SUPPLEMENTAL DOSE AND ADMINISTRATION OF ANTI-C5 ANTIBODIES FOR THE TREATMENT OF HEmatopoietic STEM CELL GRAFT-ASSOCIATED

Abstract

Provided herein are methods for treating HSCT-TMA in specific subpopulations of patients (e.g., HSCT-TMA patients having a weight of > = 30 kg that receive transfusion (e.g., platelet or red blood cell (RBC) transfusion) in 4 weeks following maintenance of a 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 for administration) according to a specific clinical dosage regimen (e.g., at a specific loading dose, maintenance dose, and supplemental dose, and according to a specific schedule).

Description

[0001] Cross - reference to related applications

[0002] This application claims priority and the benefit of U.S. Provisional Application No. 63 / 404,061, filed on September 6, 2022, and U.S. Provisional Application No. 63 / 440,984, filed on January 25, 2023. The entire contents of the above applications are incorporated herein by reference. Background of the Invention

[0003] Thrombotic microangiopathy (TMA) is a post - transplant complication of hematopoietic stem cell transplantation (HSCT) that can affect 10% to 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 arises via endothelial injury and affects the kidneys and other organs. It is estimated that 30% of patients with HSCT - TMA will exhibit severe disease (Rosenthal et al., J Blood Med 2016; 7:181 - 186), and in these cases, patients with HSCT - TMA develop systemic vascular injury, manifested as kidney injury, serositis, pulmonary hypertension, and multi - system organ failure. It has been reported that the 1 - year survival rate of patients with HSCT - TMA ranges from 18% to 40% (Wanchoo et al., Am J Kidney Dis 2018; 72(6):857 - 865). Severe HSCT - TMA is associated with approximately 80% of long - term morbidity and mortality. Studies have shown that the majority of patients die within 6 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).

[0004] In pediatric patients, HSCT-TMA typically occurs early after allogeneic HSCT, with a median diagnosis 35 to 47 days after HSCT, and 88% to 92% occurring before day +100. However, cases up to 2 years after HSCT have been reported. Autologous recipients may develop HSCT TMA even earlier, with a median of 18 days after HSCT (Dvorak et al., Front Pediatr 2019;7:133).

[0005] Endothelial injury is the basis of the pathogenesis of HSCT-TMA, and dysregulated complement activation may be a consequence of endothelial injury. Risk factors associated with the development of HSCT-TMA, which also trigger 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).

[0006] Currently, there are no approved therapies for treating HSCT-TMA. The main interventions for HSCT-TMA involve excluding inciting agents (e.g., CNIs) and / or treating any triggering disorders (e.g., treating infections) (Dvorak et al., Front Pediatr 2019;7:133); Seaby et al., Pediatr Nephrol 2018;33(9):1489-1500). In some patients, excluding inciting agents and / or treating any related triggering disorders does not reverse HSCT-TMA. Accordingly, one object of the present disclosure is to provide improved methods for treating patients suffering from HSCT-TMA. SUMMARY OF THE INVENTION

[0007] With the present invention, it has been found that HSCT-TMA patients treated with ravulizumab according to a specific clinical dosing regimen (e.g., at a specific loading dose amount and maintenance dose amount and according to a specific dosing schedule), who have received one or more blood transfusions such as platelet or red blood cell (RBC) transfusions, experience faster antibody clearance (e.g., compared to non-transfused patients), such that treating a cohort of transfused HSCT-TMA patients with a supplemental dose of ravulizumab provides a meaningful clinical benefit. Specifically, using a supplemental dosing simulation model, the inventors have determined that delivering a supplemental dose of ravulizumab to achieve mean (standard deviation) minimum and maximum ravulizumab plasma concentrations between 474 (200) μg / mL and 1350 (430) μg / mL, respectively, during the dosing interval provides a more effective treatment for HSCT-TMA patients who have experienced a blood transfusion such as an RBC transfusion during treatment. In particular, as illustrated in a non-limiting example, HSCT patients weighing ≥30 kg who receive any (e.g., one, two, three, or more) RBC transfusions 4 weeks after a maintenance dose are administered a supplemental dose of ravulizumab 4 weeks after that maintenance dose. The supplemental ravulizumab dosing regimen achieves immediate, complete, and sustained terminal complement inhibition. The supplemental dosing regimen is also applied to effectively treat HSCT-TMA patients in lower weight (e.g., <30 kg) and particularly very low weight (e.g., <20 kg, and particularly <10 kg) cohorts.

[0008] In other embodiments, as illustrated in a non-limiting example, HSCT patients weighing <30 kg who receive any (e.g., one, two, three, or more) RBC transfusions within a specific time frame after a maintenance dose (e.g., 2 weeks for patients <20 kg and 4 weeks for patients ≥20 kg (e.g., 20 kg < 30 kg; 30 kg < 40 kg; 40 kg < 60 kg; 60 kg < 100 kg; or ≥100 kg)) are administered a supplemental dose of ravulizumab under that specific time frame after that maintenance dose. The supplemental ravulizumab dosing regimen achieves immediate, complete, and sustained terminal complement inhibition.

[0009] Accordingly, provided herein are methods of treating HSCT-TMA in a specific patient subset (e.g., HSCT-TMA patients ≥30 kg in body weight who receive a blood transfusion (e.g., platelet or RBC transfusion) during the 4 weeks following a maintenance dose), the methods comprising administering to the patient an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered (or for administration) according to a specific clinical dosing regimen (e.g., at a specific loading dose amount, maintenance dose amount, and one or more supplemental dose amounts, and according to a specific schedule). Also provided herein are methods of treating HSCT-TMA in a specific patient subset (e.g., HSCT-TMA patients <30 kg in body weight who receive a blood transfusion (e.g., platelet or RBC transfusion) during the 2 weeks (<20 kg) or 4 weeks (≥20 kg to 30 kg) following a maintenance dose), the methods comprising administering to the patient an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered (or for administration) according to a specific clinical dosing regimen (e.g., at a specific loading dose amount, maintenance dose amount, and one or more supplemental dose amounts, and according to a specific schedule).

[0010] An exemplary anti-C5 antibody is ravulizumab ( ) that comprises a heavy chain and a light chain having the sequences shown in SEQ ID NO: 14 and SEQ ID NO: 11, respectively, or an antigen-binding fragment and variant thereof. In other embodiments, the antibody comprises the heavy chain 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 shown in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of the light chain variable (VL) region of ravulizumab having the sequence shown in SEQ ID NO: 8. In another embodiment, the antibody comprises CDR1, CDR2, and CDR3 heavy chain sequences as shown in SEQ ID NO: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as shown in SEQ ID NO: 4, 5, and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences shown in SEQ ID NO: 12 and SEQ ID NO: 8, respectively. In another embodiment, the antibody comprises a heavy chain constant region as shown in SEQ ID NO: 13.

[0011] 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 the native human IgG Fc constant region, respectively, according to the EU numbering convention.

[0012] In another embodiment, the antibody comprises CDR1, CDR2, and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively, and a variant human Fc constant region that binds to 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 the native human IgG Fc constant region, respectively, according to the EU numbering convention.

[0013] In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the BNJ42 1 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 REGN39 1 8 antibody.

[0014] In another embodiment, the anti-C5 antibody is a biosimilar of eculizumab ( ). For example, in one embodiment, the anti-C5 antibody is, for example, the ABP 959 antibody (manufactured by Amgen Inc., USA), (manufactured by Generium JNC, Russia), SB12 (manufactured by Samsung Bioepis, Incheon, Korea), ISU305 (a biosimilar of eculizumab from ISU Abxis, Korea), Eculizumab biosimilar from CinnaGen of Iran, BCD 148 (Eculizumab biosimilar from Biocad Medical of Quebec, Canada), tesidolumab (manufactured by Novartis), Crovalimab (manufactured by Roche), CAN106 (manufactured by CanBridge Pharmaceuticals of Beihai, China) or Pozelimab (manufactured by Regeneron).

[0015] In another embodiment, the antibody competes with any of the above antibodies for binding to the same epitope on C5. In another embodiment, the antibody has at least about 90% variable region amino acid sequence identity with any of the above antibodies (e.g., at least about 90%, 95% or 99% variable region identity with SEQ ID NO: 12 or SEQ ID NO: 8).

[0016] In another embodiment, the antibody binds to human C5 with an affinity dissociation constant (KD) in the range of 0.1 nM ≤ K D ≤ 1 nM at pH 7.4 and 25 °C. In another embodiment, the antibody binds to human C5 with an affinity dissociation constant (K D ) of approximately 0.5 nM at pH 7.4 and 25 °C. In another embodiment, the antibody binds to human C5 with K D ≥ 10 nM at pH 6.0 and 25 °C. In another embodiment, the antibody binds to human C5 with a K D of approximately 22 nM at pH 6.0 and 25 °C. In yet another embodiment, [(K D ) of the antibody or its antigen-binding fragment for human C5 at pH 6.0 and 25 °C) / (K D ) of the antibody or its antigen-binding fragment for human C5 at pH 7.4 and 25 °C)] of the antibody is greater than 25.

[0017] 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.

[0018] According to the present disclosure, methods for treating HSCT-TMA in patients who have undergone a blood transfusion (e.g., platelet or RBC transfusion) are provided, wherein the anti-C5 antibody (or antigen-binding fragment) of the present disclosure is administered in a dosing cycle that includes a loading dose, followed by a maintenance dose, and a supplemental dose. In an embodiment, the anti-C5 antibody or its antigen-binding fragment is administered as follows: a loading dose is administered once on day 1 (e.g., of the dosing cycle), a loading dose is administered once on day 5 (e.g., of the dosing cycle), a loading dose is administered once on day 10 (e.g., of the dosing cycle), and a maintenance dose is administered once every eight weeks starting on day 15. In another embodiment, the maintenance dose of the anti-C5 antibody or its antigen-binding fragment is administered once every eight weeks (e.g., of the dosing cycle) after treatment for an extended period of up to two years.

[0019] In an embodiment, the anti-C5 antibody or its antigen-binding fragment is administered as follows: a loading dose is administered once on day 1 (e.g., of the dosing cycle), a loading dose is administered once on day 5 (e.g., of the dosing cycle), a loading dose is administered once on day 10 (e.g., of the dosing cycle), and a maintenance dose is administered once every eight weeks starting on day 15, along with a supplemental dose. In one embodiment, a supplemental dose is administered to a patient who receives an RBC transfusion within four weeks of the maintenance dose, wherein the supplemental dose is administered four weeks after the maintenance dose. In another embodiment, a supplemental dose is administered to a patient weighing ≥30 kg who receives an RBC transfusion within four weeks of the maintenance dose, wherein the supplemental dose is administered four weeks after the maintenance dose at the following doses: 2700 mg for patients weighing ≥30 to <40 kg, 3000 mg for patients weighing ≥40 to <60 kg, 3300 mg for patients weighing ≥60 to <100 kg, or 3600 mg for patients weighing ≥100 kg.

[0020] In another embodiment, a method for treating a human patient with HSCT-TMA, preferably a patient with HSCT-TMA who has received an RBC transfusion, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or its antigen-binding fragment, the anti-C5 antibody or its antigen-binding fragment comprising CDR1, CDR2, and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or its antigen-binding fragment is administered as follows:

[0021] (a) On the 1st day, 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;

[0022] (b) On the 5th day, 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;

[0023] (c) On the 10th day, 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; and

[0024] (d) On the 15th day and

[0025] (i) Thereafter, every four weeks, 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, once, or

[0026] (ii) Thereafter, every eight weeks, 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, once;

[0027] And the supplementary dose is administered as follows:

[0028] (i) Administered to patients weighing < 30 kg who receive red blood cell (RBC) transfusions within a specific time frame of the maintenance dose, where the supplementary dose is administered at the following dose under this specific time frame after the maintenance dose:

[0029] a. 300 mg or 400 mg for patients weighing 5 kg to <10 kg, wherein the specific time frame is two weeks,

[0030] b. 600 mg or 800 mg for patients weighing 10 kg to <20 kg, wherein the specific time frame is two weeks, or

[0031] c. 2100 mg for patients weighing 20 kg to <30 kg, wherein the specific time frame is four weeks, or

[0032] (ii) Administering to patients weighing ≥30 kg who receive red blood cell (RBC) transfusions within four weeks of the maintenance dose, wherein the supplemental dose is administered four weeks after the maintenance dose at the following doses:

[0033] a. 2700 mg for patients weighing ≥30 kg to <40 kg,

[0034] b. 3000 mg for patients weighing ≥40 kg to <60 kg,

[0035] c. 3300 mg for patients weighing ≥60 to <100 kg, or

[0036] d. 3600 mg for patients weighing ≥100 kg.

[0037] In another embodiment, there is provided a method of treating a human patient suffering from HSCT-TMA, preferably an HSCT-TMA patient who has received an RBC transfusion, the method comprising administering to the patient an effective amount of an anti-C5 antibody, the anti-C5 antibody comprising CDR1, CDR2, and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively, and a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region contains Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of the native human IgG Fc constant region, each according to the EU numbering convention, wherein the anti-C5 antibody is administered as follows:

[0038] (a) On the first day, 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;

[0039] (b) On the fifth day, 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;

[0040] (c) On the tenth day, 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; and

[0041] (d) On the fifteenth day and

[0042] (i) Thereafter, every four weeks, 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, once, or

[0043] (ii) Thereafter, every eight weeks, 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, once;

[0044] And the supplementary dose is administered as follows:

[0045] (i) Administered to patients weighing <30 kg who receive red blood cell (RBC) transfusions within a specific time frame of the maintenance dose, where the supplementary dose is administered at the following dose under this specific time frame after the maintenance dose:

[0046] a. 300 mg or 400 mg for patients weighing 5 kg to <10 kg, where the specific time frame is two weeks,

[0047] b. 600 mg or 800 mg for patients weighing 10 kg to <20 kg, where the specific time frame is two weeks, or

[0048] c. 2100 mg for patients weighing 20 kg to <30 kg, where the specific time frame is four weeks, or

[0049] (ii) Administer to patients weighing ≥30 kg who receive red blood cell (RBC) transfusions within four weeks of the maintenance dose, where the supplemental dose is administered four weeks after the maintenance dose at the following doses:

[0050] a. 2700 mg for patients weighing ≥30 kg to <40 kg,

[0051] b. 3000 mg for patients weighing ≥40 kg to <60 kg,

[0052] c. 3300 mg for patients weighing ≥60 to <100 kg, or

[0053] d. 3600 mg for patients weighing ≥100 kg.

[0054] In another embodiment, a method of treating a human patient suffering from HSCT-TMA, preferably a patient with HSCT-TMA who has received an RBC transfusion, is provided, the method comprising administering to the patient an effective amount of ravulizumab, where ravulizumab is administered as follows:

[0055] (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 on day 1;

[0056] (b) A loading dose of 300 mg is administered once on day 5 to patients weighing 5 kg to < 10 kg, 300 mg to patients weighing 10 kg to < 20 kg, 300 mg to patients weighing 20 kg to < 30 kg, 300 mg to patients weighing ≥ 30 kg to < 40 kg, 600 mg to patients weighing ≥ 40 kg to < 60 kg, 900 mg to patients weighing ≥ 60 kg to < 100 kg, or 900 mg to patients weighing ≥ 100 kg;

[0057] (c) A loading dose of 300 mg is administered once on day 10 to patients weighing 5 kg to < 10 kg, 300 mg to patients weighing 10 kg to < 20 kg, 300 mg to patients weighing 20 kg to < 30 kg, 300 mg to patients weighing ≥ 30 kg to < 40 kg, 600 mg to patients weighing ≥ 40 kg to < 60 kg, 900 mg to patients weighing ≥ 60 kg to < 100 kg, or 900 mg to patients weighing ≥ 100 kg; and

[0058] (d) On day 15 and

[0059] (i) Thereafter, a maintenance dose of 300 mg or 400 mg is administered once every four weeks to patients weighing 5 kg to < 10 kg or 600 mg or 800 mg to patients weighing 10 kg to < 20 kg, or

[0060] (ii) Thereafter, a maintenance dose of 2100 mg is administered once every eight weeks to patients weighing 20 kg to < 30 kg, 2700 mg to patients weighing ≥ 30 kg to < 40 kg, 3000 mg to patients weighing ≥ 40 kg to < 60 kg, 3300 mg to patients weighing ≥ 60 kg to < 100 kg, or 3600 mg to patients weighing ≥ 100 kg;

[0061] And the supplementary dose is administered as follows:

[0062] (i) It is administered to patients weighing < 30 kg who receive red blood cell (RBC) transfusions within a specific time frame of the maintenance dose, and the supplementary dose is administered at the following dose within this specific time frame after the maintenance dose:

[0063] a. 300 mg or 400 mg to patients weighing 5 kg to < 10 kg, where the specific time frame is two weeks,

[0064] b. 600 mg or 800 mg to patients weighing 10 kg to < 20 kg, where the specific time frame is two weeks, or

[0065] c. 2100 mg for patients weighing 20 kg to < 30 kg, where the specific time frame is four weeks, or

[0066] (ii) Administer to patients weighing ≥ 30 kg who receive red blood cell (RBC) transfusions within four weeks of the maintenance dose, where the supplemental dose is administered four weeks after the maintenance dose at the following doses:

[0067] a. 2700 mg for patients weighing ≥ 30 kg to < 40 kg,

[0068] b. 3000 mg for patients weighing ≥ 40 kg to < 60 kg,

[0069] c. 3300 mg for patients weighing ≥ 60 to < 100 kg, or

[0070] d. 3600 mg for patients weighing ≥ 100 kg.

[0071] And where the treatment results in the LDH level being reduced to within normal levels or reduced to within 50% of the ULN level (e.g., within 105 IU / L - 333 IU / L (international units per liter)), the serum trough concentration of the anti-C5 antibody or its antigen-binding fragment is at least 175 μg / mL or greater, and / or the free C5 concentration is 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).

[0072] In another embodiment, provided is a method of treating a human patient suffering from HSCT-TMA, preferably an HSCT-TMA patient who has received an RBC transfusion, the method comprising administering to the patient an effective amount of an anti-C5 antibody or its antigen-binding fragment, the anti-C5 antibody or its antigen-binding fragment comprising CDR1, CDR2, and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively, where the anti-C5 antibody or its antigen-binding fragment (e.g., ravulizumab) is administered to patients weighing 5 kg to < 10 kg as follows:

[0073] (a) As a single 600 mg loading dose on day 1;

[0074] (b) As a single 300 mg loading dose on day 5;

[0075] (c) As a single 300 mg loading dose on day 10;

[0076] (d) As a single 300 mg maintenance dose on day 15 and every four weeks thereafter; and

[0077] (e) Administer a supplemental dose of 300 mg to a patient who receives an RBC transfusion within a specific time frame of a maintenance dose, wherein the supplemental dose is administered within the specific time frame after the maintenance dose, and wherein the specific time frame is two weeks.

[0078] In another embodiment, there is provided a method of treating a human patient having HSCT-TMA, preferably an HSCT-TMA patient who has received an RBC transfusion, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof, the anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to a patient weighing 5 kg to <10 kg as follows:

[0079] (a) As a single loading dose of 600 mg on Day 1;

[0080] (b) As a single loading dose of 300 mg on Day 5;

[0081] (c) As a single loading dose of 300 mg on Day 10;

[0082] (d) As a maintenance dose of 400 mg on Day 15 and every four weeks thereafter; and

[0083] (e) Administer a supplemental dose of 400 mg to a patient who receives an RBC transfusion within a specific time frame of a maintenance dose, wherein the supplemental dose is administered within the specific time frame after the maintenance dose, and wherein the specific time frame is two weeks.

[0084] In another embodiment, there is provided a method of treating a human patient having HSCT-TMA, preferably an HSCT-TMA patient who has received an RBC transfusion, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof, the anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to a patient weighing 10 kg to <20 kg as follows:

[0085] (a) As a single loading dose of 600 mg on Day 1;

[0086] (b) As a single 300 mg loading dose on day 5;

[0087] (c) As a single 300 mg loading dose on day 10;

[0088] (d) As a single 600 mg maintenance dose on day 15 and every four weeks thereafter, and

[0089] (e) Administering a 600 mg supplemental dose to patients who receive an RBC transfusion within a specific time frame of the maintenance dose, wherein the supplemental dose is administered under the specific time frame after the maintenance dose, and wherein the specific time frame is two weeks.

[0090] In another embodiment, there is provided a method of treating a human patient with HSCT-TMA, preferably an HSCT-TMA patient who has received an RBC transfusion, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof, the anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences as set forth in SEQ ID NO: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NO: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to patients weighing 10 kg to <20 kg as follows:

[0091] (a) As a single 600 mg loading dose on day 1;

[0092] (b) As a single 300 mg loading dose on day 5;

[0093] (c) As a single 300 mg loading dose on day 10;

[0094] (d) As a single 800 mg maintenance dose on day 15 and every four weeks thereafter, and

[0095] (e) Administering an 800 mg supplemental dose to patients who receive an RBC transfusion within a specific time frame of the maintenance dose, wherein the supplemental dose is administered under the specific time frame after the maintenance dose, and wherein the specific time frame is two weeks.

[0096] In another embodiment, a method of treating a human patient with HSCT-TMA, preferably an HSCT-TMA patient who has received an RBC transfusion, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof, the anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to a patient weighing 20 kg to <30 kg as follows:

[0097] (a) As a single 900 mg loading dose on Day 1;

[0098] (b) As a single 300 mg loading dose on Day 5;

[0099] (c) As a single 300 mg loading dose on Day 10;

[0100] (d) As a single 2100 mg maintenance dose on Day 15 and every eight weeks thereafter; and

[0101] (e) Administering a 2100 mg supplemental dose to a patient who receives an RBC transfusion within a specific time frame of the maintenance dose, wherein the supplemental dose is administered under the specific time frame after the maintenance dose, wherein the specific time frame is four weeks.

[0102] In some embodiments, the supplemental dose is administered if necessary according to a clinical algorithm as shown in Figure 3 In some embodiments, the supplemental dose is administered if necessary according to a clinical algorithm as shown in Table 7.

[0103] In another embodiment, a method of treating a human patient with HSCT-TMA, preferably an HSCT-TMA patient who has received an RBC transfusion, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof, the anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences as set forth in SEQ ID NO: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NO: 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 as follows:

[0104] (a) As a single 1200 mg loading dose on Day 1;

[0105] (b) As a single 300 mg loading dose on Day 5;

[0106] (c) once at a loading dose of 300 mg on day 10; and

[0107] (d) once at a maintenance dose of 2700 mg on day 15 and every eight weeks thereafter,

[0108] and wherein the patient receives an RBC transfusion within four weeks of the maintenance dose and then a supplemental dose of 2700 mg is administered to the patient four weeks after the maintenance dose.

[0109] In another embodiment, provided is a method of treating a human patient suffering from HSCT-TMA, preferably an HSCT-TMA patient who has received an RBC transfusion, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof, the anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to patients weighing ≥ 30 kg to < 40 kg as follows:

[0110] (a) once at a loading dose of 1200 mg on day 1;

[0111] (b) once at a loading dose of 300 mg on day 5;

[0112] (c) once at a loading dose of 300 mg on day 10; and

[0113] (d) once at a maintenance dose of 2700 mg on day 15 and every eight weeks thereafter,

[0114] wherein the patient receives an RBC transfusion within four weeks of the maintenance dose and then a supplemental dose of 2700 mg is administered to the patient four weeks after the maintenance dose, and wherein the treatment results in immediate, complete, and sustained terminal complement inhibition.

[0115] In another embodiment, there is provided a method of treating a human patient suffering from HSCT-TMA, preferably an HSCT-TMA patient who has received RBC transfusions, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof, the anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to patients weighing ≥40 kg to <60 kg as follows:

[0116] (a) As a single 2400 mg loading dose on Day 1;

[0117] (b) As a single 600 mg loading dose on Day 5;

[0118] (c) As a single 600 mg loading dose on Day 10; and

[0119] (d) As a single 3000 mg maintenance dose on Day 15 and every eight weeks thereafter,

[0120] and wherein the patient receives an RBC transfusion within four weeks of the maintenance dose and then a 3000 mg supplemental dose is administered to the patient four weeks after the maintenance dose.

[0121] In another embodiment, there is provided a method of treating a human patient suffering from HSCT-TMA, preferably an HSCT-TMA patient who has received RBC transfusions, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof, the anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to patients weighing ≥40 kg to <60 kg as follows:

[0122] (a) As a single 2400 mg loading dose on Day 1;

[0123] (b) As a single 600 mg loading dose on Day 5;

[0124] (c) As a single 600 mg loading dose on Day 10; and

[0125] (d) As a single 3000 mg maintenance dose on Day 15 and every eight weeks thereafter,

[0126] Wherein the patient receives RBC transfusions within four weeks of the maintenance dose, then a 3000 mg supplement is administered to the patient four weeks after the maintenance dose and wherein the treatment results in immediate, complete, and sustained terminal complement inhibition.

[0127] In another embodiment, provided is a method of treating a human patient having HSCT-TMA, preferably an HSCT-TMA patient who has received an RBC transfusion, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof, the anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to patients weighing ≥60 kg to <100 kg as follows:

[0128] (a) As a single 2700 mg loading dose on Day 1;

[0129] (b) As a single 900 mg loading dose on Day 5;

[0130] (c) As a single 900 mg loading dose on Day 10; and

[0131] (d) As a single 3300 mg maintenance dose on Day 15 and every eight weeks thereafter,

[0132] and wherein the patient receives RBC transfusions within four weeks of the maintenance dose, then a 3300 mg supplemental dose is administered to the patient four weeks after the maintenance dose.

[0133] In another embodiment, provided is a method of treating a human patient having HSCT-TMA, preferably an HSCT-TMA patient who has received an RBC transfusion, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof, the anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to patients weighing ≥60 kg to <100 kg as follows:

[0134] (a) As a single 2700 mg loading dose on Day 1;

[0135] (b) As a single 900 mg loading dose on Day 5;

[0136] (c) as a single 900 mg loading dose on day 10; and

[0137] (d) as a single 3300 mg maintenance dose on day 15 and every eight weeks thereafter,

[0138] wherein the patient receives an RBC transfusion within four weeks of the maintenance dose and then a 3300 mg supplement is administered to the patient four weeks after the maintenance dose and wherein the treatment results in immediate, complete, and sustained terminal complement inhibition.

[0139] In another embodiment, there is provided a method of treating a human patient having HSCT-TMA, preferably an HSCT-TMA patient who has received an RBC transfusion, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof, the anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to patients weighing ≥ 100 kg as follows:

[0140] (a) as a single 3000 mg loading dose on day 1;

[0141] (b) as a single 900 mg loading dose on day 5;

[0142] (c) as a single 900 mg loading dose on day 10; and

[0143] (d) as a single 3600 mg maintenance dose on day 15 and every eight weeks thereafter,

[0144] and wherein the patient receives an RBC transfusion within four weeks of the maintenance dose and then a 3600 mg supplemental dose is administered to the patient four weeks after the maintenance dose.

[0145] In another embodiment, there is provided a method of treating a human patient having HSCT-TMA, preferably an HSCT-TMA patient who has received an RBC transfusion, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof, the anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to patients weighing ≥ 100 kg as follows:

[0146] (a) Once at a loading dose of 3000 mg on Day 1;

[0147] (b) Once at a loading dose of 900 mg on Day 5;

[0148] (c) Once at a loading dose of 900 mg on Day 10; and

[0149] (d) Once at a maintenance dose of 3600 mg on Day 15 and every eight weeks thereafter,

[0150] wherein the patient receives an RBC transfusion within four weeks of the maintenance dose and then 3600 mg of supplementation is administered to the patient four weeks after the maintenance dose and wherein the treatment results in immediate, complete, and sustained terminal complement inhibition.

[0151] In some embodiments, where the patient experiences an RBC transfusion within two weeks after the first maintenance dose, the patient receives a post - transfusion supplemental dose of an anti - C5 antibody (e.g., ravulizumab) only at the mid - point between two maintenance doses. Since the maintenance dose is administered every four weeks (Q4W) for some lower - body - weight cohorts (e.g., 20 kg; see Table 8), the post - transfusion supplemental dose of an anti - C5 antibody (e.g., ravulizumab) is administered two weeks after the maintenance dose, e.g., 14 days later.

[0152] In some embodiments, where the patient experiences an RBC transfusion within four weeks after the first maintenance dose, the patient receives a post - transfusion supplemental dose of an anti - C5 antibody (e.g., ravulizumab) only at the mid - point between two maintenance doses. Since the maintenance dose is administered every eight weeks (Q8W), the post - transfusion supplemental dose of an anti - C5 antibody (e.g., ravulizumab) is administered four weeks after the maintenance dose, e.g., 28 days later. In such embodiments, if the patient does not experience any transfusion during the second maintenance dosing phase, no supplemental dose is required during that maintenance dosing cycle. Similarly, if the patient experiences an RBC transfusion during the second half of the second maintenance dosing phase, no supplemental dosing is required during that maintenance dosing cycle. In other words, if the first RBC transfusion occurs more than four weeks after the previous maintenance dose, no post - transfusion supplemental dose is required. Additionally, if the patient receives a transfusion during the loading dose phase, no supplemental dosing is administered.

[0153] In some embodiments of the treatment method of the present disclosure, after a given maintenance dose, the supplemental dosing regimen is continued for up to two weeks for participants with a body weight < 20 kg or four weeks for participants with a body weight ≥ 20 kg until no transfusion is administered.

[0154] According to the treatment methods described herein, if any amount of RBC transfusion is provided to a patient within 2 weeks or 4 weeks after the last maintenance dose, a post-transfusion supplemental dose of an anti-C5 antibody or an antigen-binding fragment thereof (e.g., ravulizumab) is administered once to the HSCT-TMA patient, for example, only 2 weeks (<20 kg patients) or only 4 weeks (≥20 kg patients) after the last maintenance dose.

[0155] In another embodiment, the anti-C5 antibody or an antigen-binding fragment thereof is administered in one or more dosing cycles. In one embodiment, the treatment (e.g., dosing cycle) is at least 26 weeks, at least 52 weeks, at least 1.5 years, at least 2 years.

[0156] In another embodiment, immediate, complete, and sustained terminal complement inhibition is achieved after administration of a supplemental dose of an anti-C5 antibody or an antigen-binding fragment thereof (e.g., ravulizumab).

[0157] In one embodiment, the treatment methods disclosed herein further include administering best supportive care (BSC) measures. BSC measures include, but are not limited to, transfusion support, corticosteroids, dialysis, and antihypertensive drugs.

[0158] 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 the dosing cycle) is two weeks or more from the patient's last dose of eculizumab.

[0159] In another aspect, the treatment regimen is sufficient to maintain a specific serum trough concentration of the anti-C5 antibody or an antigen-binding fragment thereof. In one embodiment, for example, the treatment regimen maintains a serum trough concentration of the anti-C5 antibody or an antigen-binding fragment thereof at 50 μg / mL, 55 μg / mL, 60 μg / mL, 65 μg / mL, 70 μg / mL, 75 μg / mL, 80 μg / mL, 85 μg / mL, 90 μg / mL, 95 μg / mL, 100 μg / mL, 105 μg / mL, 110 μg / mL, 115 μg / mL, 120 μg / mL, 125 μg / mL, 130 μg / mL, 135 μg / mL, 140 μg / mL, 145 μg / mL, 150 μg / mL, 155 μg / mL, 160 μg / mL, 165 μg / mL, 170 μg / mL, 175 μg / mL, 180 μg / mL, 185 μg / mL, 190 μg / mL, 200 μg / mL, 205 μg / mL, 210 μg / mL, 215 μg / mL, 220 μg / mL, 225 μg / mL, 230 μg / mL, 240 μg / mL, 245 μg / mL, 250 μg / mL, 255 μg / mL, 260 μg / mL, 265 μg / mL, 270 μg / mL, 280 μg / mL, 290 μg / mL, 300 μg / mL, 305 μg / mL, 310 μg / mL, 315 μg / mL, 320 μg / mL, 325 μg / mL, 330 μg / mL, 335 μg / mL, 340 μg / mL, 345 μg / mL, 350 μg / mL, 355 μg / mL, 360 μg / mL, 365 μg / mL, 370 μg / mL, 375 μg / mL, 380 μg / mL, 385 μg / mL, 390 μg / mL, 395 μg / mL, 400 μg / mL, 405 μg / mL, 410 μg / mL, 415 μg / mL, 420 μg / mL, 425 μg / mL, 430 μg / mL, 435 μg / mL, 440 μg / mL, 445 μg / mL, 450 μg / mL, 455 μg / mL, 460 μg / mL, 465 μg / mL, 470 μg / mL, 475 μg / mL, 480 μg / mL, 485 μg / mL, 490 μg / mL, 495 μg / mL, 500 μg / mL, 505 μg / mL, 510 μg / mL, 515 μg / mL, 520 μg / mL, 525 μg / mL, 530 μg / mL, 535 μg / mL, 540 μg / mL, 545 μg / mL, 550 μg / mL, 555 μg / mL, 560 μg / mL, 565 μg / mL, 570 μg / mL, 575 μg / mL, 580 μg / mL, 585 μg / mL,590 μg / mL, 595 μg / mL, 600 μg / mL, 605 μg / mL, 610 μg / mL, 615 μg / mL, 620 μg / mL, 625 μg / mL, 630 μg / mL, 635 μg / mL, 640 μg / mL, 645 μg / mL, 650 μg / mL, 655 μg / mL, 660 μg / mL, 665 μg / mL, 670 μg / mL, 675 μg / mL, 680 μg / mL, 685 μg / mL, 690 μg / mL, 695 μg / mL, 700 μg / mL or greater. In one embodiment, the treatment regimen maintains the trough serum concentration of the anti-C5 antibody or antigen-binding fragment thereof at 100 μg / mL or greater, 150 μg / mL or greater, 200 μg / mL or greater, 250 μg / mL or greater, 300 μg / mL or greater, 350 μg / mL or greater, 400 μg / mL or greater, or 450 μg / mL or greater. In another embodiment, the treatment maintains the trough serum 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, the treatment maintains the trough serum concentration of the anti-C5 antibody or antigen-binding fragment thereof at about 475 μg / mL. In one embodiment, the treatment regimen maintains the peak serum concentration of the anti-C5 antibody or antigen-binding fragment thereof at less than about 1800 μg / mL, 1780 μg / mL, 1760 μg / mL, 1740 μg / mL, 1720 μg / mL, 1700 μg / mL, 1680 μg / mL, 1660 μg / mL, 1640 μg / mL, 1620 μg / mL, 1600 μg / mL, 1580 μg / mL, 1560 μg / mL, 1540 μg / mL, 1520 μg / mL, 1500 μg / mL, 1480 μg / mL, 1460 μg / mL, 1440 μg / mL, 1420 μg / mL, 1400 μg / mL, 1380 μg / mL, 1360 μg / mL, 1340 μg / mL, 1320 μg / mL, 1300 μg / mL, 1280 μg / mL, 1260 μg / mL, 1240 μg / mL, 1220 μg / mL, 1200 μg / mL, 1180 μg / mL, 1160 μg / mL, 1140 μg / mL, 1120 μg / mL, 1100 μg / mL, 1080 μg / mL, 1060 μg / mL, 1040 μg / mL, 1020 μg / mL, 1000 μg / mL, 980 μg / mL, 960 μg / mL, 940 μg / mL,920 μg / mL or 900 μg / mL or less. In embodiments, treatment maintains the 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 of about 1350 μg / mL.

[0160] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains 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, 195 μg, 200 μg, 205 μg, 210 μg, 215 μg, 220 μg, 225 μg, 230 μg, 235 μg, 240 μg, 245 μg, 250 μg, 255 μg, 260 μg, 270 μg, 280 μg, 290 μg, 300 μg, 320 μg, 340 μg, 360 μg, 380 μg, 400 μg, 420 μg, 440 μg, 460 μg, 480 μg, 500 μg, 550 μg, 600 μg, 650 μg, 700 μg, 750 μg, 800 μg, 850 μg, 900 μg, 950 μg, 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, such as 1800 μg of the antibody per milliliter of the patient's blood.

[0161] In embodiments, to obtain an effective response, the anti-C5 antibody (e.g., ravulizumab) is administered to the patient in an amount and frequency that maintains the minimum and maximum plasma concentrations (± standard deviation) of the anti-C5 antibody (e.g., ravulizumab) preferably between 474 (±200) μg / mL and 1350 (±430) μg / mL during the dosing interval.

[0162] In another embodiment, to obtain an effective response, an anti-C5 antibody is administered to a patient in an amount and frequency to maintain a minimum free C5 concentration. In one embodiment, for example, the anti-C5 antibody is administered to the patient in an amount and frequency 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).

[0163] The anti-C5 antibody or its antigen-binding fragment can be administered to the patient by any suitable means. In one embodiment, the antibody is formulated for intravenous administration.

[0164] The efficacy of the treatment methods provided herein can be evaluated using any suitable means. In one embodiment, for HSCT-TMA patients, the treatment produces at least one treatment effect selected from the group consisting of: reduction or cessation of microangiopathic hemolytic anemia, thrombocytopenia, endothelial damage, kidney injury, kidney failure, serositis, pulmonary hypertension, and multi-system organ failure, compared to baseline.

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

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

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

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

[0169] and disappearance of schistocytes.

[0170] In another embodiment, the treatment enables the patient to maintain a hemoglobin ≥ 8 g / dL without blood transfusion support. In another embodiment, the treatment results in a hemoglobin ≥ 8 g / dL without blood transfusion support.

[0171] In another embodiment, compared to baseline, the treatment results in a decrease in LDH, an increase in platelets, and / or an increase in hemoglobin.

[0172] In another embodiment, treatment results in normal levels of serum creatinine compared to baseline.

[0173] In another embodiment, treatment results in improvement in TMA-related organ dysfunction in the kidney, cardiovascular, pulmonary, CNS, and / or GI systems compared to baseline.

[0174] In another embodiment, treatment results in terminal complement inhibition.

[0175] In another embodiment, treatment results in a reduction in adverse events.

[0176] In another embodiment, treatment results in a shift of biomarkers related to vascular inflammation (e.g., soluble tumor necrosis factor receptor 1 [TNF-R1]), endothelial injury and / or activation (e.g., thrombomodulin and soluble vascular cell adhesion molecule 1 [VCAM-1]), kidney injury (e.g., cystatin C), and / or complement proteins and complement activation pathway products to normal levels. In another embodiment, treatment results in a shift of thrombomodulin (TM) and / or syndecan-1 (SYND1) to normal levels. In another embodiment, treatment results in a shift of complement factor Ba to normal levels.

[0177] In another embodiment, treatment results in a change in quality of life relative to baseline, as assessed by a quality of life assessment (e.g., Pediatric Quality of Life Inventory (PedsQL) scale or EQ-5D-5L questionnaire).

[0178] In another embodiment, treatment results in a reduction in hemolysis compared to baseline, as assessed by lactate dehydrogenase (LDH) levels. In one embodiment, a patient treated according to the disclosed method experiences a reduction in LDH levels to near normal levels or within 10% or 20% above normal levels (e.g., within 105 IU / L - 333 IU / L (international units per liter)). In another embodiment, the LDH levels of the treated patient normalize throughout the maintenance phase of treatment. In another embodiment, the LDH levels of the treated patient normalize for at least 95% of the time during the maintenance phase of treatment. In another embodiment, the LDH levels of the treated patient normalize for at least 90%, 85%, or 80% of the time during the maintenance phase of treatment. In one embodiment, prior to initiation of treatment, the patient's LDH level is ≥1.5 times the upper limit of normal (LDH > 1.5×ULN).

[0179] In one embodiment, a patient treated according to the disclosed method experiences a decrease in LDH level to within normal levels or to 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 50% below the ULN level (e.g., within 105 IU / L - 333 IU / L (International Units per liter)). In one embodiment, prior to initiation of treatment, the patient's LDH level is ≥ 1.5 - fold the ULN (LDH ≥ 1.5 × ULN).

[0180] In one embodiment, a patient treated according to the disclosed method 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% change in LDH percentage compared to baseline.

[0181] Also provided are kits that include a pharmaceutical composition comprising an anti - C5 antibody or an antigen - binding fragment thereof, such as ravulizumab, in a therapeutically effective amount suitable for use in the methods described herein, and a pharmaceutically acceptable carrier, the pharmaceutical composition being, for example, for effectively treating HSCT - TMA patients who have undergone at least one transfusion, such as a platelet or RBC transfusion. In one embodiment, the kit includes: (a) a dose of an anti - C5 antibody or an antigen - binding fragment thereof that comprises the CDR1, CDR2, and CDR3 domains of the heavy - chain variable region having the sequence shown in SEQ ID NO:12, and the CDR1, CDR2, and CDR3 domains of the light - chain variable region having the sequence shown in SEQ ID NO:8; and (b) instructions for using the anti - C5 antibody or an antigen - binding fragment thereof in the methods described herein.

[0182] In another embodiment, the kit includes a loading dose, a maintenance dose, and a supplemental dose of an anti - C5 antibody or an antigen - binding fragment thereof, wherein the anti - C5 antibody or an antigen - binding fragment thereof is administered to a patient weighing 5 kg to < 10 kg as follows:

[0183] (a) As a single 600 mg loading dose on Day 1;

[0184] (b) As a single 300 mg loading dose on Day 5;

[0185] (c) As a single 300 mg loading dose on Day 10;

[0186] (d) As a single 300 mg maintenance dose on Day 15 and every four weeks thereafter; and

[0187] (e) A 300 mg supplemental dose, and instructions for administering the supplemental dose to patients who receive a red blood cell (RBC) transfusion within two weeks of the maintenance dose, wherein the supplemental dose is administered two weeks after the maintenance dose.

[0188] 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 as follows:

[0189] (a) As a single 600 mg loading dose on Day 1;

[0190] (b) As a single 300 mg loading dose on Day 5;

[0191] (c) As a single 300 mg loading dose on Day 10;

[0192] (d) As a single 400 mg maintenance dose on Day 15 and every four weeks thereafter; and

[0193] (e) A 400 mg supplemental dose, and instructions for administering the supplemental dose to patients who receive an RBC transfusion within two weeks of the maintenance dose, wherein the supplemental dose is administered two 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 10 kg to <20 kg as follows:

[0195] (a) As a single 600 mg loading dose on Day 1;

[0196] (b) As a single 300 mg loading dose on Day 5;

[0197] (c) As a single 300 mg loading dose on Day 10;

[0198] (d) As a single 600 mg maintenance dose on Day 15 and every four weeks thereafter, and

[0199] (e) A supplemental dose of 600 mg, and instructions for administering the supplemental dose to a patient who has received an RBC transfusion within 2 weeks of the maintenance dose, wherein the supplemental dose is administered two weeks after the maintenance dose.

[0200] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient weighing 10 kg to <20 kg as follows:

[0201] (a) As a single loading dose of 600 mg on Day 1;

[0202] (b) As a single loading dose of 300 mg on Day 5;

[0203] (c) As a single loading dose of 300 mg on Day 10;

[0204] (d) As a single maintenance dose of 800 mg on Day 15 and every four weeks thereafter, and

[0205] (e) An 800 mg supplemental dose, and instructions for administering the supplemental dose to a patient who has received an RBC transfusion within 2 weeks of the maintenance dose, wherein the supplemental dose is administered two weeks after the maintenance dose.

[0206] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient weighing 20 kg to <30 kg as follows:

[0207] (a) As a single loading dose of 900 mg on Day 1;

[0208] (b) As a single loading dose of 300 mg on Day 5;

[0209] (c) As a single loading dose of 300 mg on Day 10;

[0210] (d) As a single maintenance dose of 2100 mg on Day 15 and every eight weeks thereafter; and

[0211] (e) A 2100 mg supplemental dose, and instructions for administering the supplemental dose to a patient who has received an RBC transfusion within 4 weeks of the maintenance dose, wherein the supplemental dose is administered four weeks after the maintenance dose.

[0212] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient weighing ≥30 kg to <40 kg as follows:

[0213] (a) As a single loading dose of 1200 mg on Day 1;

[0214] (b) As a single loading dose of 300 mg on Day 5;

[0215] (c) As a single loading dose of 300 mg on Day 10;

[0216] (d) As a single maintenance dose of 2700 mg on Day 15 and every eight weeks thereafter,

[0217] and (e) a supplemental dose of 2700 mg, and instructions for administering the supplemental dose to patients who receive an RBC transfusion within 4 weeks of the maintenance dose, wherein the supplemental dose is administered four weeks after the maintenance dose.

[0218] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or an antigen-binding fragment thereof is administered to patients weighing ≥40 kg to <60 kg as follows:

[0219] (a) As a single loading dose of 2400 mg on Day 1;

[0220] (b) As a single loading dose of 600 mg on Day 5;

[0221] (c) As a single loading dose of 600 mg on Day 10;

[0222] (d) As a single maintenance dose of 3000 mg on Day 15 and every eight weeks thereafter,

[0223] and (e) a supplemental dose of 3000 mg, and instructions for administering the supplemental dose to patients who receive an RBC transfusion within 4 weeks of the maintenance dose, wherein the supplemental dose is administered four weeks after the maintenance dose.

[0224] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or an antigen-binding fragment thereof is administered to patients weighing ≥60 kg to <100 kg as follows:

[0225] (a) As a single loading dose of 2700 mg on Day 1;

[0226] (b) As a single loading dose of 900 mg on Day 5;

[0227] (c) As a single loading dose of 900 mg on Day 10;

[0228] (d) As a single maintenance dose of 3300 mg on Day 15 and every eight weeks thereafter,

[0229] and (e) a supplemental dose of 3300 mg, and instructions for administering the supplemental dose to patients who receive an RBC transfusion within 4 weeks of the maintenance dose, wherein the supplemental dose is administered four weeks after the maintenance dose.

[0230] 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 patients weighing ≥ 100 kg as follows:

[0231] (a) as a single loading dose of 3000 mg on Day 1;

[0232] (b) as a single loading dose of 900 mg on Day 5;

[0233] (c) as a single loading dose of 900 mg on Day 10;

[0234] (d) as a single maintenance dose of 3600 mg on Day 15 and every eight weeks thereafter,

[0235] and (e) a supplemental dose of 3600 mg, and instructions for administering the supplemental dose to patients who receive an RBC transfusion within 4 weeks of the maintenance dose, wherein the supplemental dose is administered four weeks after the maintenance dose.

[0236] In another aspect, there is provided an anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab )) for treating HSCT-TMA patients who have experienced an RBC transfusion during the first half of the maintenance phase of treatment, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered as follows:

[0237] (a) as a single loading dose of 600 mg on Day 1 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;

[0238] (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 on day 5 once;

[0239] (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 on day 10 once; and

[0240] (d) On day 15 and

[0241] (i) Thereafter, 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 once every four weeks, or

[0242] (ii) Thereafter, 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 once every eight weeks;

[0243] And the supplementary dose is administered as follows:

[0244] (i) Administered to patients weighing < 30 kg who receive RBC transfusions within a specific time frame of the maintenance dose, where the supplementary dose is administered at the following doses under this specific time frame after the maintenance dose:

[0245] a. 300 mg or 400 mg for patients weighing 5 kg to < 10 kg, where the specific time frame is two weeks,

[0246] b. 600 mg or 800 mg for patients weighing 10 kg to < 20 kg, where the specific time frame is two weeks, or

[0247] c. 2100 mg for patients weighing 20 kg to < 30 kg, where the specific time frame is four weeks, or

[0248] (ii) Administer to patients weighing ≥ 30 kg who receive red blood cell (RBC) transfusions within four weeks of the maintenance dose, where the supplemental dose is administered four weeks after the maintenance dose at the following doses:

[0249] a. 2700 mg for patients weighing ≥ 30 kg to < 40 kg,

[0250] b. 3000 mg for patients weighing ≥ 40 kg to < 60 kg,

[0251] c. 3300 mg for patients weighing ≥ 60 to < 100 kg, or

[0252] d. 3600 mg for patients weighing ≥ 100 kg.

[0253] The present invention also provides the use of an anti-C5 antibody or an antigen-binding fragment thereof (e.g., ravulizumab ( )) for treating HSCT-TMA patients who have experienced RBC transfusions during the first half of the maintenance phase of treatment, where the anti-C5 antibody or an antigen-binding fragment thereof is administered as follows:

[0254] (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 on day 1;

[0255] (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 on day 5;

[0256] (c) A loading dose of 300 mg is administered once to patients weighing 5 kg to < 10 kg, 300 mg to patients weighing 10 kg to < 20 kg, 300 mg to patients weighing 20 kg to < 30 kg, 300 mg to patients weighing ≥ 30 kg to < 40 kg, 600 mg to patients weighing ≥ 40 kg to < 60 kg, 900 mg to patients weighing ≥ 60 kg to < 100 kg, or 900 mg to patients weighing ≥ 100 kg on day 10; and

[0257] (d) On day 15 and

[0258] (i) A maintenance dose of 300 mg or 400 mg is administered once every four weeks thereafter to patients weighing 5 kg to < 10 kg or 600 mg or 800 mg to patients weighing 10 kg to < 20 kg, or

[0259] (ii) A maintenance dose of 2100 mg is administered once every eight weeks thereafter to patients weighing 20 kg to < 30 kg, 2700 mg to patients weighing ≥ 30 kg to < 40 kg, 3000 mg to patients weighing ≥ 40 kg to < 60 kg, 3300 mg to patients weighing > 60 kg to < 100 kg, or 3600 mg to patients weighing ≥ 100 kg;

[0260] And the supplementary dose is administered as follows:

[0261] (i) It is administered to patients weighing < 30 kg who receive RBC transfusions within a specific time frame of the maintenance dose, and the supplementary dose is administered at the following doses within that specific time frame after the maintenance dose:

[0262] a. 300 mg or 400 mg to patients weighing 5 kg to < 10 kg, two weeks after the maintenance dose,

[0263] b. 600 mg or 800 mg to patients weighing 10 kg to < 20 kg, two weeks after the maintenance dose, or

[0264] c. 2100 mg to patients weighing 20 kg to < 30 kg, four weeks after the maintenance dose, or

[0265] (ii) It is administered to patients weighing ≥ 30 kg who receive red blood cell (RBC) transfusions within four weeks of the maintenance dose, and the supplementary dose is administered at the following doses four weeks after the maintenance dose:

[0266] a. 2700 mg to patients weighing ≥ 30 kg to < 40 kg,

[0267] b. 3000 mg to patients weighing ≥ 40 kg to < 60 kg,

[0268] c. 3300 mg for patients weighing ≥60 to <100 kg, or

[0269] d. 3600 mg for patients weighing ≥100 kg. BRIEF DESCRIPTION OF THE DRAWINGS

[0270] Figure 1 is a graph showing the ravulizumab pharmacokinetic (PK) curves for each patient. At Day 5 and Day 10, the ravulizumab concentration was maintained above the 175 μg / mL threshold (dashed line).

[0271] Figure 2 is a graph showing the free C5 concentration-time curve (i.e., the pharmacodynamic (PD) curve) for each patient. All patients showed a free C5 concentration below the 0.5 μg / mL threshold (dashed line).

[0272] Figure 3 is a schematic diagram depicting the clinical algorithm for evaluating supplemental dosing after RBC. DETAILED DESCRIPTION

[0273] I. Definitions.

[0274] As used herein, the term "subject" or "patient" is a human patient (e.g., a patient with hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA)).

[0275] As used herein, the term "pediatric" patient is a human patient who has been classified by a physician or caregiver as belonging to a non-adult category and may include, for example, neonates (both premature and full-term), infants, children, and adolescents. Generally, a pediatric patient is a patient less than 18 years of age (<18 years).

[0276] As used herein, the term "adult" patient is a human patient who has been classified by a physician or caregiver, etc., such as based on age, developmental status, physiological characteristics, etc., as a non-neonate, infant, child, or adolescent. Generally, an adult patient is a patient 18 years of age or older (≥18 years).

[0277] HSCT-TMA is a multifactorial disorder caused by systemic vascular endothelial injury, which can be triggered by several mechanisms during the transplantation process. It presents via endothelial injury and affects the kidneys and other organs. It is estimated that 30% of patients with HSCT TMA will exhibit severe disease (Rosenthal et al., J. Blood Med 2016;7:181-186), and in these cases, patients with HSCT-TMA develop systemic vascular injury, manifested as kidney injury, serositis, pulmonary hypertension, and multi-system organ failure. In one embodiment, the diagnosis of TMA is based on all of the following criteria occurring simultaneously: (a) neonatal thrombocytopenia or platelet transfusion refractoriness, where: neonatal thrombocytopenia is defined as a new decrease in platelet count to ≤50,000 / mm 3 , and transfusion refractoriness is defined as failure of the platelet increment to exceed the transfusion trigger between 10 minutes and 60 minutes after transfusion, or a rise of less than 10×10 9 / L at 20 hours to 24 hours after at least 2 platelet transfusions, (b) neonatal anemia (defined as a new decrease in heme to ≤8 g / dL) or increased transfusion requirement (defined as the need for more frequent transfusions to maintain a heme ≥8 g / dL), (c) one of the following hemolysis markers: LDH > 1.5×ULN or the presence of ≥2 schistocytes per high power field (HPF) in a peripheral blood smear, (d) spot urinalysis proteinuria, where proteinuria is defined as a protein / creatinine ratio ≥0.5 mg / mg. The presence of proteinuria should be confirmed by a second measurement (with at least a 4-hour interval between the 2 measurements); (e) the presence of hypertension defined as the presence of any one of the following 3 conditions: systolic blood pressure ≥139 mm Hg or diastolic blood pressure >80 mm Hg in 2 consecutive measurements taken at least 1 hour apart.

[0278] As used herein, "effective treatment" refers to treatment that produces a beneficial effect, e.g., improvement of at least one symptom of a disease or disorder. The beneficial effect may take the form of an improvement relative to a baseline, e.g., an improvement relative to a measurement or observation made prior to the commencement of therapy according to the method. Effective treatment may refer to alleviation of at least one symptom of HSCT-TMA (e.g., microangiopathic hemolytic anemia, thrombocytopenia, endothelial injury, kidney injury, renal failure, serositis, pulmonary hypertension, and multi-system organ failure).

[0279] 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, improvement, alleviation, mitigation, delay, and / or remission of one or more of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. In one example, an "effective amount" is the amount of an anti-C5 antibody or an antigen-binding fragment thereof that is clinically demonstrated to alleviate at least one symptom of HSCT-TMA (e.g., microangiopathic hemolytic anemia, thrombocytopenia, endothelial damage, kidney injury, renal failure, serositis, pulmonary hypertension, and multi-system organ failure). The effective amount can be administered in one or more administrations.

[0280] As used herein, the term "loading dose" refers to the initial dose administered during a dosing cycle (e.g., on Day 1, Day 5, and Day 10).

[0281] As used herein, the terms "maintenance" and "maintenance phase" are used interchangeably and refer to the second phase of treatment (e.g., administering a dose once every eight weeks starting on Day 15). In certain embodiments, treatment continues as long as clinical benefit is observed, or treatment continues until intractable toxicity or disease progression occurs.

[0282] As used herein, the term "supplemental dose" refers to an additional dose administered to an HSCT-TMA patient (e.g., weighing ≥ 30 kg) who receives an RBC transfusion within 4 weeks after a maintenance dose.

[0283] As used herein, the term "transfusion" refers to the procedure of putting whole blood or a portion of blood, e.g., by vein, into the bloodstream of a patient. The blood can be donated by another person, or the blood can be taken from the patient and stored until needed.

[0284] As used herein, the term "red blood cell (RBC) transfusion" refers to transfusing red blood cells (i.e., from donated whole blood or concentrated red blood cells obtained by donor apheresis) into the bloodstream of a patient, e.g., by vein. Most RBC transfusions are by infusion of packed RBCs, which are prepared by removing plasma from whole blood collections or by apheresis and then stored with additives to enhance cell viability and improve storage.

[0285] As used herein, the term "serum trough level" refers to the lowest level of an agent (e.g., an anti-C5 antibody or an antigen-binding fragment thereof) or drug present in serum. In contrast, "peak serum level" refers to the highest level of an agent in serum. "Average serum level" refers to the average level of an agent in serum over time.

[0286] The term "antibody" describes a polypeptide that includes at least one antibody-derived antigen-binding site (e.g., VH / VL region or Fv or 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. The antibody can be a naturally occurring antibody or an antibody altered by protein engineering techniques (e.g., by mutation, deletion, substitution, conjugation with a non-antibody moiety). An antibody can include, for example, one or more variant amino acids that alter the properties of the antibody (e.g., functional properties) compared to a naturally occurring antibody. Many such alterations are known in the art and affect, for example, the half-life, effector function, and / or immune response to the antibody in a patient. The term antibody also includes artificial or engineered polypeptide constructs that include at least one antibody-derived antigen-binding site.

[0287] II. Anti-C5 Antibodies

[0288] The anti-C5 antibodies described herein bind to complement component C5 (e.g., human C5) and inhibit the cleavage of C5 into fragments C5a and C5b. As described above, such antibodies also have, for example, improved pharmacokinetic properties compared to other anti-C5 antibodies (e.g., eculizumab) used for therapeutic purposes.

[0289] 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, anti-C5 antibodies recognized in the art 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.

[0290] An exemplary anti-C5 antibody is ravulizumab, which includes a heavy chain and a light chain having the sequences shown in SEQ ID NO: 14 and SEQ ID NO: 11, respectively, or an antigen-binding fragment and variant thereof. Ravulizumab (also known as BNJ441 and ALXN1210 are described in WO2015134894 and U.S. Patent No. 9,079,949, the entire teachings of which are hereby incorporated by reference. The terms ravulizumab, BNJ441, and ALXN1210 are used interchangeably throughout the document and all refer to the same antibody. Ravulizumab selectively binds to human complement protein C5 and inhibits the cleavage of human complement protein C5 into C5a and C5b during complement activation. This inhibition prevents the release of the proinflammatory mediator C5a and the formation of the lytic pore-forming membrane attack complex (MAC) C5b-9, while preserving the proximal or early components of complement activation (e.g., C3 and C3b) necessary for opsonization of microorganisms and clearance of immune complexes.

[0291] The polypeptide sequence of ravulizumab registered in the KEGG DRUG database (https: / / www.kegg.jp / entry / D11054) specifies 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) of ravulizumab (CAS 1803171-55-2) also provides that the N-terminal X is pyroglutamic acid (designated as "chain 1 pyroglutamic acid-1" in the CAS report). Although this information may appear different from the VH sequence of ravulizumab (e.g., the heavy chain variable region polypeptide comprising the amino acid sequence shown in SEQ ID NO:12 and / or the heavy chain polypeptide comprising the amino acid sequence shown in SEQ ID NO:14), there is an alignment between the patent sequence and the drug database / CAS sequence because it is well recognized in the art that the N-terminal Q in a polypeptide and / or antibody sequence cyclizes during process development to result in a nearly 100% conversion of the drug product to pyroglutamic acid (Pryo-Q), as disclosed in Liu et al. (J Pharm Sci. October 2019;108(10):3194-3200) https: / / pubmed.ncbi.nlm.nih.gov / 31145921 / and Nguyen et al. (Int.J.Mol.Sci. July 20, 2017;18(7):1575) https: / / www.researchgate.net / figure / Cyclization-reactions-of-N-terminal-glutamine-and-glutamate-residues-in-a-polypeptide_fig4_318926365.Additional information is provided on page 7 and in Table 4 of Xu et al. (MAbs, February / March 2019; 11(2):239-264), as well as in the following reference 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 Dick 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 herein by reference in their entirety.

[0292] 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 sequences shown in SEQ ID NO:12, and the CDR1, CDR2, and CDR3 domains of the VL region of ravulizumab having the sequences shown in SEQ ID NO:8. In another embodiment, the antibody comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NO:19, 18, and 3, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NO:4, 5, and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences shown in SEQ ID NO:12 and SEQ ID NO:8, respectively.

[0293] Another exemplary anti-C5 antibody is the antibody BNJ421, which comprises heavy and light chains having the sequences shown in SEQ ID NO:20 and 11, respectively, or antigen-binding fragments and variants thereof. BNJ421 (also known as ALXN1211) is described in WO2015134894 and U.S. Patent No. 9,079,949, the entire teachings of which are incorporated herein by reference.

[0294] 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 shown in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of the VL region of BNJ421 having the sequence shown in SEQ ID NO: 8. In another embodiment, the antibody comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 19, 18, and 3, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 4, 5, and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences shown in SEQ ID NOs: 12 and SEQ ID NO: 8, respectively.

[0295] The exact boundaries of the CDRs are defined differently according to different methods. In some embodiments, the positions of the CDRs or framework regions within the light or heavy chain variable domains are as defined by Kabat et al. [(1991) "Sequences of Proteins of Immunological Interest" NIH Publication No. 91-3242, Department 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 positions of the CDRs of the light or heavy chain variable regions are as defined by Chothia et al. (Nature, 342:877-83, 1989). Thus, these regions may be referred to as "Chothia CDRs" (e.g., "Chothia LCDR2" or "Chothia HCDR3"). In some embodiments, the positions of the CDRs of the light and heavy chain variable regions may be defined by a Kabat-Chothia combined definition. In such embodiments, these regions may be referred to as "combined Kabat-Chothia CDRs". Thomas, C. et al. (Mol. Immunol., 33:1389-401, 1996) illustrated the identification of CDR boundaries according to the Kabat and Chothia numbering schemes.

[0296] 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 an antigen-binding fragment thereof comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 21, 22, and 23, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 24, 25, and 26, respectively. In another embodiment, the antibody or an antigen-binding fragment thereof comprises the VH region of the 7086 antibody having the sequence shown in SEQ ID NO: 27, and the VL region of the 7086 antibody having the sequence shown in SEQ ID NO: 28.

[0297] Another exemplary anti-C5 antibody is the 8110 antibody 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 an antigen-binding fragment thereof comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 29, 30, and 31, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences shown 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 shown in SEQ ID NO: 35, and the VL region of the 8110 antibody having the sequence shown in SEQ ID NO: 36.

[0298] 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 an antigen-binding fragment thereof comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NO: 37, 38, and 39, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NO: 40, 41, and 42, respectively. In another embodiment, the antibody comprises the VH region of the 305LO5 antibody having the sequence shown in SEQ ID NO: 43, and the VL region of the 305LO5 antibody having the sequence shown in SEQ ID NO: 44.

[0299] 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 another embodiment, the antibody or its antigen-binding fragment comprises a heavy chain comprising SEQ ID NO: 45 and a light chain comprising SEQ ID NO: 46.

[0300] In some embodiments, the anti-C5 antibody comprises the heavy and light chain variable regions or the heavy and light chains of the REGN3918 antibody (see U.S. Patent No. 10,633,434). In some embodiments, the anti-C5 antibody or its antigen-binding fragment comprises the heavy chain variable region sequence shown in SEQ ID NO: 47 and a light chain variable region comprising the sequence shown in SEQ ID NO: 48. In some embodiments, the anti-C5 antibody or its antigen-binding fragment comprises the heavy chain sequence shown in SEQ ID NO: 49 and the light chain sequence shown in SEQ ID NO: 50.

[0301] In another embodiment, the anti-C5 antibody is a biosimilar of eculizumab ( ). For example, in one embodiment, the anti-C5 antibody is, for example, the ABP 959 antibody (a biosimilar of eculizumab manufactured by Amgen, Inc., USA), (a biosimilar of eculizumab manufactured by Generium JNC, Russia), SB12 (a biosimilar of eculizumab manufactured by Samsung Bioepis, Incheon, Korea), ISU305 (a biosimilar of eculizumab from ISU Abxis, Korea), (a biosimilar of eculizumab from CinnaGen, Iran), BCD 148 (a biosimilar of eculizumab from Biocad Medical, Quebec, Canada), teduglutide (manufactured by Novartis), ravulizumab (manufactured by Roche Pharmaceuticals), CAN106 (manufactured by Beijing KangCheng Biopharma Co., Ltd., China) or pazelimab (manufactured by Regeneron Pharmaceuticals).

[0302] In some embodiments, the anti-C5 antibody described herein comprises a heavy chain CDR1 that comprises or consists of the following amino acid sequence: GHIFSNYWIQ (SEQ ID NO: 19). In some embodiments, the anti-C5 antibody described herein comprises a heavy chain CDR2 that comprises or consists of the following amino acid sequence: EILPGSGHTEYTENFKD (SEQ ID NO: 18). In some embodiments, the anti-C5 antibody described herein comprises a heavy chain variable region that comprises the following amino acid sequence:

[0303]

[0304] In some embodiments, the anti-C5 antibodies described herein comprise a light chain variable region comprising the following amino acid sequence:

[0305]

[0306] In some embodiments, the anti-C5 antibodies described herein may comprise a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn) with a greater affinity than the native human Fc constant region from which the variant human Fc constant region is derived. For example, relative to the native human Fc constant region from which the variant human Fc constant region is derived, the Fc constant region may comprise one or more (e.g., two, three, four, five, six, seven, or eight or more) amino acid substitutions. The substitutions may 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 illustrated in the working examples. See, e.g., WO2015134894 and U.S. Patent No. 9,079,949, the disclosures of which are incorporated herein by reference in their entireties.

[0307] Substitutions that enhance the binding affinity of an antibody Fc constant region for FcRn are known in the art and include, for example, (1) the M252Y / S254T / T256E triple substitution (Dall’Acqua, W. et al., J. Biol. Chem., 281:23514-24, 2006); (2) the M428L or T250Q / M428L substitution (Hinton, P. et al., J. Biol. Chem., 279： .6213-6, 2004; Hinton, P. et al., J. Immunol., 176:346-56, 2006); and (3) the N434A or T307 / E380A / N434A substitution (Petkova, S. et al., Int. Immunol., 18:1759-69, 2006). Additional substitution pairs: P257I / Q311I, P257I / N434H, and D376V / N434H (Datta-Mannan, A. et al., J. Biol. Chem., 282:1709-17, 2007), the disclosures of which are incorporated herein by reference in their entireties.

[0308] In some embodiments, the variant constant region has a substitution for valine at EU amino acid position 255. In some embodiments, the variant constant region has a substitution for asparagine at EU amino acid position 309. In some embodiments, the variant constant region has a substitution for isoleucine at EU amino acid position 312. In some embodiments, the variant constant region has a substitution at EU amino acid position 386.

[0309] In some embodiments, the variant Fc constant region contains no more than 30 (e.g., no more than 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2) amino acid substitutions, insertions, or deletions relative to the native constant region from which it is derived. In some embodiments, the variant Fc constant region contains 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 contains methionine at position 428 and asparagine at position 434 of the native human IgG Fc constant region, each in EU numbering. In some embodiments, the variant Fc constant region contains the 428L / 434S double substitution as described, for example, in U.S. Patent No. 8,088,376.

[0310] In some embodiments, due to antibody engineering, the precise positions of these mutations can be shifted from the native human Fc constant region positions. For example, when used in an IgG2 / 4 chimeric Fc, the 428L / 434S double substitution can correspond to 429L and 435S in the M429L and N435S variants 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.

[0311] In some embodiments, the variant constant region contains substitutions at amino acid positions 237, 238, 239, 248, 250, 252, 254, 255, 256, 257, 258, 265, 270, 286, 289, 297, 298, 303, 305, 307, 308, 309, 311, 312, 314, 315, 317, 325, 332, 334, 360, 376, 380, 382, 384, 385, 386, 387, 389, 424, 428, 433, 434 or 436 (EU numbering) relative to the native human Fc constant region. In some embodiments, the substitutions are selected from the group consisting of: methionine substituting for glycine at position 237; alanine substituting for proline at position 238; lysine substituting for serine at position 239; isoleucine substituting for lysine at position 248; alanine, phenylalanine, isoleucine, methionine, glutamine, serine, valine, tryptophan or tyrosine substituting for threonine at position 250; phenylalanine, tryptophan or tyrosine substituting for methionine at position 252; threonine substituting for serine at position 254; glutamate substituting for arginine at position 255; aspartate, glutamate or glutamine substituting for threonine at position 256; alanine, glycine, isoleucine, leucine, methionine, asparagine, serine, threonine or valine substituting for proline at position 257; histidine substituting for glutamate at position 258; alanine substituting for aspartate at position 265; phenylalanine substituting for aspartate at position 270; alanine or glutamate substituting for asparagine at position 286; histidine substituting for threonine at position 289; alanine substituting for asparagine at position 297; glycine substituting for serine at position 298; alanine substituting for valine at position 303; alanine substituting for valine at position 305; alanine, aspartate, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, valine, tryptophan or tyrosine substituting for threonine at position 307; alanine, phenylalanine, isoleucine, leucine, methionine, proline, glutamine or threonine substituting for valine at position 308; alanine, aspartate, glutamate, proline or arginine substituting for leucine or valine at position 309; alanine, histidine or isoleucine substituting for glutamine at position 311; alanine or histidine substituting for aspartate at position 312; lysine or arginine substituting for leucine at position 314; alanine or histidine substituting for asparagine at position 315; alanine substituting for lysine at position 317; glycine substituting for asparagine at position 325; valine substituting for isoleucine at position 332; leucine substituting for lysine at position 334; histidine substituting for lysine at position 360;Aspartic acid at position 376 substituted with alanine; Glutamic acid at position 380 substituted with alanine; Glutamic acid at position 382 substituted with alanine; Asparagine or serine at position 384 substituted with alanine; Glycine at position 385 substituted with aspartic acid or histidine; Glutamine at position 386 substituted with proline; Proline at position 387 substituted with glutamic acid; Asparagine at position 389 substituted with alanine or serine; Serine at position 424 substituted with alanine; Methionine at position 428 substituted with alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, asparagine, proline, glutamine, serine, threonine, valine, tryptophan or tyrosine; Histidine at position 433 substituted with lysine; Asparagine at position 434 substituted with alanine, phenylalanine, histidine, serine, tryptophan or tyrosine; and Tyrosine or phenylalanine at position 436 substituted with histidine, all in EU numbering;

[0312] In some embodiments, suitable anti-C5 antibodies for use in the methods described herein 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, in some embodiments, the anti-C5 antibody for use in the methods described herein comprises 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.

[0313] In one embodiment, the antibody binds to C5 with an affinity dissociation constant (K D ) 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 at pH 7.4 and 25°C (and additionally under physiological conditions). In one embodiment, the antibody binds to C5 with an affinity dissociation constant (KD) of about 0.5 nM at pH 7.4 and 25°C (and additionally under physiological conditions). In some embodiments, the KD of the anti-C5 antibody or its antigen-binding fragment is no greater than 1 (e.g., no greater than 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3 or 0.2) nM. In some embodiments, the antibody binds to C5 with a K D of about 22 nM at pH 6.0 and 25°C (and additionally under physiological conditions).

[0314] In other embodiments, [(the K of the antibody against C5 at 25°C and pH 6.0 D ) / (the K of the antibody against C5 at 25°C and pH 7.4 D )] is greater than 21 (e.g., greater than 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500 or 8000).

[0315] Methods for determining whether an antibody binds a protein antigen and / or the affinity of an antibody for a protein antigen are known in the art. For example, a variety of techniques can be used to detect and / or quantify the binding of an antibody to a protein antigen, such as, but not limited to, Western blotting, dot blotting, surface plasmon resonance (SPR) detection (e.g., BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.) or enzyme-linked immunosorbent assay (ELISA; Benny K.C. Lo (2004) "Antibody Engineering: Methods and Protocols", Humana Press (ISBN: 1588290921); Johne, B. et al., J. Immunol. Meth., 160:191 - 8, 1993; U. et al., Ann. Biol. Clin., 51:19 - 26, 1993; U. et al., Biotechniques, 11:620 - 7, 1991). In addition, methods for measuring affinity (e.g., dissociation and association constants) are set forth in the working examples.

[0316] As used herein, the term "k a " refers to the rate constant of association of an antibody with an antigen. The term "k d " refers to the rate constant of dissociation of an antibody from an antibody / antigen complex. The term "k D″refers to the equilibrium dissociation constant of the antibody-antigen interaction. The equilibrium dissociation constant K is derived from the ratio of kinetic rate constants D = k a / k d . Such determinations can be made, for example, at 25 °C or 37 °C (see Working Examples). The kinetics of antibody binding to human C5 can be determined, for example, at pH 8.0, 7.4, 7.0, 6.5, and 6.0 via SPR on a BIAcore 3000 instrument using an anti-Fc capture method to immobilize the antibody

[0317] In one embodiment, the anti-C5 antibody or its antigen-binding fragment blocks the cleavage of C5 into C5a and C5b. By this blocking action, for example, the pro-inflammatory effects of C5a on the cell surface and the formation of the C5b-9 membrane attack complex (MAC) are inhibited

[0318] Methods for determining whether a particular antibody as described herein inhibits C5 cleavage are known in the art. Inhibition of human complement component C5 can reduce the complement-mediated cytolytic capacity in the body fluids of a subject. The reduction in the cytolytic capacity of complement present in body fluids can be measured by methods known in the art, such as, for example, by conventional hemolytic assays, such as the hemolytic assay (Kabat and Mayer (eds.), ″Experimental Immunochemistry,″ 2nd ed., ″135-240, Springfield, IL, CC Thomas (1961), pp. 135-139), or a conventional variant of this 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 the C5a and C5b forms are known in the art (Evans, M. et al., Molecular Immunology, 32:1183-95, 1995). The concentration and / or biological activity of C5a and C5b in body fluids can be measured, for example, by methods known in the art. For C5b, a hemolytic assay or an assay for soluble C5b-9 as discussed herein can be used. Other assays known in the art can also be used. Using these or other suitable types of assays, candidate agents capable of inhibiting human complement component C5 can be screened

[0319] Immunological techniques such as, but not limited to, ELISA can be used to measure the protein concentration of C5 and / or its cleavage products to determine the ability of an anti-C5 antibody or its antigen-binding fragment to inhibit the conversion of C5 into bioactive products. In some embodiments, C5a generation is measured. In some embodiments, a C5b-9 neoepitope-specific antibody is used to detect MAC formation

[0320] Hemolysis assays can be used to determine the inhibitory activity of an anti-C5 antibody or an antigen-binding fragment thereof on complement activation. To assay the effect of an anti-C5 antibody or an antigen-binding fragment thereof on hemolysis mediated by the classical complement pathway in an in vitro serum test solution, for example, sheep red blood cells coated with hemolysin or chicken red blood cells sensitized with an anti-chicken red blood cell antibody are used as target cells. The percent lysis is normalized by considering 100% lysis to be equivalent to the lysis that occurs in the absence of an inhibitor. In some embodiments, the classical complement pathway is activated by human IgM antibody, for example, as utilized in Classical Pathway Complement Kit ( OMPL CP310, Euro-Diagnostica, Sweden). Briefly, in the presence of human IgM antibody, the test serum is incubated with the anti-C5 antibody or an antigen-binding fragment thereof. The amount of C5b-9 produced is measured by contacting the mixture with an enzyme-conjugated anti-C5b-9 antibody and a fluorescent substrate and measuring the absorbance at an appropriate wavelength. As a control, the test serum is incubated in the absence of the anti-C5 antibody or an antigen-binding fragment thereof. In some embodiments, the test serum is C5-deficient serum reconstituted with C5 polypeptide.

[0321] To assay the effect of an anti-C5 antibody or an antigen-binding fragment thereof on hemolysis mediated by the alternative pathway, unsensitized 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 percent lysis is normalized by considering 100% lysis to be equivalent to the lysis that occurs in the absence of an inhibitor. In some embodiments, the complement alternative pathway is activated by lipopolysaccharide molecules, for example, as utilized in Alternative Pathway Complement Kit ( COMPL AP330, Euro-Diagnostica, Sweden). Briefly, in the presence of lipopolysaccharide, the test serum is incubated with the anti-C5 antibody or an antigen-binding fragment thereof. The amount of C5b-9 produced is measured by contacting the mixture with an enzyme-conjugated anti-C5b-9 antibody and a fluorescent substrate and measuring the fluorescence at an appropriate wavelength. As a control, the test serum is incubated in the absence of the anti-C5 antibody or an antigen-binding fragment thereof.

[0322] In some embodiments, C5 activity or its inhibition is quantified using the CH50eq assay. The CH50eq assay is a method for measuring total classical complement activity in serum. The test is a lysis assay that uses antibody-sensitized red blood cells as activators of the classical complement pathway and various dilutions of test serum to determine the amount required to produce 50% lysis (CH50). The percentage of hemolysis can be determined, for example, using a spectrophotometer. The CH50eq assay provides an indirect measure of terminal complement complex (TCC) formation because the TCC itself is directly responsible for the measured hemolysis. The assay is known and commonly practiced 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 microtiter well containing antibody-sensitized red blood cells, thereby generating TCC. Subsequently, the activated serum is diluted in the microtiter well, and the microtiter well is coated with a capture reagent (e.g., an antibody that binds to one or more components of the TCC). The TCC present in the activated sample binds to the monoclonal antibody coating the surface of the microtiter well. The wells are washed and a detection reagent, which is detectably labeled and recognizes the bound TCC, is added to each well. The detectable label can be, for example, a fluorescent label or an enzyme label. The assay results are expressed as CH50 units equivalent per milliliter (CH50U Eq / mL).

[0323] Inhibitions related to terminal complement activity, for example, include at least a 5 (e.g., at least 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60) % reduction in terminal complement activity in, for example, a hemolysis assay or a CH50eq assay compared to the effect of a control antibody (or its antigen-binding fragment) under similar conditions and at equimolar concentrations. As used herein, substantially inhibiting means inhibiting at least 40 (e.g., at least 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 or higher) % 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 relative to the CDRs of eculizumab (i.e., SEQ ID NO: 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 hemolysis assay or a CH50eq assay.

[0324] The anti-C5 antibodies described herein have a serum half-life of at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55) days in humans. In another embodiment, the anti-C5 antibodies described herein have a serum half-life of at least 40 days in humans. In another embodiment, the anti-C5 antibodies described herein have a serum half-life of approximately 43 days in humans. In another embodiment, the anti-C5 antibodies described herein have a serum half-life between 39 and 48 days in humans. Methods for measuring the serum half-life of an antibody are known in the art. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof has a serum half-life that is at least 20 (e.g., 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 that of eculizumab, as measured, for example, in one of the murine model systems described in the working examples (e.g., C5-deficient / NOD / scid mice or hFcRn transgenic mouse model system).

[0325] In one embodiment, the antibody competes for binding 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, epitope mapping methods such as x-ray analysis of crystals of the antigen:antibody complex and hydrogen / deuterium exchange mass spectrometry (HDX-MS). Antibodies that are expected to bind to the same epitope have the same VH and VL or the same CDR1, CDR2, and CDR3 sequences.

[0326] An antibody that “competes for binding to a target” with another antibody is an antibody that inhibits (partially or completely) the binding of the other antibody to the target. Whether two antibodies compete with each other for binding to a target, i.e., whether one antibody inhibits the binding of the other antibody to the target and to what extent the binding of the other antibody to the target is inhibited, can be determined using known competition assays. In certain embodiments, the antibody competes with and inhibits the binding of another antibody to the target by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. The level of inhibition or competition can vary depending on which antibody is the “blocking antibody” (i.e., the antibody that is incubated with the target first). The competing antibody can bind, for example, to the same epitope, an overlapping epitope, or an adjacent epitope (e.g., as demonstrated by steric hindrance).

[0327] The anti-C5 antibodies or antigen-binding fragments thereof described herein that are used in the methods described herein can be generated using a variety of techniques well known in the art. Monoclonal antibodies can be obtained by a variety of techniques familiar to those skilled in the art. Briefly, spleen cells from animals immunized with the desired antigen are typically immortalized by fusion with myeloma cells ( 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 produced by individual immortalized cells are screened to produce antibodies having the desired specificity and affinity for the antigen, and the yield of monoclonal antibodies produced by these cells can be increased by a variety of techniques, including injection into the peritoneal cavity of a vertebrate host. Alternatively, DNA sequences encoding monoclonal antibodies or their binding fragments can be isolated by screening a DNA library from human B cells (Huse, W. et al., Science, 246: 1275-81, 1989).

[0328] III. Compositions

[0329] The present invention also provides a composition comprising an anti-C5 antibody or an antigen-binding fragment thereof. In one embodiment, the composition comprises an anti-C5 antibody that comprises CDR1, CDR2, and CDR3 domains in the heavy-chain variable region having the sequence shown in SEQ ID NO: 12, and CDR1, CDR2, and CDR3 domains in the light-chain variable region having the sequence shown in SEQ ID NO: 8. In another embodiment, the anti-C5 antibody comprises a heavy chain and a light chain having the sequences shown in SEQ ID NOs: 14 and 11, respectively. In another embodiment, the anti-C5 antibody comprises a heavy chain and a light chain having the sequences shown in SEQ ID NOs: 20 and 11, respectively.

[0330] The composition can be formulated as a pharmaceutical solution, for example, for administration to a subject to treat HSCT-TMA. The pharmaceutical composition generally comprises a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" means and includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. The composition can comprise pharmaceutically acceptable salts, for example, acid addition salts or base addition salts, sugars, carbohydrates, polyols, and / or tonicity modifiers.

[0331] The composition can be formulated according to standard methods. Pharmaceutical formulations are established technologies (see, for example, Gennaro (2000) "Remington: The Science and Practice of Pharmacy", 20th edition, Lippincott, Williams & Wilkins (ISBN: 0683306472); Ansel et al. (1999) "Pharmaceutical Dosage Forms and Drug Delivery Systems", 7th edition, Lippincott Williams & Wilkins Publishers (ISBN: 0683305727); and Kibbe (2000) "Handbook of Pharmaceutical Excipients American Pharmaceutical Association", third edition (ISBN: 091733096X)). In some embodiments, the composition can be formulated as, for example, a buffered solution at a suitable concentration and suitable for storage at 2°C - 8°C (e.g., 4°C). In some embodiments, the composition can be formulated for storage at temperatures below 0°C (e.g., -20°C or -80°C). In some embodiments, the composition can be formulated for storage at 2°C - 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 1 / 2 year or 2 years). Thus, in some embodiments, the compositions described herein are stable for at least 1 year when stored at 2°C - 8°C (e.g., 4°C).

[0332] A pharmaceutical composition can be in a variety of forms. These forms include, for example, liquid, semi-solid, and solid dosage forms such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The preferred form depends in part on the intended mode of administration and therapeutic application. A composition containing a composition 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 administration by a parenteral mode (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection). As used herein, "parenteral administration", "administered parenterally", and other grammatically equivalent phrases refer to modes of administration other than enteral and topical administration, typically by injection, and include, but are not limited to, intravenous, intranasal, intraocular, transpulmonary, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid, and intrasternal injection and infusion.

[0333] IV. Methods

[0334] Provided herein are methods for treating HSCT-TMA in a specific patient subset (e.g., HSCT-TMA patients, such as those <30 kg or ≥30 kg in body weight, who receive a transfusion (e.g., platelet or RBC transfusion) during the 4 weeks following a maintenance dose), the methods comprising administering to the patient an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered (or for administration) according to a specific clinical dosing regimen (e.g., at a specific loading dose amount, maintenance dose amount, and one or more supplemental dose amounts, and according to a specific schedule).

[0335] In one embodiment, the dose of the anti-C5 antibody or its antigen-binding fragment is based on the patient's body weight. For example, in one embodiment, a loading dose of 300 mg or 600 mg of the anti-C5 antibody or its antigen-binding fragment is administered to a patient with a body weight of ≥5 kg to <10 kg. In another embodiment, a maintenance dose of 400 mg of the anti-C5 antibody or its antigen-binding fragment is administered to a patient with a body weight of ≥5 kg to <10 kg. In another embodiment, a supplemental dose of 400 mg of the anti-C5 antibody or its antigen-binding fragment is administered to a patient with a body weight of ≥5 kg to <10 kg. In some embodiments, a loading dose of 300 mg or 600 mg of the anti-C5 antibody or its antigen-binding fragment is administered to a patient with a body weight of ≥10 kg to <20 kg. In another embodiment, a maintenance dose of 800 mg of the anti-C5 antibody or its antigen-binding fragment is administered to a patient with a body weight of ≥10 kg to <20 kg. In another embodiment, a supplemental dose of 800 mg of the anti-C5 antibody or its antigen-binding fragment is administered to a patient with a body weight of ≥10 kg to <20 kg. In some embodiments, a loading dose of 300 mg or 900 mg of the anti-C5 antibody or its antigen-binding fragment is administered to a patient with a body weight of ≥20 kg to <30 kg. In another embodiment, a maintenance dose of 2100 mg of the anti-C5 antibody or its antigen-binding fragment is administered to a patient with a body weight of ≥20 kg to <30 kg. In another embodiment, a supplemental dose of 2100 mg of the anti-C5 antibody or its antigen-binding fragment is administered to a patient with a body weight of ≥20 kg to <30 kg.

[0336] For example, in one embodiment, a loading dose of 300 mg or 1200 mg of the anti-C5 antibody or its antigen-binding fragment is administered to a patient with a body weight of ≥30 kg to <40 kg. In another embodiment, a maintenance dose of 2700 mg of the anti-C5 antibody or its antigen-binding fragment is administered to a patient with a body weight of ≥30 kg to <40 kg. In another embodiment, a supplemental dose of 2700 mg of the anti-C5 antibody or its antigen-binding fragment is administered to a patient with a body weight of ≥30 kg to <40 kg.

[0337] In another embodiment, a loading dose of 600 mg or 2400 mg of the anti-C5 antibody or its antigen-binding fragment is administered to a patient with a body weight of ≥40 kg to <60 kg. In another embodiment, a maintenance dose of 3000 mg of the anti-C5 antibody or its antigen-binding fragment is administered to a patient with a body weight of ≥40 kg to <60 kg. In another embodiment, a supplemental dose of 3000 mg of the anti-C5 antibody or its antigen-binding fragment is administered to a patient with a body weight of >40 kg to <60 kg.

[0338] In another embodiment, a loading dose of 900 mg or 2700 mg of an anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient having a body weight of ≥60 kg to <100 kg. In another embodiment, a maintenance dose of 3300 mg of an anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient having a body weight of ≥60 kg to <100 kg. In another embodiment, a supplemental dose of 3300 mg of an anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient having a body weight of >60 kg to <100 kg.

[0339] In another embodiment, a loading dose of 900 mg or 3000 mg of an anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient having a body weight of ≥100 kg. In another embodiment, a maintenance dose of 3600 mg of an anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient having a body weight of ≥100 kg. In another embodiment, a supplemental dose of 3600 mg of an anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient having a body weight of ≥100 kg.

[0340] In certain embodiments, the dosing regimen is adjusted to provide an optimal desired response (e.g., an effective response).

[0341] In some embodiments, where a patient experiences an RBC transfusion within 4 weeks after a first maintenance dose, the patient receives a post-transfusion supplemental dose of an anti-C5 antibody (e.g., ravulizumab) only at the midpoint between two maintenance doses. Since maintenance doses are administered every four weeks (Q4W) for lower (e.g., <20 kg) weight classes and every eight weeks (Q8W) for higher (e.g., ≥20 kg) weight classes, the post-transfusion supplemental dose of an anti-C5 antibody (e.g., ravulizumab) is administered 14 days or 28 days after the second week (<20 kg patients) and the fourth week (≥20 kg patients) after the maintenance dose. In such an embodiment, if a patient does not experience any transfusion during the second maintenance dosing phase, no supplemental dose is required during that maintenance dosing cycle. Similarly, if a patient experiences an RBC transfusion during the second half of the second maintenance dosing phase, no supplemental dosing is required during that maintenance dosing cycle. In other words, if the first RBC transfusion occurs more than 4 weeks after the previous maintenance dose, no post-transfusion supplemental dose is required. Additionally, if a patient receives a transfusion during the loading dose phase, no supplemental dosing is administered.

[0342] According to the treatment methods described herein, if any amount of RBC transfusion is provided to a patient within 4 weeks after the last maintenance dose, a post-transfusion supplemental dose of an anti-C5 antibody or an antigen-binding fragment thereof (e.g., ravulizumab) is administered to the HSCT-TMA patient only once 4 weeks after the last maintenance dose.

[0343] In another embodiment, an anti-C5 antibody or an antigen-binding fragment thereof is administered in one or more dosing cycles. In one embodiment, the treatment (e.g., dosing cycle) is 26 weeks. In one embodiment, the anti-C5 antibody or an antigen-binding fragment thereof is administered as a loading dose once on day 1 (e.g., of the dosing cycle), once on day 5 (e.g., of the dosing cycle), and once on day 10 (e.g., of the dosing cycle). In another embodiment, the anti-C5 antibody or an antigen-binding fragment thereof is administered as a loading dose once on day 1 (e.g., of the dosing cycle), as a loading dose once on day 5 (e.g., of the dosing cycle), as a loading dose once on day 10 (e.g., of the dosing cycle) and thereafter a maintenance dose is administered once every eight weeks starting on day 15. In another embodiment, the anti-C5 antibody or an antigen-binding fragment thereof is administered once every eight weeks after the treatment (e.g., dosing cycle) for an extension period of up to two 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).

[0344] In another embodiment, a supplemental dose is administered to a patient receiving a blood transfusion (e.g., platelet or RBC transfusion) within two or four weeks of the maintenance dose, wherein the supplemental dose is administered two or four weeks after the maintenance dose. In an embodiment, a supplemental dose is administered to a patient <20 kg in body weight receiving an RBC transfusion within two weeks of the maintenance dose, wherein the supplemental dose is administered two weeks after the maintenance dose at the following doses: 400 mg for patients with a body weight ≥5 kg to <10 kg and 800 mg for patients with a body weight ≥10 kg to <20 kg. In an embodiment, a supplemental dose is administered to a patient ≥20 kg <30 kg in body weight receiving an RBC transfusion within four weeks of the maintenance dose, wherein the supplemental dose is administered four weeks after the maintenance dose at the following dose: 2100 mg for patients with a body weight ≥20 kg <30 kg.

[0345] In another embodiment, a supplemental dose is administered to a patient ≥30 kg in body weight receiving an RBC transfusion within four weeks of the maintenance dose, wherein the supplemental dose is administered four weeks after the maintenance dose at the following doses: 2700 mg for patients with a body weight ≥30 to <40 kg, 3000 mg for patients with a body weight ≥40 to <60 kg, 3300 mg for patients with a body weight ≥60 to <100 kg or 3600 mg for patients with a body weight ≥100 kg.

[0346] In one embodiment, provided is a method of treating a human patient suffering from HSCT-TMA, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof, the anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NO: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NO: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered as follows:

[0347] (a) As a loading dose of 600 mg for a patient weighing 5 kg to <10 kg, 600 mg for a patient weighing 10 kg to <20 kg, 900 mg for a patient weighing 20 kg to <30 kg, 1200 mg for a patient weighing ≥30 kg to <40 kg, 2400 mg for a patient weighing ≥40 kg to <60 kg, 2700 mg for a patient weighing ≥60 kg to <100 kg or 3000 mg for a patient weighing ≥100 kg on day 1;

[0348] (b) As a loading dose of 300 mg for a patient weighing 5 kg to <10 kg, 300 mg for a patient weighing 10 kg to <20 kg, 300 mg for a patient weighing 20 kg to <30 kg, 300 mg for a patient weighing ≥30 kg to <40 kg, 600 mg for a patient weighing ≥40 kg to <60 kg, 900 mg for a patient weighing ≥60 kg to <100 kg or 900 mg for a patient weighing ≥100 kg on day 5;

[0349] (c) As a loading dose of 300 mg for a patient weighing 5 kg to <10 kg, 300 mg for a patient weighing 10 kg to <20 kg, 300 mg for a patient weighing 20 kg to <30 kg, 300 mg for a patient weighing ≥30 kg to <40 kg, 600 mg for a patient weighing ≥40 kg to <60 kg, 900 mg for a patient weighing ≥60 kg to <100 kg or 900 mg for a patient weighing ≥100 kg on day 10; and

[0350] (d) On day 15 and

[0351] (i) Thereafter, as a maintenance dose of 300 mg or 400 mg for a patient weighing 5 kg to <10 kg or 600 mg or 800 mg for a patient weighing 10 kg to <20 kg every four weeks, or

[0352] (ii) Thereafter, a maintenance dose of 2100 mg once every eight weeks 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;

[0353] And the supplemental doses are administered as follows:

[0354] (i) Administered to patients weighing < 30 kg who receive RBC transfusions within a specific time frame of the maintenance dose, where the supplemental dose is administered at the following doses within that specific time frame after the maintenance dose:

[0355] a. 300 mg or 400 mg for patients weighing 5 kg to < 10 kg, where the specific time frame is two weeks,

[0356] b. 600 mg or 800 mg for patients weighing 10 kg to < 20 kg, where the specific time frame is two weeks, or

[0357] c. 2100 mg for patients weighing 20 kg to < 30 kg, where the specific time frame is four weeks, or

[0358] (ii) Administered to patients weighing ≥ 30 kg who receive red blood cell (RBC) transfusions within four weeks of the maintenance dose, where the supplemental dose is administered at the following doses four weeks after the maintenance dose:

[0359] a. 2700 mg for patients weighing ≥ 30 kg to < 40 kg,

[0360] b. 3000 mg for patients weighing ≥ 40 kg to < 60 kg,

[0361] c. 3300 mg for patients weighing ≥ 60 to < 100 kg, or

[0362] d. 3600 mg for patients weighing ≥ 100 kg.

[0363] In another embodiment, a method of treating a human patient suffering from HSCT-TMA is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody, the anti-C5 antibody comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NO: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NO: 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 of the native human IgG Fc constant region, each according to the EU numbering convention, wherein the anti-C5 antibody is administered as follows:

[0364] (a) as a loading dose of 600 mg on day 1 for a patient weighing 5 kg to <10 kg, 600 mg for a patient weighing 10 kg to <20 kg, 900 mg for a patient weighing 20 kg to <30 kg, 1200 mg for a patient weighing ≥30 kg to <40 kg, 2400 mg for a patient weighing ≥40 kg to <60 kg, 2700 mg for a patient weighing ≥60 kg to <100 kg or 3000 mg for a patient weighing ≥100 kg, once;

[0365] (b) as a loading dose of 300 mg on day 5 for a patient weighing 5 kg to <10 kg, 300 mg for a patient weighing 10 kg to <20 kg, 300 mg for a patient weighing 20 kg to <30 kg, 300 mg for a patient weighing ≥30 kg to <40 kg, 600 mg for a patient weighing ≥40 kg to <60 kg, 900 mg for a patient weighing ≥60 kg to <100 kg or 900 mg for a patient weighing ≥100 kg, once;

[0366] (c) as a loading dose of 300 mg on day 10 for a patient weighing 5 kg to <10 kg, 300 mg for a patient weighing 10 kg to <20 kg, 300 mg for a patient weighing 20 kg to <30 kg, 300 mg for a patient weighing ≥30 kg to <40 kg, 600 mg for a patient weighing ≥40 kg to <60 kg, 900 mg for a patient weighing ≥60 kg to <100 kg or 900 mg for a patient weighing ≥100 kg, once; and

[0367] (d) on day 15 and

[0368] (i) thereafter every four weeks as a maintenance dose of 300 mg or 400 mg for a patient weighing 5 kg to <10 kg or 600 mg or 800 mg for a patient weighing 10 kg to <20 kg, once, or

[0369] (ii) Thereafter, a maintenance dose of 2100 mg once every eight weeks 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;

[0370] And wherein the supplemental dose is administered as follows:

[0371] (i) Administered to patients weighing < 30 kg who receive an RBC transfusion within a specific time frame of the maintenance dose, wherein the supplemental dose is administered at the following dose within the specific time frame after the maintenance dose:

[0372] a. 300 mg or 400 mg for patients weighing 5 kg to < 10 kg, wherein the specific time frame is two weeks,

[0373] b. 600 mg or 800 mg for patients weighing 10 kg to < 20 kg, wherein the specific time frame is two weeks, or

[0374] c. 2100 mg for patients weighing 20 kg to < 30 kg, wherein the specific time frame is four weeks, or

[0375] (ii) Administered to patients weighing ≥ 30 kg who receive a red blood cell (RBC) transfusion within four weeks of the maintenance dose, wherein the supplemental dose is administered at the following dose four weeks after the maintenance dose:

[0376] a. 2700 mg for patients weighing ≥ 30 kg to < 40 kg,

[0377] b. 3000 mg for patients weighing ≥ 40 kg to < 60 kg,

[0378] c. 3300 mg for patients weighing ≥ 60 to < 100 kg, or

[0379] d. 3600 mg for patients weighing ≥ 100 kg.

[0380] In another embodiment, a method of treating a patient with HSCT-TMA is provided, the method comprising administering to the patient an effective amount of ravulizumab, wherein ravulizumab is administered as follows:

[0381] (a) On the 1st day, 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;

[0382] (b) On the 5th day, 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;

[0383] (c) On the 10th day, 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; and

[0384] (d) On the 15th day and

[0385] (i) Thereafter, every four weeks, 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, once, or

[0386] (ii) Thereafter, every eight weeks, 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, once;

[0387] And the supplementary dose is administered as follows:

[0388] (i) Administered to patients weighing <30 kg who receive RBC transfusions within a specific time frame of the maintenance dose,

[0389] wherein the supplemental dose is administered at the following doses within the specific time frame after the maintenance dose:

[0390] a. 300 mg or 400 mg for patients weighing 5 kg to <10 kg, wherein the specific time frame is two weeks,

[0391] b. 600 mg or 800 mg for patients weighing 10 kg to <20 kg, wherein the specific time frame is two weeks, or

[0392] c. 2100 mg for patients weighing 20 kg to <30 kg, wherein the specific time frame is four weeks, or

[0393] (ii) administered to patients weighing ≥30 kg who receive red blood cell (RBC) transfusions within four weeks of the maintenance dose,

[0394] wherein the supplemental dose is administered at the following doses four weeks after the maintenance dose:

[0395] a. 2700 mg for patients weighing ≥30 kg to <40 kg,

[0396] b. 3000 mg for patients weighing ≥40 kg to <60 kg,

[0397] c. 3300 mg for patients weighing ≥60 to <100 kg, or

[0398] d. 3600 mg for patients weighing ≥100 kg.

[0399] In another embodiment, a method of treating a patient with HSCT-TMA is provided, the method comprising administering to the patient an effective amount of ravulizumab, wherein ravulizumab is administered as follows:

[0400] (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 on day 1;

[0401] (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 is administered once on day 5;

[0402] (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 is administered once on day 10; and

[0403] (d) On day 15 and

[0404] (i) 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 is administered once every four weeks thereafter, or

[0405] (ii) 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 is administered once every eight weeks thereafter;

[0406] And the supplementary dose is administered as follows:

[0407] (i) Administered to patients weighing <30 kg who receive RBC transfusions within a specific time frame of the maintenance dose,

[0408] wherein the supplementary dose is administered at the following dose within the specific time frame after the maintenance dose:

[0409] a. 300 mg or 400 mg for patients weighing 5 kg to <10 kg, wherein the specific time frame is two weeks,

[0410] b. 600 mg or 800 mg for patients weighing 10 kg to <20 kg, wherein the specific time frame is two weeks, or

[0411] c. 2100 mg for patients weighing 20 kg to < 30 kg, wherein the specific time frame is four weeks, or

[0412] (ii) administered to patients weighing ≥ 30 kg who receive red blood cell (RBC) transfusions within four weeks of the maintenance dose,

[0413] wherein the supplemental dose is administered four weeks after the maintenance dose at the following doses:

[0414] a. 2700 mg for patients weighing ≥ 30 kg to < 40 kg,

[0415] b. 3000 mg for patients weighing ≥ 40 kg to < 60 kg,

[0416] c. 3300 mg for patients weighing ≥ 60 to < 100 kg, or

[0417] d. 3600 mg for patients weighing ≥ 100 kg.

[0418] And

[0419] wherein the treatment results in a decrease in the LDH level to within the normal level or a decrease to within 50% of the ULN level (e.g., within 105 IU / L - 333 IU / L (international units per liter)), the serum trough concentration of the anti-C5 antibody or its antigen-binding fragment is at least 175 μg / mL or greater, and / or the free C5 concentration is 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).

[0420] In another embodiment, a method of treating a human patient with HSCT-TMA is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or its antigen-binding fragment, the anti-C5 antibody or its antigen-binding fragment comprising CDR1, CDR2, and CDR3 heavy chain sequences as shown in SEQ ID NO: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as shown in SEQ ID NO: 4, 5, and 6, respectively, wherein the anti-C5 antibody or its antigen-binding fragment (e.g., ravulizumab) is administered to patients weighing 5 kg to < 10 kg as follows:

[0421] (a) as a single 600 mg loading dose on day 1;

[0422] (b) as a single 300 mg loading dose on day 5;

[0423] (c) as a single 300 mg loading dose on day 10;

[0424] (d) once at a maintenance dose of 300 mg on day 15 and every four weeks thereafter; and

[0425] (e) administer a supplemental dose of 300 mg to patients receiving RBC transfusions within two weeks of the maintenance dose, wherein the supplemental dose is administered two weeks after the maintenance dose.

[0426] In another embodiment, a method of treating a human patient suffering from HSCT-TMA is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof, the anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to patients weighing 5 kg to <10 kg as follows:

[0427] (a) once at a loading dose of 600 mg on day 1;

[0428] (b) once at a loading dose of 300 mg on day 5;

[0429] (c) once at a loading dose of 300 mg on day 10;

[0430] (d) once at a maintenance dose of 400 mg on day 15 and every four weeks thereafter; and

[0431] (e) administer a supplemental dose of 400 mg to patients receiving RBC transfusions within two weeks of the maintenance dose, and wherein the supplemental dose is administered two weeks after the maintenance dose.

[0432] In another embodiment, a method of treating a human patient suffering from HSCT-TMA is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof, the anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to patients weighing 10 kg to <20 kg as follows:

[0433] (a) once at a loading dose of 600 mg on day 1;

[0434] (b) once at a loading dose of 300 mg on day 5;

[0435] (c) as a single 300 mg loading dose on day 10;

[0436] (d) as a single 600 mg maintenance dose on day 15 and every four weeks thereafter, and

[0437] (e) a supplemental dose of 600 mg is administered to patients receiving RBC transfusions within two weeks of the maintenance dose, and wherein the supplemental dose is administered two weeks after the maintenance dose.

[0438] In another embodiment, a method of treating a human patient suffering from HSCT-TMA is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof, the anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NO: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NO: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to patients weighing 10 kg to <20 kg as follows:

[0439] (a) as a single 600 mg loading dose on day 1;

[0440] (b) as a single 300 mg loading dose on day 5;

[0441] (c) as a single 300 mg loading dose on day 10;

[0442] (d) as a single 800 mg maintenance dose on day 15 and every four weeks thereafter, and

[0443] (e) a supplemental dose of 800 mg is administered to patients receiving RBC transfusions within two weeks of the maintenance dose, and wherein the supplemental dose is administered two weeks after the maintenance dose.

[0444] In another embodiment, a method of treating a human patient suffering from HSCT-TMA is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof, the anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NO: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NO: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to patients weighing 20 kg to <30 kg as follows:

[0445] (a) as a single 900 mg loading dose on day 1;

[0446] (b) once as a loading dose of 300 mg on day 5;

[0447] (c) once as a loading dose of 300 mg on day 10;

[0448] (d) once as a maintenance dose of 2100 mg on day 15 and every eight weeks thereafter; and

[0449] (e) administer a 2100 mg supplement to patients receiving RBC transfusions within two weeks of the maintenance dose and administer the supplemental dose four weeks after the maintenance dose.

[0450] In some embodiments, a supplemental dose is administered if necessary according to a clinical algorithm as Figure 3 shown. In some embodiments, a supplemental dose is administered if approved according to a clinical algorithm as shown in Table 7.

[0451] In another embodiment, a method of treating a human patient with HSCT-TMA is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof, the anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences as set forth in SEQ ID NO: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NO: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to patients weighing ≥ 30 kg to < 40 kg as follows:

[0452] (a) once as a loading dose of 1200 mg on day 1;

[0453] (b) once as a loading dose of 300 mg on day 5;

[0454] (c) once as a loading dose of 300 mg on day 10; and

[0455] (d) once as a maintenance dose of 2700 mg on day 15 and every eight weeks thereafter,

[0456] and wherein the patient receives an RBC transfusion within four weeks of the maintenance dose and then a 2700 mg supplemental dose is administered to the patient four weeks after the maintenance dose.

[0457] In another embodiment, a method of treating a human patient with HSCT-TMA is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof, the anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NO: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NO: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to patients weighing ≥40 kg to <60 kg as follows:

[0458] (a) As a single 2400 mg loading dose on Day 1;

[0459] (b) As a single 600 mg loading dose on Day 5;

[0460] (c) As a single 600 mg loading dose on Day 10; and

[0461] (d) As a single 3000 mg maintenance dose on Day 15 and every eight weeks thereafter,

[0462] and wherein the patient receives an RBC transfusion within four weeks of the maintenance dose and then a 3000 mg supplemental dose is administered to the patient four weeks after the maintenance dose.

[0463] In another embodiment, a method of treating a human patient with HSCT-TMA is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof, the anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NO: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NO: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to patients weighing ≥60 kg to <100 kg as follows:

[0464] (a) As a single 2700 mg loading dose on Day 1;

[0465] (b) As a single 900 mg loading dose on Day 5;

[0466] (c) As a single 900 mg loading dose on Day 10; and

[0467] (d) As a single 3300 mg maintenance dose on Day 15 and every eight weeks thereafter,

[0468] And wherein the patient receives RBC transfusions within four weeks of the maintenance dose and then a supplemental dose of 3300 mg is administered to the patient four weeks after the maintenance dose.

[0469] 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, the anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab) is administered to patients weighing ≥ 100 kg as follows:

[0470] (a) As a single 3000 mg loading dose on Day 1;

[0471] (b) As a single 900 mg loading dose on Day 5;

[0472] (c) As a single 900 mg loading dose on Day 10; and

[0473] (d) As a single 3600 mg maintenance dose on Day 15 and every eight weeks thereafter,

[0474] And wherein the patient receives RBC transfusions within four weeks of the maintenance dose and then a supplemental dose of 3600 mg is administered to the patient four weeks after the maintenance dose.

[0475] In another embodiment, immediate, complete and sustained terminal complement inhibition is achieved following administration of a supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab).

[0476] In one embodiment, the treatment methods disclosed herein further comprise administering best supportive care (BSC) measures. BSC measures include, but are not limited to, transfusion support, corticosteroids, dialysis, and antihypertensive medications.

[0477] 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 the administration cycle) is two weeks or more from the patient's last dose of eculizumab.

[0478] V. Results

[0479] The present disclosure provides methods for treating HSCT-TMA in a patient, the method comprising administering an anti-C5 antibody to the patient. Symptoms of HSCT-TMA include, but are not limited to, for example, microangiopathic hemolytic anemia, thrombocytopenia, endothelial damage, kidney injury, kidney failure, serositis, pulmonary hypertension, and multi-system organ failure.

[0480] A patient treated according to the methods disclosed herein experiences an improvement in at least one sign of HSCT-TMA. Treatment can result in at least one treatment effect selected from the group consisting of, for example, reduction or cessation of microangiopathic hemolytic anemia, thrombocytopenia, endothelial damage, kidney injury, kidney failure, serositis, pulmonary hypertension, and multi-system organ failure, as compared to baseline.

[0481] In another embodiment, treatment results in: (a) a platelet count ≥ 50,000 / mm 3 without transfusion support during the first 7 days, (b) LDH < 1.5 × ULN, and (c) absence of schistocytes (if schistocytes were present at baseline).

[0482] In another embodiment, treatment results in: (a) a platelet count ≥ 50,000 / mm 3 without transfusion support during the first 7 days, (b) LDH < 1.5 × ULN, (c) absence of schistocytes (if schistocytes were present at baseline), and (d) a reduction in proteinuria of at least 50% from baseline. In one embodiment, proteinuria is a protein / creatinine ratio ≥ 0.5 mg / mg.

[0483] In another embodiment, treatment results in a favorable hematological response.

[0484] In another embodiment, treatment results in normalization of LDH, elimination of the need for red blood cell and platelet transfusions

[0485] and disappearance of schistocytes.

[0486] In another embodiment, treatment enables the patient to maintain a hemoglobin ≥ 8 g / dL without transfusion support. In another embodiment, treatment results in a hemoglobin ≥ 8 g / dL without transfusion support.

[0487] In another embodiment, treatment results in a decrease in LDH, an increase in platelets, and / or an increase in hemoglobin as compared to baseline.

[0488] In another embodiment, treatment results in normal levels of serum creatinine as compared to baseline.

[0489] In another embodiment, the treatment results in an improvement in TMA-related organ dysfunction in the renal, cardiovascular, pulmonary, CNS, and / or GI systems compared to baseline.

[0490] In another embodiment, the treatment results in terminal complement inhibition.

[0491] In another embodiment, the treatment results in a reduction in adverse events.

[0492] In another embodiment, the treatment results in a shift of biomarkers related to vascular inflammation (e.g., soluble tumor necrosis factor receptor 1 [TNF-R1]), endothelial injury and / or activation (e.g., thrombomodulin and soluble vascular cell adhesion molecule 1 [VCAM-1]), kidney injury (e.g., cystatin C), and / or complement proteins and complement activation pathway products to normal levels. In another embodiment, the treatment results in a shift of thrombomodulin (TM) and / or syndecan-1 (SYND1) to normal levels. In another embodiment, the treatment results in a shift of complement factor Ba to normal levels.

[0493] In another embodiment, the treatment results in a change in quality of life relative to baseline, as assessed via quality of life assessments (e.g., Pediatric Quality of Life Inventory (PedsQL) scale or EQ-5D-5L questionnaire). The PedsQL 4.0 Generic Core Scale is a multidimensional child self-report and parent proxy-report standardized tool for measuring health-related quality of life (QoL) in children and adolescents aged 2 to 18 years.

[0494] In another embodiment, lactate dehydrogenase (LDH) levels can be used to assess responsiveness to therapy. 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). Red blood cells contain large amounts of LDH, and relationships between cell-free hemoglobin and LDH concentrations have 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). The results of hemolysis are independent of anemia (Hill, A. et al., Haematologica, 93(s1):359Abs.0903, 2008; Kanakura, Y. et al., Int. J. Hematol, 93:36-46, 2011). LDH concentrations obtained at baseline and subsequently serially throughout the treatment phase are important measures of hemolysis. The normal range of LDH values is 105 IU / L - 333 IU / L (International Units per liter).

[0495] LDH levels can be measured using any suitable test or assay, such as those described by Ferri FF, editor, Ferri's Clinical Advisor 2014, Philadelphia: Pa: Elsevier Mosby; 2014: Section IV - Laboratory tests and interpretation of results. LDH concentrations can be measured in a variety of samples obtained from a patient, particularly serum samples. As used herein, the term "sample" refers to a biological material from a subject. Although serum LDH concentration is of interest, samples can be derived from other sources, including for example single cells, multi-cellular, tissue, tumor, biological fluid, biomolecule, or supernatant or extract of any of the foregoing. Examples include tissue removed for biopsy, tissue removed during resection, blood, urine, lymphoid tissue, lymph fluid, cerebrospinal fluid, mucus, and fecal samples. The samples used can vary based on the assay type, detection method, and nature of the tumor, tissue, cell, or extract to be assayed. Methods for preparing samples are known in the art and can be readily adapted to obtain samples compatible with the methods used.

[0496] In one embodiment, a patient treated according to the disclosed method experiences a decrease in LDH level to a normal level or to within 10% or 20% above the normal level (e.g., within 105 IU / L - 333 IU / L). For example, a patient treated according to the disclosed method experiences a decrease in LDH level to within the normal level or to 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 50% below the ULN level (e.g., within 105 IU / L - 333 IU / L (International Units per liter). In one embodiment, prior to initiation of treatment, the patient's LDH level is ≥ 1.5 times the ULN (LDH ≥ 1.5 × ULN).

[0497] In one embodiment, a patient treated according to the disclosed method 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% change in LDH percentage compared to baseline.

[0498] In another aspect, the treatment regimen is sufficient to maintain a specific serum trough concentration of the anti-C5 antibody or an antigen-binding fragment thereof. In one embodiment, for example, the treatment regimen maintains a serum trough concentration of the anti-C5 antibody or an antigen-binding fragment thereof at 50 μg / mL, 55 μg / mL, 60 μg / mL, 65 μg / mL, 70 μg / mL, 75 μg / mL, 80 μg / mL, 85 μg / mL, 90 μg / mL, 95 μg / mL, 100 μg / mL, 105 μg / mL, 110 μg / mL, 115 μg / mL, 120 μg / mL, 125 μg / mL, 130 μg / mL, 135 μg / mL, 140 μg / mL, 145 μg / mL, 150 μg / mL, 155 μg / mL, 160 μg / mL, 165 μg / mL, 170 μg / mL, 175 μg / mL, 180 μg / mL, 185 μg / mL, 190 μg / mL, 200 μg / mL, 205 μg / mL, 210 μg / mL, 215 μg / mL, 220 μg / mL, 225 μg / mL, 230 μg / mL, 240 μg / mL, 245 μg / mL, 250 μg / mL, 255 μg / mL, 260 μg / mL, 265 μg / mL, 270 μg / mL, 280 μg / mL, 290 μg / mL, 300 μg / mL, 305 μg / mL, 310 μg / mL, 315 μg / mL, 320 μg / mL, 325 μg / mL, 330 μg / mL, 335 μg / mL, 340 μg / mL, 345 μg / mL, 350 μg / mL, 355 μg / mL, 360 μg / mL, 365 μg / mL, 370 μg / mL, 375 μg / mL, 380 μg / mL, 385 μg / mL, 390 μg / mL, 395 μg / mL, 400 μg / mL, 405 μg / mL, 410 μg / mL, 415 μg / mL, 420 μg / mL, 425 μg / mL, 430 μg / mL, 435 μg / mL, 440 μg / mL, 445 μg / mL, 450 μg / mL, 455 μg / mL, 460 μg / mL, 465 μg / mL, 470 μg / mL, 475 μg / mL, 480 μg / mL, 485 μg / mL, 490 μg / mL, 495 μg / mL, 500 μg / mL, 505 μg / mL, 510 μg / mL, 515 μg / mL, 520 μg / mL, 525 μg / mL, 530 μg / mL, 535 μg / mL, 540 μg / mL, 545 μg / mL, 550 μg / mL, 555 μg / mL, 560 μg / mL, 565 μg / mL, 570 μg / mL, 575 μg / mL, 580 μg / mL, 585 μg / mL,590 μg / mL, 595 μg / mL, 600 μg / mL, 605 μg / mL, 610 μg / mL, 615 μg / mL, 620 μg / mL, 625 μg / mL, 630 μg / mL, 635 μg / mL, 640 μg / mL, 645 μg / mL, 650 μg / mL, 655 μg / mL, 660 μg / mL, 665 μg / mL, 670 μg / mL, 675 μg / mL, 680 μg / mL, 685 μg / mL, 690 μg / mL, 695 μg / mL, 700 μg / mL or greater. In one embodiment, the treatment regimen maintains a trough serum concentration of the anti-C5 antibody or antigen-binding fragment thereof at 100 μg / mL or greater, 150 μg / mL or greater, 200 μg / mL or greater, 250 μg / mL or greater, 300 μg / mL or greater, 350 μg / mL or greater, 400 μg / mL or greater, or 450 μg / mL or greater. In another embodiment, the treatment maintains the trough serum 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, the treatment maintains the trough serum concentration of the anti-C5 antibody or antigen-binding fragment thereof at about 475 μg / mL. In one embodiment, the treatment regimen maintains a peak serum concentration of the anti-C5 antibody or antigen-binding fragment thereof at less than about 1800 μg / mL, 1780 μg / mL, 1760 μg / mL, 1740 μg / mL, 1720 μg / mL, 1700 μg / mL, 1680 μg / mL, 1660 μg / mL, 1640 μg / mL, 1620 μg / mL, 1600 μg / mL, 1580 μg / mL, 1560 μg / mL, 1540 μg / mL, 1520 μg / mL, 1500 μg / mL, 1480 μg / mL, 1460 μg / mL, 1440 μg / mL, 1420 μg / mL, 1400 μg / mL, 1380 μg / mL, 1360 μg / mL, 1340 μg / mL, 1320 μg / mL, 1300 μg / mL, 1280 μg / mL, 1260 μg / mL, 1240 μg / mL, 1220 μg / mL, 1200 μg / mL, 1180 μg / mL, 1160 μg / mL, 1140 μg / mL, 1120 μg / mL, 1100 μg / mL, 1080 μg / mL, 1060 μg / mL, 1040 μg / mL, 1020 μg / mL, 1000 μg / mL, 980 μg / mL, 960 μg / mL, 940 μg / mL,920 μg / mL or 900 μg / mL or less. In an embodiment, treatment maintains the peak serum concentration of the anti-C5 antibody or its antigen-binding fragment 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 its antigen-binding fragment of about 1350 μg / mL.

[0499] In another embodiment, to obtain an effective response, an anti-C5 antibody is administered to a patient in an amount and frequency to maintain 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, 195 μg, 200 μg, 205 μg, 210 μg, 215 μg, 220 μg, 225 μg, 230 μg, 235 μg, 240 μg, 245 μg, 250 μg, 255 μg, 260 μg, 270 μg, 280 μg, 290 μg, 300 μg, 320 μg, 340 μg, 360 μg, 380 μg, 400 μg, 420 μg, 440 μg, 460 μg, 480 μg, 500 μg, 550 μg, 600 μg, 650 μg, 700 μg, 750 μg, 800 μg, 850 μg, 900 μg, 950 μg, 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 such as 1800 μg of the antibody per milliliter of the patient's blood.

[0500] In an embodiment, to obtain an effective response, an anti-C5 antibody (e.g., ravulizumab) is administered to a patient in an amount and frequency to maintain the minimum and maximum plasma concentrations (± standard deviation) of the anti-C5 antibody (e.g., ravulizumab) preferably between 474 (±200) μg / mL and 1350 (±430) μg / mL during the dosing interval.

[0501] In one embodiment, a patient being treated according to the disclosed method 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).

[0502] In another embodiment, patients treated according to the disclosed methods achieve immediate, complete, and sustained terminal complement inhibition.

[0503] VI. Kits and Unit Dosages

[0504] Also provided herein are kits that include a therapeutically effective amount of a pharmaceutical composition suitable for use in the foregoing methods, the pharmaceutical composition containing an anti-C5 antibody or an antigen-binding fragment thereof such as ravulizumab and a pharmaceutically acceptable carrier. The kit may optionally further include instructions, which for example include an administration schedule, to permit a physician (e.g., doctor, nurse, or patient) to administer the composition contained therein to a patient having HSCT-TMA. The kit may also include a syringe.

[0505] Optionally, the kit includes multiple packages of single-dose pharmaceutical compositions, each package containing an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof for a single administration according to the methods provided above. Instruments or devices necessary for administering the pharmaceutical composition may also be included in the kit. For example, the kit may provide one or more pre-filled syringes containing a quantity of an anti-C5 antibody or an antigen-binding fragment thereof.

[0506] In one embodiment, a kit for treating HSCT-TMA in a human pediatric patient includes: (a) a dose of an anti-C5 antibody or an antigen-binding fragment thereof that includes CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence shown in SEQ ID NO:12, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence shown in SEQ ID NO:8; and (b) instructions for using the anti-C5 antibody or an antigen-binding fragment thereof according to any of the methods described herein.

[0507] In another embodiment, the kit includes loading, maintenance, and supplemental doses of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient weighing 5 kg to <10 kg as follows:

[0508] (a) as a single loading dose of 600 mg on day 1;

[0509] (b) as a single loading dose of 300 mg on day 5;

[0510] (c) as a single loading dose of 300 mg on day 10;

[0511] (d) as a maintenance dose of 300 mg on day 15 and every four weeks thereafter; and

[0512] (e) A supplemental dose of 300 mg, and instructions for administering the supplemental dose to a patient who has received an RBC transfusion within 2 weeks of the maintenance dose, wherein the supplemental dose is administered two weeks after the maintenance dose.

[0513] 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 as follows:

[0514] (a) As a single loading dose of 600 mg on day 1;

[0515] (b) As a single loading dose of 300 mg on day 5;

[0516] (c) As a single loading dose of 300 mg on day 10;

[0517] (d) As a single maintenance dose of 400 mg on day 15 and every four weeks thereafter; and

[0518] (e) A supplemental dose of 400 mg, and instructions for administering the supplemental dose to a patient who has received an RBC transfusion within 2 weeks of the maintenance dose, wherein the supplemental dose is administered two weeks after the maintenance dose.

[0519] 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 as follows:

[0520] (a) As a single loading dose of 600 mg on day 1;

[0521] (b) As a single loading dose of 300 mg on day 5;

[0522] (c) As a single loading dose of 300 mg on day 10;

[0523] (d) As a single maintenance dose of 600 mg on day 15 and every four weeks thereafter, and

[0524] (e) A supplemental dose of 600 mg, and instructions for administering the supplemental dose to a patient who has received an RBC transfusion within 2 weeks of the maintenance dose, wherein the supplemental dose is administered two weeks after the maintenance dose.

[0525] 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 as follows:

[0526] (a) As a single 600 mg loading dose on Day 1;

[0527] (b) As a single 300 mg loading dose on Day 5;

[0528] (c) As a single 300 mg loading dose on Day 10;

[0529] (d) As a single 800 mg maintenance dose on Day 15 and every four weeks thereafter, and

[0530] (e) An 800 mg supplemental dose, and instructions for administering the supplemental dose to a patient who receives an RBC transfusion within two weeks of the maintenance dose, wherein the supplemental dose is administered two weeks after the maintenance dose.

[0531] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient weighing 20 kg to < 30 kg as follows:

[0532] (a) As a single 900 mg loading dose on Day 1;

[0533] (b) As a single 300 mg loading dose on Day 5;

[0534] (c) As a single 300 mg loading dose on Day 10;

[0535] (d) As a single 2100 mg maintenance dose on Day 15 and every eight weeks thereafter; and

[0536] (e) A 2100 mg supplemental dose, and instructions for administering the supplemental dose to a patient who receives an RBC transfusion within four weeks of the maintenance dose, wherein the supplemental dose is administered four weeks after the maintenance dose.

[0537] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient weighing ≥ 30 kg to < 40 kg as follows:

[0538] (a) As a single 1200 mg loading dose on Day 1;

[0539] (b) As a single 300 mg loading dose on Day 5;

[0540] (c) As a single 300 mg loading dose on Day 10;

[0541] (d) As a single 2700 mg maintenance dose on Day 15 and every eight weeks thereafter,

[0542] and (e) a supplemental dose of 2700 mg, and instructions for administering the supplemental dose to a patient who receives an RBC transfusion within 4 weeks of the maintenance dose, wherein the supplemental dose is administered four weeks after the maintenance dose.

[0543] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient having a body weight of ≥ 40 kg to < 60 kg as follows:

[0544] (a) as a single loading dose of 2400 mg on Day 1;

[0545] (b) as a single loading dose of 600 mg on Day 5;

[0546] (c) as a single loading dose of 600 mg on Day 10;

[0547] (d) as a single maintenance dose of 3000 mg on Day 15 and every eight weeks thereafter,

[0548] and (e) a supplemental dose of 3000 mg, and instructions for administering the supplemental dose to a patient who receives an RBC transfusion within 4 weeks of the maintenance dose, wherein the supplemental dose is administered four weeks after the maintenance dose.

[0549] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient having a body weight of ≥ 60 kg to < 100 kg as follows:

[0550] (a) as a single loading dose of 2700 mg on Day 1;

[0551] (b) as a single loading dose of 900 mg on Day 5;

[0552] (c) as a single loading dose of 900 mg on Day 10; and

[0553] (d) as a single maintenance dose of 3300 mg on Day 15 and every eight weeks thereafter,

[0554] and (e) a supplemental dose of 3300 mg, and instructions for administering the supplemental dose to a patient who receives an RBC transfusion within 4 weeks of the maintenance dose, wherein the supplemental dose is administered four weeks after the maintenance dose.

[0555] In another embodiment, the kit comprises a loading dose, a maintenance dose, and a supplemental dose of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient having a body weight of ≥ 100 kg as follows:

[0556] (a) As a single loading dose of 3000 mg on Day 1;

[0557] (b) As a single loading dose of 900 mg on Day 5;

[0558] (c) As a single loading dose of 900 mg on Day 10; and

[0559] (d) As a single maintenance dose of 3600 mg on Day 15 and every eight weeks thereafter,

[0560] and (e) a supplemental dose of 3600 mg, and instructions for administering the supplemental dose to patients who receive an RBC transfusion within 4 weeks of the maintenance dose, wherein the supplemental dose is administered four weeks after the maintenance dose.

[0561] The following examples are illustrative only and should not be construed as limiting the scope of the disclosure in any way, as many variations and equivalents will become apparent to those skilled in the art after reading the disclosure. The contents of all references, GENBANK entries, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference.

[0562] Examples

[0563] Example 1: Evaluation of Ravulizumab Dose Confirmation Analysis in a Global Phase 3 Study of Pharmacokinetics / Pharmacodynamics in Adults and Adolescents Developing Thrombotic Microangiopathy after Hematopoietic Stem Cell Transplantation Figure 1

[0564] A pharmacokinetic-pharmacodynamic (PK-PD) analysis was conducted to confirm the ravulizumab dosing regimen for treating patients with HSCT-TMA in a Phase 3 study, which is described in WO / 2022 / 036151, the content of which is expressly incorporated herein by reference. In addition, a new supplemental dosing regimen was implemented in this study for patients who received platelet or RBC transfusions during treatment.

[0565] The first stage (NCT04543591) of a Phase 3 study of ravulizumab for treating adults and adolescents (aged ≥ 12 years) with HSCT-TMA was an open-label single-arm stage designed to confirm the ravulizumab dosing regimen. Participants received weight-based loading doses on Day 1, Day 5, and Day 10, followed by a maintenance dose on Day 15 and every 8 weeks thereafter. A supplemental dose was administered within 24 hours after any platelet or red blood cell (RBC) transfusion. There was no limit to the number of supplemental doses. Blood samples were collected during treatment for analysis. A dose confirmation analysis (DCA) was conducted once, and at least the first 10 enrolled patients completed it on Day 21.

[0566] DCA consists of three steps. Step 1: Visualize PK and free C5 (primary PD) data. Use a previously established threshold indicating complete C5 inhibition to empirically confirm that the dosing regimen produces appropriate ravulizumab concentrations and provides immediate, complete, and sustained inhibition of free C5. Step 2: Population pharmacokinetic (popPK) modeling of ravulizumab concentration-time data. Apply body weight and transfusions to a previously developed aHUS popPK model to individualize the predicted exposure for each patient with HSCT-TMA and to evaluate the impact of these factors at the patient population level. Standard evaluations are used for model identification. Step 3: Use the qualified popPK model for simulations to confirm / adjust the ravulizumab dosing regimen, including transfusion-related supplementary doses. Perform Monte Carlo simulations of the concentration-time curve to evaluate whether the randomly generated exposures (based on the population variability of PK parameters) will remain above the PK threshold, thus ensuring complete terminal complement inhibition.

[0567] A total of 361 PK observations from 14 patients were included in the empirical evaluation ( Figure 2 and Figure 2 ), revealing that both the PK threshold and the PD threshold are met using the protocol dosing regimen. Additionally, Table 1: Updated Body Weight-Based Ravulizumab Dose Regimen showed that the loading doses on Day 5 and Day 10 appropriately controlled the high baseline levels of complement complexes, with ravulizumab concentrations maintained >175 μg / mL. The qualified popPK model well characterized the dose-concentration relationship. Furthermore, it was determined that faster clearance occurs after RBC transfusions. Taking this into account, the simulations focused on adjusting / optimizing the ravulizumab supplementary dosing related to transfusions.

[0568] The simulations confirmed that the supplementary dosing regimen can be updated such that a supplementary dose of ravulizumab is administered to patients weighing ≥30 kg who receive RBC transfusions during the 4 weeks after the maintenance dose, 4 weeks after the maintenance dose. The dose simulations predicted mean (standard deviation) minimum and maximum concentrations during the dosing interval of 474 (200) μg / mL and 1350 (430) μg / mL, respectively. The updated dosing regimen is summarized in Table 1. The supplementary dosing regimen after transfusions is listed in Table 2. A summary of the actions to be taken if one or more RBC transfusions occur is listed in Table 3.

[0569] Table 2: Post-Transfusion Supplementary Dosing Regimen

[0570]

[0571]

[0572] aWeight-based dosing is based on the patient's weight recorded on the day of the infusion visit. If the weight on the day of the infusion is not available, the weight recorded during the previous study visit is used.

[0573] b A supplemental dose of ravulizumab is administered to participants weighing ≥30 kg who received any red blood cell transfusions within 4 weeks after the maintenance dose, 4 weeks after the maintenance dose. Supplemental dosing is not required during the loading phase and is also not required after platelet transfusions. Q8W, every 8 weeks.

[0574] Table 3: Actions to Take if One or More RBC Transfusions Occur

[0575]

[0576] Example 2: Dosing Regimen for Patients Weighing Less than 30 kg

[0577]

[0578] This thorough DCA confirmed that the updated supplemental ravulizumab dosing regimen achieved immediate, complete, and sustained terminal complement inhibition. Therefore, this dosing regimen has been optimized for the second phase (double-blind, randomized, placebo-controlled phase) of the Phase 3 study of ravulizumab efficacy and safety in HSCT-TMA.

[0579] Table 4: Post-Transfusion Supplementary Dosing Regimen for Patients Weighing Less than 30 kg

[0580] PK-PD analysis was conducted to confirm the ravulizumab dosing regimen for treating patients with HSCT-TMA in the Phase 3 study, substantially as described in Example 1 above and WO / 2022 / 036151. In this study, a supplemental dosing regimen was implemented for patients weighing less than 30 kg who received platelet or RBC transfusions during treatment. The post-transfusion supplemental dosing regimen is listed in Table 4.

[0581] Example 3: Revised Dosing Regimen for Patients Weighing Less than 30 kg

[0582]

[0583] A possible dose confirmation analysis (DCA) was evaluated in ten patients. One of the ten patients was non-evaluable. Two patients had a high frequency of RBC transfusions (referred to as "high ravulizumab clearance"). Seven patients had a PK > 175 mcg / mL during treatment (referred to as "low frequency RBC transfusions").

[0584] The initial DCA failed in 9 / 9 patients (<175 mcg / mL). However, after further investigation, it was determined that "high ravulizumab clearance" patients were the cause of the failed DCA. After removing these two patients with unconfirmed doses (22%), DCA confirmed the doses in the remaining 7 / 9 patients. However, patients <30 kg may further benefit from the revised dosing regimen because it is not possible to know when a patient may become a "high ravulizumab clearance" patient.

[0585] Table 5: Revised Dosing Regimen for Patients Weighing Less than 30 kg

[0586] In Example 2, the dosing regimen shown in Table 4 was confirmed in 7 / 9 patients (22%). However, it was determined that certain patients with a body weight <30 kg and frequent RBC transfusions (e.g., "high ravulizumab clearance" patients with a body weight <30 kg) may not be able to maintain the target trough level (175 mcg / mL) and thus may not achieve complete C5 inhibition. Therefore, this specific group of patients may further benefit from the revised dosing regimen. Therefore, substantially according to the methods described in Examples 1 - 2 and WO / 2022 / 036151, the revised dosing regimen shown in Table 5 was evaluated in this group of patients and the modifications shown were made.

[0587] Table 6: Timing of Post-Transfusion Supplementary Dosing

[0588]

[0589] For all patients, when the patient reaches the midpoint between the maintenance doses shown in Table 6, the need for ravulizumab as a supplemental dose after RBC transfusion is evaluated. For participants with a body weight ≥30 kg, if the participant has received at least 1 RBC transfusion since the last maintenance dose, the supplemental dose after RBC transfusion is administered. For participants with a body weight <20 kg or a body weight ≥20 kg to <30 kg, a clinical algorithm is followed to evaluate the need for supplemental dosing after RBC transfusion.

[0590] Figure 3

[0591]

[0592] * Administer the supplemental dose within the same window for each body weight category. If supplemental dosing is required at the same time as a scheduled study visit, the dosing can be done at that visit.

[0593] When the RBC transfusion daily frequency exceeds > 3.5 days / week (i.e., the threshold when > 10% of patients have a trough level < 175 mcg / mL), the revised dosing regimen triggers the clinical algorithm. Specifically, the clinical algorithm monitors the RBC transfusion days (days under at least one RBC transfusion) and clinical deterioration. Previously, researchers only evaluated whether participants had received at least one RBC transfusion since the last maintenance dose. The revised dosing regimen is proposed to increase both the maintenance dose and the supplemental dose to mitigate the problem. The clinical algorithm is listed in Table 7: Assessment of the Need for Post-Transfusion Supplementary Dosing and summarized in Table 7.

[0594] Table 8: Supplementary Dosing Regimen

[0595]

[0596] For all participants, if no RBC transfusion is administered, no supplemental dosing is required.

[0597] For patients who exhibit clinical deterioration, supplemental doses of ravulizumab are permitted during the treatment phase after the first maintenance dose is administered on Day 15. Clinical deterioration is defined as meeting two or more of the following criteria:

[0598] 1. Serum creatinine doubles relative to baseline or new dialysis is required;

[0599] 2. LDH increases > 25% compared to baseline;

[0600] 3. Thrombocytopenia > 25% compared to baseline;

[0601] 4. Hemoglobin decreases > 10% compared to baseline; and / or

[0602] 5. An increase in the need for platelets or RBCs at any time.

[0603] The criteria for clinical deterioration are confirmed by two independent samples collected at least 8 hours apart (ideally 24 hours apart).

[0604] The supplemental dosing regimen according to the present disclosure is summarized in Table 8 below:

[0605] Sequence Overview

[0606]

[0607] The minimum assessments conducted during any supplemental dosing visit for the administration of ravulizumab include a urine pregnancy test, pre-dose PK / PD blood sample collection, and vital signs.

[0608] ​

[0609]

[0610]

[0611]

[0612]

[0613]

Claims

1. A method of treating a human patient suffering from 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 an antigen-binding fragment thereof, the anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NO: 19, 18 and 3 respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NO: 4, 5 and 6 respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered as follows: (a) As a loading dose of 600 mg on day 1 for a patient weighing 5 kg to < 10 kg, 600 mg for a patient weighing 10 kg to < 20 kg, 900 mg for a patient weighing 20 kg to < 30 kg, 1200 mg for a patient weighing ≥ 30 kg to < 40 kg, 2400 mg for a patient weighing ≥ 40 kg to < 60 kg, 2700 mg for a patient weighing ≥ 60 kg to < 100 kg or 3000 mg for a patient weighing ≥ 100 kg, once; (b) As a loading dose of 300 mg on day 5 for a patient weighing 5 kg to < 10 kg, 300 mg for a patient weighing 10 kg to < 20 kg, 300 mg for a patient weighing 20 kg to < 30 kg, 300 mg for a patient weighing ≥ 30 kg to < 40 kg, 600 mg for a patient weighing ≥ 40 kg to < 60 kg, 900 mg for a patient weighing ≥ 60 kg to < 100 kg or 900 mg for a patient weighing ≥ 100 kg, once; (c) As a loading dose of 300 mg on day 10 for a patient weighing 5 kg to < 10 kg, 300 mg for a patient weighing 10 kg to < 20 kg, 300 mg for a patient weighing 20 kg to < 30 kg, 300 mg for a patient weighing ≥ 30 kg to < 40 kg, 600 mg for a patient weighing ≥ 40 kg to < 60 kg, 900 mg for a patient weighing ≥ 60 kg to < 100 kg or 900 mg for a patient weighing ≥ 100 kg, once; and (d) On day 15 and (i) Thereafter, as a maintenance dose of 300 mg or 400 mg every four weeks for a patient weighing 5 kg to < 10 kg or 600 mg or 800 mg every four weeks for a patient weighing 10 kg to < 20 kg, once, or (ii) Thereafter, as a maintenance dose of 2100 mg every eight weeks for a patient weighing 20 kg to < 30 kg, 2700 mg every eight weeks for a patient weighing ≥ 30 kg to < 40 kg, 3000 mg every eight weeks for a patient weighing ≥ 40 kg to < 60 kg, 3300 mg every eight weeks for a patient weighing ≥ 60 kg to < 100 kg or 3600 mg every eight weeks for a patient weighing ≥ 100 kg; And wherein the supplemental dose is administered as follows: (i) Administered to patients weighing < 30 kg who receive red blood cell (RBC) transfusions within a specific time frame of the maintenance dose, wherein the supplementary dose is administered at the following dose under the specific time frame after the maintenance dose: a. 300 mg or 400 mg for patients weighing 5 kg to < 10 kg, wherein the specific time frame is two weeks, b. 600 mg or 800 mg for patients weighing 10 kg to < 20 kg, wherein the specific time frame is two weeks, or c. 2100 mg for patients weighing 20 kg to < 30 kg, wherein the specific time frame is four weeks, or (ii) Administered to patients weighing ≥ 30 kg who receive red blood cell (RBC) transfusions within four weeks of the maintenance dose, wherein the supplementary dose is administered at the following dose four weeks after the maintenance dose: a. 2700 mg for patients weighing ≥ 30 kg to < 40 kg, b. 3000 mg for patients weighing ≥ 40 kg to < 60 kg, c. 3300 mg for patients weighing ≥ 60 to < 100 kg, or d. 3600 mg for patients weighing ≥ 100 kg.

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

3. The method according to claim 1 or 2, wherein the anti-C5 antibody comprises a heavy chain variable region shown in SEQ ID NO: 12 and a light chain variable region shown in SEQ ID NO:

8.

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

13.

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

11.

6. The method according to any one of the preceding claims, wherein the anti-C5 antibody binds to human C5 with an affinity dissociation constant (K D ) in the range of 0.1 nM ≤ K D ≤ 1 nM (e.g., about 0.5 nM) at pH 7.4 and 25 °C.

7. The method according to any one of the preceding claims, wherein the anti-C5 antibody binds to human C5 at pH 6.0 and 25 °C with a K D ≥ 10 nM (e.g., about 22 nM).

8. The method according to any one of the preceding claims, wherein the anti-C5 antibody is administered to patients weighing 5 kg to < 10 kg as follows: (a) As a single loading dose of 600 mg on day 1; (b) As a single loading dose of 300 mg on day 5; (c) As a single loading dose of 300 mg on day 10; (d) As a single maintenance dose of 300 mg on day 15 and every four weeks thereafter; and (e) A supplementary dose of 300 mg is administered to patients receiving RBC transfusions within 2 weeks of the maintenance dose, and wherein the supplementary dose is administered two weeks after the maintenance dose.

9. The method according to any one of claims 1 to 7, wherein the anti-C5 antibody is administered to patients weighing 5 kg to < 10 kg as follows: (a) As a single loading dose of 600 mg on day 1; (b) as a single 300 mg loading dose on day 5; (c) as a single 300 mg loading dose on day 10; (d) as a single 400 mg maintenance dose on day 15 and every four weeks thereafter; and (e) a supplemental dose of 400 mg is administered to patients receiving RBC transfusions two weeks into the maintenance dose, and wherein the supplemental dose is administered two weeks after the maintenance dose.

10. The method according to any one of claims 1 to 7, wherein the anti-C5 antibody is administered to a patient weighing 10 kg to <20 kg as follows: (a) as a single 600 mg loading dose on day 1; (b) as a single 300 mg loading dose on day 5; (c) as a single 300 mg loading dose on day 10; (d) as a single 600 mg maintenance dose on day 15 and every four weeks thereafter, and (e) a supplemental dose of 600 mg is administered to patients receiving RBC transfusions two weeks into the maintenance dose, and wherein the supplemental dose is administered two weeks after the maintenance dose.

11. The method according to any one of claims 1 to 7, wherein the anti-C5 antibody is administered to a patient weighing 10 kg to <20 kg as follows: (a) as a single 600 mg loading dose on day 1; (b) as a single 300 mg loading dose on day 5; (c) as a single 300 mg loading dose on day 10; (d) as a single 800 mg maintenance dose on day 15 and every four weeks thereafter, and (e) a supplemental dose of 800 mg is administered to patients receiving RBC transfusions two weeks into the maintenance dose, and wherein the supplemental dose is administered two weeks after the maintenance dose.

12. The method according to any one of claims 8 to 12, wherein the supplemental dose is administered if necessary according to the clinical algorithm shown in Figure 3. (a) as a single 900 mg loading dose on day 1; (b) as a single 300 mg loading dose on day 5; (c) as a single 300 mg loading dose on day 10; (d) as a single 2100 mg maintenance dose on day 15 and every eight weeks thereafter; and (e) a supplemental dose of 2100 mg is administered to patients receiving RBC transfusions four weeks into the maintenance dose, and wherein the supplemental dose is administered four weeks after the maintenance dose.

13. The method according to any one of claims 8 to 12, wherein the supplemental dose is administered if necessary according to the clinical algorithm shown in Figure 3.

14. The method according to any one of claims 1 to 7, wherein the anti-C5 antibody is administered to a patient weighing ≥30 kg to <40 kg as follows: (a) as a single 1200 mg loading dose on day 1; (b) as a single 300 mg loading dose on day 5; (c) as a single 300 mg loading dose on day 10; (d) as a single 2700 mg maintenance dose on day 15 and every eight weeks thereafter.

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

16. The method according to any one of claims 1 to 7, wherein the anti-C5 antibody is administered to a patient with a body weight of ≥40 kg to <60 kg as follows: (a) As a single loading dose of 2400 mg on day 1; (b) As a single loading dose of 600 mg on day 5; (c) As a single loading dose of 600 mg on day 10; and (d) As a maintenance dose of 3000 mg on day 15 and every eight weeks thereafter.

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

18. The method according to any one of claims 1 to 7, wherein the anti-C5 antibody is administered to a patient with a body weight of ≥60 kg to <100 kg as follows: (a) As a single loading dose of 2700 mg on day 1; (b) As a single loading dose of 900 mg on day 5; (c) As a single loading dose of 900 mg on day 10; and (d) As a maintenance dose of 3300 mg on day 15 and every eight weeks thereafter.

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

20. The method according to any one of claims 1 to 7, wherein the anti-C5 antibody is administered to a patient with a body weight of ≥100 kg as follows: (a) As a single loading dose of 3000 mg on day 1; (b) As a single loading dose of 900 mg on day 5; (c) As a single loading dose of 900 mg on day 10; and (d) As a maintenance dose of 3600 mg on day 15 and every eight weeks thereafter.

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

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

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

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

25. The method according to any one of the preceding claims, wherein the treatment is an administration cycle comprising a total of 26 weeks of treatment.

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

27. The method according to any one of the preceding claims, wherein the treatment results in: (a) a platelet count ≥ 50,000 / mm without blood transfusion support during the first 7 days 3 , (b) LDH < 1.5 × ULN, and (c) the absence of schistocytes (if schistocytes were present at baseline).

28. The method according to any one of the preceding claims, wherein the treatment results in: (a) a platelet count ≥ 50,000 / mm without blood transfusion support during the first 7 days 3 , (b) LDH < 1.5 × ULN, (c) absence of schistocytes (if schistocytes are present at baseline) and (d) a reduction in proteinuria of at least 50% from baseline.

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

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

31. The method according to any one of the preceding claims, wherein the treatment results in a hemoglobin level of ≥ 8 g / dL without transfusion support.

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

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

34. The method according to any one of the preceding claims, wherein the treatment results in improvement of TMA-related organ dysfunction in the kidney, cardiovascular, pulmonary, CNS, and / or GI systems as compared to the baseline.

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

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

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

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

39. The method according to any one of the preceding claims, wherein the treatment results in a change in quality of life as compared to the baseline as evaluated by quality of life assessment.

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

41. The method according to any one of the preceding claims, wherein the treatment results in a decrease in lactate dehydrogenase (LDH) level as compared to the baseline.

42. The method according to any one of the preceding claims, wherein the treatment results in a decrease in free C5 concentration or a decrease in red blood cell (RBC) hemolysis in the patient; in particular, wherein the treatment results in a free C5 concentration of 0.5 μg / mL or lower and / or RBC hemolysis of 20% or lower as compared to untreated patients.

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

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

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

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

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

48. An anti-C5 antibody or an antigen-binding fragment thereof for treating HSCT-TMA patients who have undergone an RBC transfusion during the first half of the maintenance phase of treatment, wherein the anti-C5 antibody or an antigen-binding fragment thereof is administered as follows: (a) a single loading dose of 600 mg on day 1 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; (b) a single loading dose of 300 mg on day 5 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; (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 on day 10; and (d) On day 15 and (i) Thereafter, 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 every four weeks, or (ii) Thereafter, 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 every eight weeks; And the supplementary dose is administered as follows: (i) Administered to patients weighing < 30 kg who receive red blood cell (RBC) transfusions within a specific time frame of the maintenance dose, where the supplementary dose is administered at the following doses under the specific time frame: a. 300 mg or 400 mg for patients weighing 5 kg to < 10 kg, where the specific time frame is two weeks, b. 600 mg or 800 mg for patients weighing 10 kg to < 20 kg, where the specific time frame is two weeks, or c. 2100 mg for patients weighing 20 kg to < 30 kg, where the specific time frame is four weeks, or (ii) Administered to patients weighing ≥ 30 kg who receive red blood cell (RBC) transfusions within four weeks of the maintenance dose, where the supplementary dose is administered at the following doses four weeks after the maintenance dose: a. 2700 mg for patients weighing ≥ 30 kg to < 40 kg, b. 3000 mg for patients weighing ≥ 40 kg to < 60 kg, c. 3300 mg for patients weighing ≥ 60 to < 100 kg, or d. 3600 mg for patients weighing ≥ 100 kg.

49. Use of an anti-C5 antibody or an antigen-binding fragment thereof for treating HSCT-TMA patients who have undergone RBC transfusions during the first half of the maintenance phase of treatment, where the anti-C5 antibody or an antigen-binding fragment thereof is administered as follows: (a) On the first day, 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; (b) On the fifth day, 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; (c) On the tenth day, 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; and (d) On the fifteenth day and (i) Thereafter, 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 once every four weeks, or (ii) Thereafter, 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 once every eight weeks; And wherein the supplementary dose is administered as follows: (i) To patients weighing < 30 kg who receive red blood cell (RBC) transfusions within a specific time frame of the maintenance dose, wherein the supplementary dose is administered at the following doses within the specific time frame: a. 300 mg or 400 mg for patients weighing 5 kg to < 10 kg, wherein the specific time frame is two weeks, b. 600 mg or 800 mg for patients weighing 10 kg to < 20 kg, wherein the specific time frame is two weeks, or c. 2100 mg for patients weighing 20 kg to < 30 kg, wherein the specific time frame is four weeks, or (ii) Administered to patients weighing ≥ 30 kg who receive red blood cell (RBC) transfusions within four weeks of the maintenance dose, wherein the supplemental dose is administered four weeks after the maintenance dose at the following doses: a. 2700 mg for patients weighing ≥ 30 kg to < 40 kg, b. 3000 mg for patients weighing ≥ 40 kg to < 60 kg, c. 3300 mg for patients weighing ≥ 60 to < 100 kg, or d. 3600 mg for patients weighing ≥ 100 kg.

50. The anti-C5 antibody or antigen-binding fragment thereof according to claim 48, wherein the anti-C5 antibody or antigen-binding fragment thereof is ravulizumab 51. The use according to claim 49, wherein the anti-C5 antibody or antigen-binding fragment thereof is ravulizumab

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