.g., 0.4 μg / mL, 0.3 μg / mL, 0.2 μg / mL, or 0.1 μg / mL or less).

[0185] In another embodiment, a patient treated according to the disclosed methods achieves immediate, complete, and sustained terminal complement inhibition.

[0186] VI. Kits and Unit Dosage Forms Also provided herein is a kit containing a pharmaceutical composition containing an anti-C5 antibody or antigen-binding fragment thereof, e.g., ravulizumab, and a pharmaceutically acceptable carrier in a therapeutically effective amount adapted for use in the aforementioned method. The kit may also optionally contain instructions, including, for example, an administration schedule, to enable a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to a patient with HSCT-TMA. The kit may also include a syringe.

[0187] 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 method provided above. The kit may also include an instrument or device necessary for administering the pharmaceutical composition. For example, the kit may provide one or more pre-filled syringes containing a certain amount of an anti-C5 antibody or an antigen-binding fragment thereof.

[0188] In one embodiment, a kit for treating HSCT-TMA in a human pediatric patient includes (a) a dose of an anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 12 and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 8, and (b) instructions for using the anti-C5 antibody or antigen-binding fragment thereof according to any of the methods described herein.

[0189] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 5 kg to <10 kg, (a) 600 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 300 mg on day 15 and every 4 weeks thereafter; and (e) Administered in a supplemental dose of 300 mg with instructions that the supplemental dose be administered to patients receiving an RBC transfusion within 2 weeks of the maintenance dose, with this supplemental dose being administered 2 weeks after the maintenance dose.

[0190] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 5 kg to <10 kg, (a) 600 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 400 mg on day 15 and every 4 weeks thereafter; and (e) Administered in a supplemental dose of 400 mg with instructions that the supplemental dose be administered to patients receiving an RBC transfusion within 2 weeks of the maintenance dose, with this supplemental dose being administered 2 weeks after the maintenance dose.

[0191] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 10 kg to <20 kg. (a) 600 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 600 mg on day 15 and every 4 weeks thereafter; and (e) Administered in a supplemental dose of 600 mg with instructions that the supplemental dose be administered to patients receiving an RBC transfusion within 2 weeks of the maintenance dose, with this supplemental dose being administered 2 weeks after the maintenance dose.

[0192] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 10 kg to <20 kg. (a) 600 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 800 mg on day 15 and every 4 weeks thereafter; and (e) An 800 mg supplemental dose with instructions that the supplemental dose be administered to patients who receive an RBC transfusion within 2 weeks of the maintenance dose, the supplemental dose being administered 2 weeks after the maintenance dose.

[0193] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 20 kg to <30 kg. (a) 900 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 2100 mg on day 15 and every 8 weeks thereafter; and (e) Administered at a supplemental dose of 2100 mg with instructions that the supplemental dose be administered to patients receiving an RBC transfusion within 4 weeks of the maintenance dose, with this supplemental dose being administered 4 weeks after the maintenance dose.

[0194] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 30 kg to < 40 kg. (a) 1200 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 2700 mg on day 15 and every 8 weeks thereafter; and (e) administered at a supplemental dose of 2700 mg according to instructions that the supplemental dose be administered to a patient receiving an RBC transfusion within 4 weeks of the maintenance dose, with the supplemental dose being administered 4 weeks after the maintenance dose.

[0195] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 40 kg to < 60 kg. (a) 2400 mg loading dose once on day 1; (b) a loading dose of 600 mg once on day 5; (c) a loading dose of 600 mg once on day 10; (d) a maintenance dose of 3000 mg on day 15 and every 8 weeks thereafter; and (e) administered at a supplemental dose of 3000 mg according to instructions that the supplemental dose be administered to a patient receiving an RBC transfusion within 4 weeks of the maintenance dose, with the supplemental dose being administered 4 weeks after the maintenance dose.

[0196] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 60 kg to < 100 kg. (a) 2700 mg loading dose once on day 1; (b) a loading dose of 900 mg once on day 5; (c) a loading dose of 900 mg once on day 10; and (d) a maintenance dose of 3300 mg on day 15 and every 8 weeks thereafter; and (e) administered at a supplemental dose of 3300 mg according to instructions that the supplemental dose be administered to a patient receiving an RBC transfusion within 4 weeks of the maintenance dose, with the supplemental dose being administered 4 weeks after the maintenance dose.

[0197] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 100 kg, (a) 3000 mg loading dose once on day 1; (b) a loading dose of 900 mg once on day 5; (c) a loading dose of 900 mg once on day 10; and (d) a maintenance dose of 3600 mg on day 15 and every 8 weeks thereafter; and (e) administered at a supplemental dose of 3600 mg according to instructions that the supplemental dose be administered to a patient receiving an RBC transfusion within 4 weeks of the maintenance dose, with the supplemental dose being administered 4 weeks after the maintenance dose.

[0198] The following examples are merely illustrative and should not be construed as limiting the scope of the disclosure in any way, as numerous variations and equivalents will become apparent to those skilled in the art upon reading this disclosure. The contents of all references, GENBANK entries, patents and published patent applications cited throughout this application are expressly incorporated herein by reference. [Example]

[0199] Example 1: Dose-Finding Analysis of Ravulizumab in a Global Phase 3 Study to Evaluate Pharmacokinetics / Pharmacodynamics in Adults and Adolescents with Thrombotic Microangiopathy After Hematopoietic Stem Cell Transplantation A pharmacokinetic-pharmacodynamic (PK-PD) analysis was performed to confirm the ravulizumab dosing regimen used to treat patients with HSCT-TMA in a Phase 3 study, which is described in WO 2022 / 036151, the contents of which are expressly incorporated herein by reference. Additionally, a novel supplemental dosing regimen was administered in this study for patients who received platelet or RBC transfusions during treatment.

[0200] Stage 1 of the Phase 3 study of ULTOMIRIS for the treatment of adults and adolescents (age ≥ 12 years) with HSCT-TMA (NCT04543591) was an open-label, single-arm period designed to confirm the ULTOMIRIS dosing regimen. Participants received weight-based loading doses on days 1, 5, and 10, followed by maintenance doses on day 15 and every 8 weeks thereafter. Supplemental doses were given within 24 hours after any platelet or red blood cell (RBC) transfusion. There was no limit on the number of supplemental doses. Blood samples for analysis were collected during the treatment period. A dose confirmation analysis (DCA) was performed once at least the first 10 patients enrolled had completed day 21.

[0201] DCA included three steps. Step 1: PK and free C5 (primary PD) data were visualized. Using a previously established threshold indicating complete C5 inhibition, we empirically confirmed that the dosing regimen resulted in appropriate ravulizumab concentrations and provided immediate, complete, and sustained inhibition of free C5. Step 2: Population pharmacokinetic (popPK) modeling of ravulizumab concentration-time data. Body weight and transfusions were applied to a previously developed aHUS popPK model to individualize predicted exposure for each patient with HSCT-TMA and evaluate the impact of these factors from the patient population level. Standard assessments were used for model qualification. Step 3: Simulations were performed to confirm / adjust the ravulizumab dosing regimen, including transfusion-related supplemental doses, using the qualified popPK model. Monte Carlo simulations of concentration-time profiles were performed to evaluate whether randomly generated exposures (based on population variability of PK parameters) remained above the PK threshold, thus ensuring complete terminal complement inhibition.

[0202] A total of 361 PK observations from 14 patients were included in the empirical evaluation (Figures 1 and 2), revealing that both PK and PD thresholds were met using the protocol dosing regimen. Additionally, Figure 2 shows that the loading doses on days 5 and 10 adequately managed the high baseline levels of complement complexes while maintaining ULTOMIRIS concentrations >175 μg / mL. A qualified popPK model adequately characterized the dose-concentration relationship. Furthermore, it was determined that faster clearance occurred after RBC transfusion. Taking this into account, the simulation focused on adjusting / optimizing transfusion-related replacement dosing of ULTOMIRIS.

[0203] Simulation confirmed that the supplemental dosing regimen could be updated so that patients weighing ≥ 30 kg who received an RBC transfusion 4 weeks after the maintenance dose received a supplemental dose of ULTOMIRIS 4 weeks after the maintenance dose. The dose simulation predicted mean (standard deviation) minimum and maximum concentrations during the dosing interval to be 474 (200) μg / mL and 1350 (430) μg / mL, respectively. The updated dosing regimen is summarized in Table 1. The post-transfusion supplemental dosing schedule is listed in Table 2. Actions to be taken if one or more RBC transfusions occur are outlined in Table 3.

[0204] [Table 1] a Weight-based dosing was based on the patient's weight recorded on the day of the infusion visit. If the weight on the day of the infusion was not available, the weight recorded during the previous study visit was used. b Participants weighing ≥30 kg who received any red blood cell transfusions 4 weeks after the maintenance dose were administered a supplemental dose of ULTOMIRIS 4 weeks after the maintenance dose. No supplemental medication was required during the loading phase or after platelet transfusions. Q8W, every 8 weeks.

[0205] [Table 2]

[0206] [Table 3]

[0207] This thorough DCA confirmed that the updated supplemental ULTOMIRIS dosing regimen achieved immediate, complete, and sustained terminal complement inhibition, and is therefore optimized for use in Stage 2 (double-blind, randomized, placebo-controlled period) of a Phase 3 study of ULTOMIRIS efficacy and safety in HSCT-TMA.

[0208] Example 2: Dosing Regimen for Patients Weighing Less than 30 kg A PK-PD analysis was performed to confirm the ravulizumab dosing regimen used to treat patients with HSCT-TMA in a Phase 3 study, substantially as described in Example 1 and WO 2022 / 036151 above. In this study, a supplemental dosing regimen was administered to patients weighing less than 30 kg who received platelet or RBC transfusions during treatment. The post-transfusion supplemental dosing schedule is listed in Table 4.

[0209] [Table 4]

[0210] Ten patients were evaluated for a possible dose-confirming analysis (DCA). One of the ten patients was unevaluable. Two of the patients had frequent RBC transfusions (referred to as "high ravulizumab clearance"). Seven patients had PK >175 mcg / mL during treatment (referred to as "infrequent RBC transfusions").

[0211] The initial DCA was unsuccessful for 9 / 9 patients (<175 mcg / mL). However, further investigation determined that "high ULTOMIRIS clearance" patients were the cause of the unsuccessful DCA. After removing these two dose-unconfirmed patients (22%), DCA confirmed the dose for the remaining 7 / 9 patients. However, patients weighing <30 kg may benefit more from a modified dosing regimen, as it is impossible to know when a patient may become a "high ULTOMIRIS clearance" patient.

[0212] Example 3: Modified Dosing Regimen for Patients Weighing Less than 30 kg In Example 2, the dosing regimen shown in Table 4 was confirmed for 7 / 9 patients (22%). However, it was determined that certain patients weighing <30 kg with frequent RBC transfusions (high ravulizumab clearance patients weighing <30 kg) may not maintain the target trough level (175 mcg / mL) and therefore may not achieve full C5 inhibition. Therefore, this particular patient group may further benefit from a modified dosing regimen. Therefore, a modified dosing regimen as shown in Table 5 is evaluated in this patient group substantially according to the methods described in Examples 1-2 and WO 2022 / 036151, with the modifications described.

[0213] [Table 5]

[0214] For all patients, the need for a supplemental dose of ULTOMIRIS after RBC transfusion will be assessed when the patient reaches the midpoint between maintenance doses as shown in Table 6. For participants weighing ≥ 30 kg, a supplemental dose after RBC transfusion will be administered if the participant has received at least one RBC transfusion since the last maintenance dose. For participants weighing < 20 kg or weighing ≥ 20 kg to < 30 kg, the need for supplemental medication after RBC transfusion will be assessed according to the clinical algorithm.

[0215] [Table 6] * Supplemental doses will be administered within the same window for each weight category. If supplemental dosing is required concurrently with a scheduled study visit, the dose can be administered at that visit.

[0216] If the RBC transfusion day frequency exceeds 3.5 days / week (i.e., the threshold when >10% of patients have trough levels <175 mcg / mL), a modified dosing regimen triggers the clinical algorithm. Specifically, the clinical algorithm monitors the number of RBC transfusion days (days with at least one RBC transfusion) and clinical deterioration. Previously, investigators only assessed whether participants had received at least one RBC transfusion since their last maintenance dose. A modified dosing regimen is proposed to increase both the maintenance and supplemental doses to alleviate the problem. The clinical algorithm is shown in Figure 3 and summarized in Table 7.

[0217] [Table 7] For all participants, if no RBC transfusions are administered, no supplemental medications are required.

[0218] For patients who demonstrate clinical deterioration, supplemental doses of ULTOMIRIS are permitted during treatment after the first maintenance dose on day 15. Clinical deterioration is defined as meeting two or more of the following criteria: 1. Doubling of serum creatinine from baseline or new need for dialysis; 2. Increase in LDH >25% compared with baseline; 3. >25% platelet decrease compared to baseline; 4. A decrease in hemoglobin of >10% compared to baseline; and / or 5. Increased need for platelets or RBCs at any given time. The criteria for clinical deterioration are confirmed by two independent samples taken at least 8 hours apart (ideally 24 hours apart).

[0219] Supplemental dosing regimens according to the present disclosure are summarized in Table 8 below.

[0220] [Table 8]

[0221] Minimum assessments performed during any supplemental dosing visit where ULTOMIRIS is administered include a urine pregnancy test, pre-dose PK / PD blood draw, and vital signs.

[0222] Array Overview

[0223] [Table 11-1]

[0224] [Table 11-2]

[0225] [Table 11-3]

[0226] [Table 11-4]

Claims

1. 1. A method of treating a human patient with hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), the method comprising administering to the patient an effective amount 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, wherein the anti-C5 antibody or antigen-binding fragment thereof is (a) a loading dose of 600 mg for patients weighing 5 kg to <10 kg, 600 mg for patients weighing 10 kg to <20 kg, 900 mg for patients weighing 20 kg to <30 kg, 1200 mg for patients weighing ≥30 kg to <40 kg, 2400 mg for patients weighing ≥40 kg to <60 kg, 2700 mg for patients weighing ≥60 kg to <100 kg, or 3000 mg for patients weighing ≥100 kg once on day 1; (b) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg once on day 5; (c) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg once on day 10; and (d) Day 15 and (i) every 4 weeks thereafter at a maintenance dose of 300 mg or 400 mg for patients weighing 5 kg to <10 kg, or 600 mg or 800 mg for patients weighing 10 kg to <20 kg; or (ii) every 8 weeks thereafter at a maintenance dose of 2100 mg for patients weighing 20 kg to <30 kg, 2700 mg for patients weighing ≥ 30 kg to < 40 kg, 3000 mg for patients weighing ≥ 40 kg to < 60 kg, 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg; The supplemental dose is (i) administered to a patient weighing <30 kg who receives a red blood cell (RBC) transfusion within a specified time frame of a maintenance dose, wherein the supplemental dose is administered within a specified time frame after the maintenance dose; a. Administered at a dose of 300 mg or 400 mg to patients weighing 5 kg to <10 kg, and the specified time frame is 2 weeks; or b. Administered at a dose of 600 mg or 800 mg to patients weighing 10 kg to <20 kg, and the specified time frame is 2 weeks; or c. A dose of 2100 mg is administered to patients weighing 20 kg to <30 kg, and the specified time frame is 4 weeks; or (ii) administered to a patient weighing ≥ 30 kg who receives a red blood cell (RBC) transfusion within 4 weeks of a maintenance dose, and the supplemental dose is administered 4 weeks after the maintenance dose; a. 2700 mg dose for patients weighing ≥ 30 kg to < 40 kg; b. 3000 mg dose for patients weighing ≥ 40 kg to < 60 kg; c. at a dose of 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d. A method wherein the dose is 3600 mg administered to a patient weighing ≧100 kg.

2. 2. The method of claim 1, wherein the C5 antibody, or antigen-binding fragment thereof, further comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), and the variant human Fc constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, according to EU numbering, of a native human IgG Fc constant region.

3. 3. The method of claim 1 or 2, wherein the anti-C5 antibody 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.

4. The method of any one of claims 1 to 3, wherein the anti-C5 antibody further comprises a heavy chain constant region set forth in SEQ ID NO:

13.

5. The method of any one of claims 1 to 4, wherein the antibody comprises a heavy chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 14 and a light chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO:

11.

6. The anti-C5 antibody has a K Ｄ Affinity dissociation constants (K) in the range of ≦1 nM (e.g., about 0.5 nM) Ｄ The method according to any one of claims 1 to 5, wherein the antibody binds to human C5 via the antibody.

7. The anti-C5 antibody is K Ｄ The method of any one of claims 1 to 6, wherein the antibody binds to human C5 with a binding affinity of ≧10 nM (e.g., about 22 nM).

8. The anti-C5 antibody is administered to a patient weighing 5 kg to <10 kg, (a) a loading dose of 600 mg once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 300 mg on day 15 and every 4 weeks thereafter; and (e) A supplemental dose of 300 mg is administered to patients who receive an RBC transfusion within two weeks of a maintenance dose, said supplemental dose being administered two weeks after said maintenance dose.

9. The anti-C5 antibody is administered to a patient weighing 5 kg to <10 kg, (a) a loading dose of 600 mg once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 400 mg on day 15 and every 4 weeks thereafter; and (e) A supplemental dose of 400 mg is administered to patients who receive an RBC transfusion within two weeks of a maintenance dose, said supplemental dose being administered two weeks after said maintenance dose.

10. The anti-C5 antibody is administered to a patient weighing 10 kg to <20 kg, (a) a loading dose of 600 mg once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 600 mg on day 15 and every 4 weeks thereafter; and (e) A supplemental dose of 600 mg is administered to patients who receive an RBC transfusion within two weeks of a maintenance dose, said supplemental dose being administered two weeks after said maintenance dose.

11. The anti-C5 antibody is administered to a patient weighing 10 kg to <20 kg, (a) a loading dose of 600 mg once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 800 mg on day 15 and every 4 weeks thereafter; and (e) A supplemental dose of 800 mg is administered to patients who receive an RBC transfusion within two weeks of a maintenance dose, said supplemental dose being administered two weeks after said maintenance dose.

12. The anti-C5 antibody is administered to a patient weighing 20 kg to <30 kg, (a) 900 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 2100 mg on day 15 and every 8 weeks thereafter; and (e) A supplemental dose of 2100 mg is administered to patients who receive an RBC transfusion within 4 weeks of a maintenance dose, said supplemental dose being administered 4 weeks after said maintenance dose.

13. 13. The method of any one of claims 8 to 12, wherein the supplemental dose is administered when warranted by the clinical algorithm described in Figure 3.

14. The anti-C5 antibody is administered to a patient weighing ≥ 30 kg to < 40 kg, (a) 1200 mg loading dose once on day 1; (b) a loading dose of 300 mg once on day 5; (c) a loading dose of 300 mg once on day 10; (d) a maintenance dose of 2700 mg administered on day 15 and every 8 weeks thereafter.

15. 15. The method of claim 14, wherein the patient receives a red blood cell (RBC) transfusion within 4 weeks of the maintenance dose, and then receives a supplemental dose of 2700 mg 4 weeks after the maintenance dose.

16. The anti-C5 antibody is administered to a patient weighing ≧40 kg to <60 kg, (a) 2400 mg loading dose once on day 1; (b) a loading dose of 600 mg once on day 5; (c) a loading dose of 600 mg once on day 10; and (d) a maintenance dose of 3000 mg administered on day 15 and every 8 weeks thereafter.

17. 17. The method of claim 16, wherein the patient receives a red blood cell (RBC) transfusion within 4 weeks of the maintenance dose, and then receives a supplemental dose of 3000 mg 4 weeks after the maintenance dose.

18. The anti-C5 antibody is administered to a patient weighing ≥ 60 kg to < 100 kg, (a) 2700 mg loading dose once on day 1; (b) a loading dose of 900 mg once on day 5; (c) a loading dose of 900 mg once on day 10; and (d) a maintenance dose of 3300 mg administered on day 15 and every 8 weeks thereafter.

19. 20. The method of claim 18, wherein the patient receives a red blood cell (RBC) transfusion within 4 weeks of the maintenance dose, and then receives a supplemental dose of 3300 mg 4 weeks after the maintenance dose.

20. The anti-C5 antibody is administered to a patient weighing ≥ 100 kg, (a) 3000 mg loading dose once on day 1; (b) a loading dose of 900 mg once on day 5; (c) a loading dose of 900 mg once on day 10; and (d) a maintenance dose of 3600 mg administered on day 15 and every 8 weeks thereafter.

21. 21. The method of claim 20, wherein the patient receives a red blood cell (RBC) transfusion within 4 weeks of the maintenance dose, and then receives a supplemental dose of 3600 mg 4 weeks after the maintenance dose.

22. 22. The method of any one of claims 1-21, wherein the treatment maintains a serum trough concentration of the C5 antibody of 175 μg / mL or greater.

23. 23. The method of any one of claims 1 to 22, wherein the treatment maintains a serum trough concentration of the C5 antibody of 200 μg / mL or greater.

24. The method of any one of claims 1 to 23, wherein the anti-C5 antibody is formulated for intravenous administration.

25. 25. The method of any one of claims 1 to 24, wherein the treatment is a dosing cycle comprising a total of 26 weeks of treatment.

26. 26. The method of any one of claims 1-25, wherein the treatment results in a reduction or cessation of microangiopathic hemolytic anemia, thrombocytopenia, endothelial damage, renal damage, renal failure, serositis, pulmonary hypertension, and multi-organ failure compared to baseline.

27. The treatment includes (a) a platelet count of ≥ 50,000 / mm without transfusion support in the past 7 days. ３ 27. The method of any one of claims 1 to 26, wherein the method results in (b) LDH<1.5xULN, and (c) the absence of schistocytes (if schistocytes were present at baseline).

28. The treatment includes (a) a platelet count of ≥ 50,000 / mm without transfusion support in the past 7 days. ３ 28. The method of any one of claims 1 to 27, wherein the method results in (b) LDH<1.5xULN, (c) absence of schistocytes (if schistocytes were present at baseline), and (d) at least a 50% reduction in proteinuria from baseline.

29. 29. The method of any one of claims 1 to 28, wherein the treatment results in a favorable hematological response.

30. 30. The method of any one of claims 1 to 29, wherein the treatment results in normalization of LDH, elimination of the need for red blood cell and platelet transfusions, and elimination of schistocytes.

31. wherein the treatment 31. The method of any one of claims 1 to 30, which results in hemoglobin > 8 g / dL without transfusion support.

32. 32. The method of any one of claims 1 to 31, wherein the treatment results in a decrease in LDH, an increase in platelets, and / or an increase in hemoglobin compared to baseline.

33. 33. The method of any one of claims 1 to 32, wherein the treatment results in a normal level of serum creatinine compared to baseline.

34. 34. The method of any one of claims 1-33, wherein the treatment results in an improvement in TMA-associated organ dysfunction in the renal, cardiovascular, pulmonary, CNS, and / or GI systems compared to baseline.

35. 35. The method of any one of claims 1 to 34, wherein the treatment results in terminal complement inhibition.

36. 36. The method of any one of claims 1 to 35, wherein the treatment results in a reduction in adverse events.

37. 37. The method of any one of claims 1 to 36, wherein the treatment results in a shift to normal levels of biomarkers associated with vascular inflammation (e.g., shed tumor necrosis factor receptor 1 [TNF-R1]), biomarkers associated with endothelial injury and / or activation (e.g., thrombomodulin and shed vascular cell adhesion molecule 1 [VCAM-1]), biomarkers associated with renal injury (e.g., cystatin C), and / or complement proteins and complement activation pathway products.

38. 38. The method of any one of claims 1 to 37, wherein the treatment results in a shift to normal levels of thrombomodulin (TM) and / or syndecan-1 (SYND1), and optionally complement factor Ba.

39. 39. The method of any one of claims 1-38, wherein the treatment results in a change from baseline in quality of life as assessed via a quality of life assessment.

40. 40. The method of any one of claims 1 to 39, wherein the quality of life assessment is the Quality of Life Inventory (PedsQL) scale or the EQ-5D-5L questionnaire.

41. 41. The method of any one of claims 1 to 40, wherein the treatment results in a decrease in lactate dehydrogenase (LDH) levels compared to baseline.

42. 42. The method of any one of claims 1 to 41, wherein the treatment results in a reduction in free C5 levels or a reduction in red blood cell (RBC) hemolysis in the patient, in particular, the treatment results in a free C5 level of 0.5 μg / mL or less and / or RBC hemolysis of 20% or less compared to an untreated patient.

43. The method according to any one of claims 1 to 42, wherein the human patient is a pediatric or adult patient, preferably a pediatric patient.

44. The method of any one of claims 1 to 43, wherein the human patient is an RBC transfusion patient, preferably a patient who received an RBC transfusion during the maintenance dosing phase of treatment with the anti-C5 antibody.

45. 45. The method of any one of claims 1 to 44, further comprising administering one or more best supportive care (BSC) measures.

46. 46. ​​The method of claim 45, wherein the one or more BSC measures are selected from the group consisting of transfusion support, corticosteroids, dialysis, and antihypertensive drugs.

47. 1. A kit for treating hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA) in a human patient who underwent an RBC transplant during the first half of a maintenance phase of treatment with an anti-C5 antibody or antigen-binding fragment thereof, the kit comprising: (a) loading doses, maintenance doses, and supplemental doses of an anti-C5 antibody, or antigen-binding fragment thereof, comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 8; (b) instructions for using the anti-C5 antibody or antigen-binding fragment thereof in the method of any one of claims 1 to 46.

48. 1. An anti-C5 antibody, or antigen-binding fragment thereof, for use in treating a patient with HSCT-TMA who received an RBC transfusion during the first half of the maintenance phase of treatment, wherein the anti-C5 antibody, or antigen-binding fragment thereof, comprises: (a) a loading dose of 600 mg for patients weighing 5 kg to <10 kg, 600 mg for patients weighing 10 kg to <20 kg, 900 mg for patients weighing 20 kg to <30 kg, 1200 mg for patients weighing ≥30 kg to <40 kg, 2400 mg for patients weighing ≥40 kg to <60 kg, 2700 mg for patients weighing ≥60 kg to <100 kg, or 3000 mg for patients weighing ≥100 kg once on day 1; (b) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg once on day 5; (c) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg once on day 10; and (d) Day 15 and (i) every 4 weeks thereafter at a maintenance dose of 300 mg or 400 mg for patients weighing 5 kg to <10 kg, or 600 mg or 800 mg for patients weighing 10 kg to <20 kg; or (ii) every 8 weeks thereafter at a maintenance dose of 2100 mg for patients weighing 20 kg to <30 kg, 2700 mg for patients weighing ≥ 30 kg to < 40 kg, 3000 mg for patients weighing ≥ 40 kg to < 60 kg, 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg; The supplemental dose is (i) administered to a patient weighing <30 kg who receives a red blood cell (RBC) transfusion within the designated time frame of a maintenance dose, wherein the supplemental dose is administered within the designated time frame; a. Administered at a dose of 300 mg or 400 mg to patients weighing 5 kg to <10 kg, and the specified time frame is 2 weeks; or b. Administered at a dose of 600 mg or 800 mg to patients weighing 10 kg to <20 kg, and the specified time frame is 2 weeks; or c. A dose of 2100 mg is administered to patients weighing 20 kg to <30 kg, and the specified time frame is 4 weeks; or (ii) administered to a patient weighing ≥ 30 kg who receives a red blood cell (RBC) transfusion within 4 weeks of a maintenance dose, and the supplemental dose is administered 4 weeks after the maintenance dose; a. 2700 mg dose for patients weighing ≥ 30 kg to < 40 kg; b. 3000 mg dose for patients weighing ≥ 40 kg to < 60 kg; c. at a dose of 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d. An anti-C5 antibody, or antigen-binding fragment thereof, administered at a dose of 3600 mg to a patient weighing ≧100 kg.

49. 1. Use of an anti-C5 antibody, or an antigen-binding fragment thereof, for the treatment of a patient with HSCT-TMA who received an RBC transfusion during the first half of the maintenance phase of treatment, wherein the anti-C5 antibody, or an antigen-binding fragment thereof, (a) a loading dose of 600 mg for patients weighing 5 kg to <10 kg, 600 mg for patients weighing 10 kg to <20 kg, 900 mg for patients weighing 20 kg to <30 kg, 1200 mg for patients weighing ≥30 kg to <40 kg, 2400 mg for patients weighing ≥40 kg to <60 kg, 2700 mg for patients weighing ≥60 kg to <100 kg, or 3000 mg for patients weighing ≥100 kg once on day 1; (b) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg once on day 5; (c) a loading dose of 300 mg for patients weighing 5 kg to <10 kg, 300 mg for patients weighing 10 kg to <20 kg, 300 mg for patients weighing 20 kg to <30 kg, 300 mg for patients weighing ≥30 kg to <40 kg, 600 mg for patients weighing ≥40 kg to <60 kg, 900 mg for patients weighing ≥60 kg to <100 kg, or 900 mg for patients weighing ≥100 kg once on day 10; and (d) Day 15 and (i) every 4 weeks thereafter at a maintenance dose of 300 mg or 400 mg for patients weighing 5 kg to <10 kg, or 600 mg or 800 mg for patients weighing 10 kg to <20 kg; or (ii) every 8 weeks thereafter at a maintenance dose of 2100 mg for patients weighing 20 kg to <30 kg, 2700 mg for patients weighing ≥ 30 kg to < 40 kg, 3000 mg for patients weighing ≥ 40 kg to < 60 kg, 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg; The supplemental dose is (i) administered to a patient weighing <30 kg who receives a red blood cell (RBC) transfusion within the designated time frame of a maintenance dose, wherein the supplemental dose is administered within the designated time frame; a. Administered at a dose of 300 mg or 400 mg to patients weighing 5 kg to <10 kg, and the specified time frame is 2 weeks; or b. Administered at a dose of 600 mg or 800 mg to patients weighing 10 kg to <20 kg, and the specified time frame is 2 weeks; or c. A dose of 2100 mg is administered to patients weighing 20 kg to <30 kg, and the specified time frame is 4 weeks; or (ii) administered to a patient weighing ≥ 30 kg who receives a red blood cell (RBC) transfusion within 4 weeks of a maintenance dose, and the supplemental dose is administered 4 weeks after the maintenance dose; a. 2700 mg dose for patients weighing ≥ 30 kg to < 40 kg; b. 3000 mg dose for patients weighing ≥ 40 kg to < 60 kg; c. at a dose of 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d. Use administered at a dose of 3600 mg to patients weighing ≥ 100 kg.

50. 49. The anti-C5 antibody, or antigen-binding fragment thereof, of claim 48, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is ravulizumab (ULTOMIRIS®).

51. 50. The use of claim 49, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is ravulizumab (ULTOMIRIS®).

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