Dosage and administration of anti-C5 antibodies for treating paroxysmal nocturnal hemoglobinuria (PNH) in pediatric patients

Abstract

Methods are provided for the clinical treatment of paroxysmal nocturnal hemoglobinuria (PNH) in pediatric patients using anti-C5 antibodies or antigen-binding fragments thereof. Provided herein are compositions and methods for treating paroxysmal nocturnal hemoglobinuria (PNH) in human pediatric patients, comprising administering to the patient an anti-C5 antibody or antigen-binding fragment thereof, where the anti-C5 antibody or antigen-binding fragment thereof is administered (or is for administration) according to a specific clinical dosing regimen (e.g., at a specific dosage and according to a specific dosing regimen).

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 049,768, filed July 9, 2020, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Paroxysmal nocturnal hemoglobinuria (PNH) is a progressive, debilitating, and life-threatening disorder characterized by complement-mediated hemolysis, thrombosis, and bone marrow dysfunction. PNH has a global estimated incidence of 1.3 per million people. Onset of PNH is usually in adulthood, with pediatric cases accounting for less than 5% of reported cases. Assuming a very small target population, research on children with PNH is limited to case reports, case series, and small clinical trials.

[0003] In adults, clinical manifestations of PNH include hemoglobinuria, chronic renal failure, erectile dysfunction, thrombosis, abdominal pain, dyspnea, and dysphagia. In contrast, children with PNH typically present with nonspecific symptoms associated with the underlying disease, such as pallor, fatigue, or jaundice, and hemoglobinuria is less common. Clinical evaluation in pediatric patients may also reveal bone marrow dysfunction syndromes, such as aplastic anemia and refractory cytopenia. If bone marrow damage is restored in children, or if the PNH clone expands (the cause of which is still unknown), the disease eventually evolves into one or more manifestations typically seen in adults.

[0004] Therefore, pediatric patients can be expected to suffer from a considerable number of pathological conditions associated with hemolysis, as seen in adult PNH patients. Accordingly, an object of the disclosure of this invention is to provide an improved method for treating patients with PNH. [Overview of the Initiative] [Means for solving the problem]

[0005] Compositions and methods for treating paroxysmal nocturnal hemoglobinuria (PNH) in human pediatric patients are provided herein, comprising administering an anti-C5 antibody or an antigen-binding fragment thereof to a patient, wherein the anti-C5 antibody or the antigen-binding fragment thereof is administered (or intended for administration) (e.g., in a specific dose and according to a specific administration plan) according to a particular clinical dosing schedule.

[0006] An exemplary anti-C5 antibody is ravulizumab (ULTOMIRIS®) comprising the heavy and light chains having the sequences shown in SEQ ID NOs: 14 and 11, respectively, or the antigen-binding fragments and variants thereof. In other embodiments, the antibody comprises the heavy and light chain complementarity-determining regions (CDRs) or variable regions (VRs) of ravulizumab. Thus, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable (VH) region of ravulizumab having the sequence 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 the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs: 4, 5, and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences described in SEQ ID NO: 12 and SEQ ID NO: 8, respectively. In yet another embodiment, the antibody comprises a heavy chain constant region described in SEQ ID NO: 13.

[0007] 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 includes Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of the natural human IgG Fc constant region, respectively, in accordance with EU numbering rules.

[0008] In another embodiment, the antibody comprises, respectively, the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs: 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs: 4, 5, and 6, and a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region includes Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of the natural human IgG Fc constant region, respectively, in accordance with EU numbering rules.

[0009] In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDR or variable region of the BNJ421 antibody (as described in International Publication No. 2015134894 and U.S. Patent No. 9,079,949). In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDR or variable region 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 CDR or variable region 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 CDR or variable region 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 CDR or variable region of the SKY59 antibody. In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the REGN3918 antibody.

[0010] In another embodiment, the antibody competes for binding to the same epitope on C5 as any of the antibodies described above, and / or binds 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 antibodies described above (e.g., at least about 90%, 95%, or 99% variable region identity with SEQ ID NO: 12 or SEQ ID NO: 8).

[0011] In another embodiment, the antibody is in the range 0.1 nM ≤ KD Affinity dissociation constant (K) for ≤1nM D ) binds to human C5 at pH 7.4 and 25°C. In another embodiment, the antibody is K D The antibody binds to human C5 at a concentration of ≥10 nM, pH 6.0, and 25°C. In yet another embodiment, the antibody or its antigen-binding fragment against human C5 at pH 6.0 and 25°C is K D ) / (Antibody against human C5 or its antigen-binding fragment at pH 7.4 and 25°C) D )] exceeds 25.

[0012] In one embodiment, the dose of anti-C5 antibody or its antigen-binding fragment is based on the patient's body weight. In one embodiment, for example, 300 mg of anti-C5 antibody or its antigen-binding fragment is administered to a patient weighing 5 kg or more but less than 10 kg. In another embodiment, for example, 600 mg of anti-C5 antibody or its antigen-binding fragment is administered to a patient weighing 10 kg or more but less than 20 kg. In another embodiment, 900 mg or 2100 mg of anti-C5 antibody or its antigen-binding fragment is administered to a patient weighing 20 kg or more but less than 30 kg. In another embodiment, 1200 mg or 2700 mg of anti-C5 antibody or its antigen-binding fragment is administered to a patient weighing 30 kg or more but less than 40 kg. In another embodiment, 2400 mg or 3000 mg of C5 antibody or its antigen-binding fragment is administered to a patient weighing 40 kg or more but less than 60 kg. In another embodiment, 2700 mg or 3300 mg of C5 antibody or its antigen-binding fragment is administered to patients weighing 60 kg or more but less than 100 kg. In yet another embodiment, 3000 mg or 3600 mg of C5 antibody or its antigen-binding fragment is administered to patients weighing 100 kg or more. In a particular embodiment, the dosing regimen is adjusted to provide the optimal desired response (e.g., an effective response).

[0013] In another embodiment, the anti-C5 antibody or its antigen-binding fragment is administered in one or more administration cycles. In one embodiment, the treatment (e.g., administration cycle) is 26 weeks. In one embodiment, the anti-C5 antibody or its antigen-binding fragment is administered once on day 1 (e.g., of the administration cycle), once on day 15 (e.g., of the administration cycle), and thereafter every 4 weeks. In another embodiment, the anti-C5 antibody or its antigen-binding fragment is administered once on day 1 (e.g., of the administration cycle), once on day 15 (e.g., of the administration cycle), and thereafter every 8 weeks. In another embodiment, an anti-C5 antibody or its antigen-binding fragment is administered every 4 or 8 weeks after treatment (e.g., in doses of 300 mg, 600 mg, 900 mg, 1200 mg, 2100 mg, 2400 mg, 2700 mg, 3000 mg, 3300 mg, or 3600 mg) for an extension period of up to 2 years.

[0014] In another embodiment, a method is provided for treating a human patient having PNH, the method comprising administering to the patient an effective amount of an anti-C5 antibody or its antigen-binding fragment, comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs: 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs: 4, 5, and 6, respectively (e.g., during a dosing cycle), wherein the anti-C5 antibody or its antigen-binding fragment is administered once on day 1 at a dose of 600 mg for patients weighing 5 kg to less than 10 kg, 600 mg for patients weighing 10 kg to less than 20 kg, 900 mg for patients weighing 20 kg to less than 30 kg, and 1200 mg for patients weighing 30 kg to less than 40 kg. (b) On the 15th day and every 4 weeks thereafter, patients weighing 5 kg or more but less than 10 kg shall be given a dose of 300 mg, or patients weighing 100 kg or more shall be given a dose of 3000 mg; or on the 15th day and every 8 weeks thereafter, patients weighing 20 kg or more but less than 30 kg shall be given a dose of 2100 mg, patients weighing 30 kg or more but less than 40 kg shall be given a dose of 2700 mg, patients weighing 40 kg or more but less than 60 kg shall be given a dose of 3000 mg, patients weighing 60 kg or more but less than 100 kg shall be given a dose of 3300 mg, or patients weighing 100 kg or more shall be given a dose of 3600 mg.

[0015] In another embodiment, a method is provided for treating a human patient having PNH, the method comprising administering to the patient (e.g., during a dosing cycle) an effective amount of an anti-C5 antibody or its antigen-binding fragment comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively, the anti-C5 antibody or its antigen-binding fragment being administered once on day 1, at a dose of 5 kg of body weight. (b) Administered at a dose of 600 mg to patients weighing 10 kg or more but less than 10 kg, 600 mg to patients weighing 10 kg or more but less than 20 kg, 900 mg to patients weighing 20 kg or more but less than 30 kg, 1200 mg to patients weighing 30 kg or more but less than 40 kg, 2400 mg to patients weighing 40 kg or more but less than 60 kg, 2700 mg to patients weighing 60 kg or more but less than 100 kg, or 3000 mg to patients weighing 100 kg or more; (b) on day 15 and every 4 weeks thereafter For patients weighing 5 kg or more but less than 10 kg, the dose is 300 mg, or for patients weighing 10 kg or more but less than 20 kg, the dose is 600 mg; or on the 15th day and every 8 weeks thereafter, the dose is 2100 mg for patients weighing 20 kg or more but less than 30 kg, 2700 mg for patients weighing 30 kg or more but less than 40 kg, 3000 mg for patients weighing 40 kg or more but less than 60 kg, 3300 mg for patients weighing 60 kg or more but less than 100 kg, or for patients weighing 100 kg or more When administered at a dose of 3600 mg, the treatment results in a reduction of LDH levels to within normal levels or to ULN levels (e.g., within 50% of values ​​considered to be 105-333 IU / L (International Units / liter)), with serum trough concentrations of at least 175 μg / mL or higher for anti-C5 antibody or its antigen-binding fragments, and / or free C5 concentrations of 0.5 μg / mL or lower (e.g., 0.4 μg / mL, 0.3 μg / mL, 0.2 μg / mL, or 0.1 μg / mL or lower).

[0016] In another embodiment, the treatment results in a reduction of at least one clinical parameter selected from (a) % change in lactate dehydrogenase (LDH) from baseline (LDH-PCHG); (b) transfusion avoidance (TA); (c) pediatric FACIT fatigue (FACIT); (d) hemoglobin stabilization (HGB-S); (e) % change in free hemoglobin from baseline (free HGB-PCHG); and (f) breakthrough hemolysis (BTH) or a combination thereof, preferably with respect to a reduction in breakthrough hemolysis (BTH).

[0017] In another embodiment, the treatment eliminates breakthrough hemolysis (BTH). In another embodiment, a method is provided for treating a human patient having PNH, the method comprising administering to the patient an effective amount of an anti-C5 antibody or its antigen-binding fragment (e.g., during an administration cycle) the variant human Fc constant region which binds to the human neonatal Fc receptor (FcRn), comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs: 19, 18, and 3, respectively, the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs: 4, 5, and 6, respectively, and a variant human Fc constant region which binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region is a natural human IgG, each conforming to the EU numbering rules. The anti-C5 antibody or its antigen-binding fragment contains Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 in the Fc constant region, and is administered once on day 1 in doses of 600 mg for patients weighing 5 kg or more but less than 10 kg, 600 mg for patients weighing 10 kg or more but less than 20 kg, 900 mg for patients weighing 20 kg or more but less than 30 kg, 1200 mg for patients weighing 30 kg or more but less than 40 kg, 2400 mg for patients weighing 40 kg or more but less than 60 kg, 2700 mg for patients weighing 60 kg or more but less than 100 kg, or (b) On day 15 and every four weeks thereafter, patients weighing 5 kg or more are given a dose of 300 mg, or patients weighing 10 kg or more but less than 20 kg are given a dose of 600 mg; or on day 15 and every eight weeks thereafter, patients weighing 20 kg or more but less than 30 kg are given a dose of 2100 mg, patients weighing 30 kg or more but less than 40 kg are given a dose of 2700 mg, patients weighing 40 kg or more but less than 60 kg are given a dose of 3000 mg, patients weighing 60 kg or more but less than 100 kg are given a dose of 3300 mg, or patients weighing 100 kg or more are given a dose of 3600 mg.

[0018] In another embodiment, an anti-C5 antibody or its antigen-binding fragment is administered to patients weighing between 5 kg and 10 kg: (a) once on day 1 at a dose of 600 mg; and (b) on day 15 and every 4 weeks thereafter at a dose of 300 mg.

[0019] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 10 kg or more but less than 20 kg: (a) once on day 1 at a dose of 600 mg; and (b) at a dose of 600 mg on day 15 and every 4 weeks thereafter.

[0020] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 20 kg or more but less than 30 kg: (a) once on day 1 at a dose of 900 mg; and (b) at a dose of 2100 mg on day 15 and every 8 weeks thereafter.

[0021] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 30 kg or more but less than 40 kg: (a) once on day 1 at a dose of 1,200 mg; and (b) at a dose of 2,700 mg on day 15 and every 8 weeks thereafter.

[0022] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 40 kg or more but less than 60 kg: (a) once on day 1 at a dose of 2,400 mg; and (b) at a dose of 3,000 mg on day 15 and every 8 weeks thereafter.

[0023] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 60 kg or more but less than `100 kg: (a) once on day 1 at a dose of 2,700 mg; and (b) at a dose of 3,300 mg on day 15 and every 8 weeks thereafter.

[0024] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 100 kg or more: (a) once on day 1 at a dose of 3,000 mg; and (b) at a dose of 3,600 mg on day 15 and every 8 weeks thereafter.

[0025] [[ID=二十]]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 2 weeks or more after the patient's last dose of eculizumab.

[0026] In another embodiment, the described therapeutic dosing schedule is sufficient to maintain a specific serum trough concentration of anti-C5 antibody or its antigen-binding fragment. In one embodiment, for example, the therapeutic dosing schedule is 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 205, 210, 215, 220, 225, 230, 240 , 245, 250, 255, 260, 265, 270, 280, 290, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395 or 400 μg / mL or higher of anti-C5 antibody or its antigen-binding fragment. In one embodiment, the treatment regimen maintains serum trough concentrations of anti-C5 antibody or its antigen-binding fragment of 100 μg / mL or higher, 150 μg / mL or higher, 200 μg / mL or higher, 250 μg / mL or higher, or 300 μg / mL or higher. In another embodiment, the treatment maintains serum trough concentrations of anti-C5 antibody or its antigen-binding fragment of 100-200 μg / mL. In another embodiment, the treatment maintains a serum trough concentration of approximately 175 μg / mL of anti-C5 antibody or its antigen-binding fragment.

[0027] In another embodiment, to obtain an effective response, 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 per milliliter of patient blood, In another embodiment, the patient is administered anti-C5 antibody at a dose and frequency that maintains 155 μg, 160 μg, 165 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg, 195 μg, 200 μg, 205 μg, 210 μg, 215 μg, 220 μg, 225 μg, 230 μg, 235 μg, 240 μg, 245 μg, 250 μg, 255 μg, or 260 μg of antibody. In yet another embodiment, the patient is administered anti-C5 antibody at a dose and frequency that maintains 50 to 250 μg of antibody per milliliter of the patient's blood. In yet another embodiment, the patient is administered anti-C5 antibody at a dose and frequency that maintains 100 to 200 μg of antibody per milliliter of the patient's blood. In another embodiment, the patient is administered anti-C5 antibody at a rate and frequency that maintains approximately 175 μg of antibody per milliliter of the patient's blood.

[0028] In another embodiment, the patient is administered an anti-C5 antibody in an amount and frequency that maintains a minimum free C5 concentration in order to obtain an effective response. In one embodiment, for example, the patient is administered an anti-C5 antibody in an amount and frequency that maintains 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).

[0029] An anti-C5 antibody, or its antigen-binding fragment, may be administered to a patient by any suitable means. In one embodiment, the antibody is formulated for intravenous administration.

[0030] The effectiveness of the therapies provided herein can be evaluated by any appropriate means. In one embodiment, in pediatric PNH patients, the treatment results in at least one therapeutic effect selected from the group consisting of a reduction or cessation of fatigue, abdominal pain, dyspnea, dysphagia, and chest pain compared to baseline. In another embodiment, the treatment results in terminal complement inhibition. In another embodiment, the treatment results in a reduction of hemolysis, as assessed by lactate dehydrogenase (LDH) levels, compared to baseline. In another embodiment, the treatment results in a shift to normal levels of at least one hemolysis-related hematological biomarker selected from the group consisting of, for example, free hemoglobin, haptoglobin, reticulocyte count, PNH red blood cell (RBC) clones, and D-dimer. In another embodiment, the treatment results in a reduction in the need for blood transfusions compared to baseline. In another embodiment, the treatment results in a reduction of major vascular adverse events (MAVEs). In another embodiment, treatment shifts the estimated glomerular filtration rate (eGFR) and a chronic disease-related biomarker selected from the group consisting of spot urine:albumin:creatinine and plasma midbrain natriuretic peptide (BNP) to normal levels. In another embodiment, treatment results in a change from baseline in quality of life, as assessed by the Functional Assessment Version 4 of the Treatment for Chronic Disease (FACIT) Fatigue Scale and the European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire Core 30 Scale, compared to baseline.

[0031] In certain embodiments, the response to therapy is evaluated using LDH levels (e.g., a reduction in hemolysis as evaluated by LDH levels indicates improvement in at least one sign of PNH). In one embodiment, a patient treated according to the method of disclosure experiences a reduction in LDH levels to near normal levels (e.g., within 105–333 IU / L (International Units / L)), or to levels within 10% or 20% above levels considered normal. In another embodiment, the patient's LDH levels are normalized throughout the entire maintenance period of treatment. In another embodiment, the treated patient's LDH levels are normalized for at least 95% of the maintenance period of treatment. In another embodiment, the treated patient's LDH levels are normalized for at least 90%, 85%, or 80% of the maintenance period of treatment. In one embodiment, the patient's LDH levels are 1.5 times the upper limit of normal (LDH ≥ 1.5 × ULN) before initiating treatment.

[0032] In one embodiment, in patients treated according to the disclosed method, LDH levels are reduced to within normal levels, or to levels 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 what is considered the ULN level (e.g., within 105–333 IU / L (International Units / L)). In one embodiment, the patient's LDH level is 1.5 times or more the ULN before initiating treatment (LDH ≥ 1.5 × ULN).

[0033] In one embodiment, a patient treated according to the method of disclosure experiences a change in LDH% of 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% compared to baseline.

[0034] In one embodiment, a patient treated according to the method of disclosure maintains a serum trough concentration of at least 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 205, 210, 215, 220, 225, 230, 240, 245, 250, 255, 260, 265, 270, 280, 290, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 μg / mL or higher of anti-C5 antibody or its antigen-binding fragment. In one embodiment, patients treated according to the disclosed method maintain a serum trough concentration of at least 175 μg / mL or higher of anti-C5 antibody or its antigen-binding fragment.

[0035] In one embodiment, a patient 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).

[0036] In one embodiment, patients treated according to the disclosed method do not experience breakthrough hemolysis (BTH).

[0037] In another embodiment, an anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence described in SEQ ID NO: 12, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence described in SEQ ID NO: 8, wherein (a) once on day 1, a dose of 600 mg for patients weighing 5 kg or more but less than 10 kg, a dose of 600 mg for patients weighing 10 kg or more but less than 20 kg, a dose of 900 mg for patients weighing 20 kg or more but less than 30 kg, a dose of 1200 mg for patients weighing 30 kg or more but less than 40 kg, a dose of 2400 mg for patients weighing 40 kg or more but less than 60 kg, and a dose of 2 (b) an anti-C5 antibody or its antigen-binding fragment is provided, which is administered at a dose of 700 mg, or 3000 mg to patients weighing 100 kg or more; (b) at a dose of 300 mg to patients weighing 5 kg or more but less than 10 kg, or at a dose of 600 mg to patients weighing 10 kg or more but less than 20 kg, on the 15th day and every 4 weeks thereafter; or at a dose of 2100 mg to patients weighing 20 kg or more but less than 30 kg, 2700 mg to patients weighing 30 kg or more but less than 40 kg, 3000 mg to patients weighing 40 kg or more but less than 60 kg, 3300 mg to patients weighing 60 kg or more but less than 100 kg, or at a dose of 3600 mg to patients weighing 100 kg or more.

[0038] In one embodiment, the antibody is determined to be safe, tolerable, and sufficiently non-immunogenic after multiple intravenous doses for use in pediatric patients with PNH.

[0039] Further provided are kits comprising a pharmaceutical composition containing an anti-C5 antibody, such as ravulizumab, or an antigen-binding fragment thereof, and a pharmaceutically acceptable carrier, in a therapeutically effective dose suitable for use in the method described herein. In one embodiment, the kit comprises: (a) a dose of an anti-C5 antibody or an antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence described in SEQ ID NO: 12 and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence described in SEQ ID NO: 8; and (b) instructions for using the anti-C5 antibody or an antigen-binding fragment thereof in the method described herein.

[0040] In one embodiment, 300 mg or 600 mg of anti-C5 antibody or its antigen-binding fragment is administered to a patient weighing 5 kg or more but less than 10 kg. In another embodiment, 600 mg of anti-C5 antibody or its antigen-binding fragment is administered to a patient weighing 10 kg or more but less than 20 kg. In another embodiment, 900 mg or 2100 mg of anti-C5 antibody or its antigen-binding fragment is administered to a patient weighing 20 kg or more but less than 30 kg. In another embodiment, 1200 mg or 2700 mg of anti-C5 antibody or its antigen-binding fragment is administered to a patient weighing 30 kg or more but less than 40 kg. In another embodiment, 2400 mg or 3000 mg of anti-C5 antibody or its antigen-binding fragment is administered to a patient weighing 40 kg or more but less than 60 kg. In another embodiment, 2700 mg or 3300 mg of anti-C5 antibody or its antigen-binding fragment is administered to a patient weighing 60 kg or more but less than 100 kg. In another embodiment, 3000 mg or 3600 mg of an anti-C5 antibody or its antigen-binding fragment is administered to a patient weighing 100 kg or more. [Brief explanation of the drawing]

[0041] [Figure 1] This is a diagram showing the overall experimental design. [Figure 2] This figure shows the overall patient diagnoses in the trial. Thirteen patients were enrolled, and 12 were included in the preliminary analysis. None of the patients interrupted the primary evaluation period. [Figure 3] Demographics of baseline patients are shown. [Figure 4] This shows the baseline characteristics of the disease. [Figure 5] This shows the serum ravulizumab concentrations over time in patients who have not received prior treatment and in patients who have received prior eculizumab treatment. [Figure 6] This graph shows the mean (SD) ravulizumab serum concentration (linear scale) over time for patients who have not received prior treatment and patients who have received prior eculizumab treatment. [Figure 7]The results for free C5 and CRBC levels over time in both treatment-naïve patients and patients with prior eculizumab treatment are shown. [Figure 8] This graph shows the mean (95% CI) cRBC over time for patients who have not received prior treatment and those who have received prior eculizumab treatment. The dashed lines for 20% hemolysis represent the separate (qualitative) thresholds for complete terminal complement inhibition. [Figure 9] This graph shows the mean (95% CI) free C5 levels over time for both treatment-naïve patients and patients with prior eculizumab treatment. The dashed line for a serum free C5 level of 0.5 μg / mL represents the threshold for complete terminal complement inhibition. [Figure 10] This graph shows the mean (95% CI) change in pediatric FACIT fatigue score from baseline over time for both treatment-naïve patients and patients with prior eculizumab treatment. The dashed line for a FACIT fatigue score of 3 represents the threshold level for clinically meaningful outcomes. [Figure 11] This graph shows the mean (95% CI) pediatric FACIT fatigue score over time for patients who have not received treatment and patients who have received eculizumab treatment. [Figure 12] The following endpoints will be summarized to assess overall efficacy, including DH% change from baseline (LDH-PCHG), transfusion avoidance (TA), pediatric FACIT fatigue (FACIT); hemoglobin stabilization (HGB-S), free hemoglobin% change from baseline (Free HGB-PCHG), and breakthrough hemolysis (BTH). [Figure 13] This graph shows the mean (95% CI) change in LDH over time for patients who have not received treatment and patients who have received eculizumab treatment. [Figure 14] This graph shows the mean (95% CI) LDH (U / L) over time for patients who have not received prior treatment and patients who have received prior eculizumab treatment. [Figure 15] This document provides an overview of key safety points. [Figure 16]This document provides an overview of serious adverse events (TESAES) that occurred during treatment. [Modes for carrying out the invention]

[0042] I. Definition As used herein, the terms “subject” or “patient” refer to a human patient (for example, a patient with paroxysmal nocturnal hemoglobinuria (PNH)).

[0043] As used herein, "pediatric" patient refers to a human patient under 18 years of age (age 18 or older).

[0044] PNH is the most common acquired hemolytic disorder in adults (Brodsky, R., Blood, 126:2459-65, 2015). The disease begins with the clonal proliferation of hematopoietic stem cells that have acquired somatic mutations in the PIGA gene (Brodsky, R., Blood, 124:2804-11, 2014). Consequently, PNH blood cells lack the lycosylphosphatidylinositol (GPI) anchored protein and are deficient in the membrane-bound complement inhibitory proteins CD55 and CD59. In the absence of CD55, there is increased deposition of complement protein C3 degradation products on the blood cell membrane surface, resulting in the cleavage of C5 into C5a and C5b. The pathophysiology and clinical symptoms in patients with PNH are caused by uncontrolled terminal complement activation.

[0045] C5a is a potent anaphylatoxin, chemotactic, and cell-activating molecule that mediates multiple pro-inflammatory and pro-inflammatory activities (Matis, L & Rollins, S., Nat. Med., 1:839-42, 1995; Prodinger et al., Complement. In: Paul WE, editor. Fundamental immunology (4th ed). Philadelphia: Lippincott Raven Publishers; 1999. p.967-95). C5b is a process that recruits terminal complement components C6, C7, C8, and C9 to form the pro-inflammatory, pro-inflammatory cytolytic pore molecule C5b-9, which under normal conditions would be blocked on the red blood cell (RBC) membrane by CD59. However, in patients with PNH, these final steps proceed unchecked, resulting in hemolysis and release of free hemoglobin, as well as platelet activation (Hill, A. et al., Blood, 121:4985-96, 2013). The signs and symptoms of PNH may be due to chronic, uncontrolled complement C5 cleavage and the release of C5a and C5b-9, which cause RBC hemolysis, and together they, • Release of intracellular free hemoglobin and lactate dehydrogenase (LDH) into circulation as a direct result of hemolysis; Irreversible binding of hemoglobin to nitric oxide (NO), inactivation of nitric oxide (NO), and inhibition of NO synthesis; • Microthrombi that may manifest as abdominal pain, dysphagia, and erectile dysfunction due to the absence of vasodilatory nitric oxide (NO); • Platelet activation; and • Pro-inflammatory and pro-thrombus formation conditions; This results in the following outcome.

[0046] A significant proportion of patients with PNH experience renal failure and pulmonary hypertension (Hillmen, P. et al., Am. J. Hematol., 85:553-9, 2010 [erratum in Am. J. Hematol., 85:911, 2010]; Hill, A. et al., Br. J. Haematol., 158:409-14, 2012). Patients also experience venous or arterial thrombosis in various locations, including the abdomen or central nervous system.

[0047] In contrast, children with PNH typically present with nonspecific symptoms associated with the underlying bone marrow disorder, such as pallor, fatigue, or jaundice, and hemoglobinuria is uncommon (Ware, R. et al., N.Engl.J.Med., 325:991-6, 1991). Clinical evaluation in pediatric patients also reveals bone marrow dysfunction syndromes, such as aplastic anemia and refractory cytopenia (van den Heuvel-Eibrink, M., Paediatr.Drugs, 9:11-6, 2007). If the bone marrow disorder is restored in children, or if the PNH clone expands (the cause of which is still unknown), the disease eventually evolves into one or more of the types commonly expressed in adults.

[0048] As used herein, “effective treatment” means treatment that yields a beneficial effect, for example, a recovery of at least one symptom of the disease or disorder. Beneficial effects may take the form of improvement compared to baseline, for example, improvement compared to measurements or observations made before the initiation of therapy by this method. Effective treatment may mean relief of at least one symptom of PNH (e.g., pallor, fatigue, jaundice, anemia, cytopenia, abdominal pain, dyspnea, dysphagia, chest pain, or erectile dysfunction).

[0049] The term “effective dose” means the amount of an agent that confers the desired biological, therapeutic, and / or prophylactic outcome. The outcome may be a reduction, recovery, remission, alleviation, delay, and / or reduction of one or more signs, symptoms, or causes of a disease, or any desired change in any biological system. In one embodiment, the “effective dose” is the amount of anti-C5 antibody or its antigen-binding fragment that has been clinically demonstrated to alleviate at least one symptom of PNH (e.g., pallor, fatigue, jaundice, anemia, cytopenia, abdominal pain, dyspnea, dysphagia, or chest pain). The effective dose may be administered in one or more doses.

[0050] As used herein, “loading dose” means the initial dose administered (e.g., during a dosing cycle).

[0051] As used herein, “maintenance” and “maintenance phase” are used interchangeably and refer to the second phase of treatment. In certain embodiments, treatment is continued as long as a clinical benefit is confirmed or until uncontrollable toxicity or exacerbation occurs.

[0052] As used herein, the term “serum trough level” refers to the lowest level of an agonist (e.g., an anti-C5 antibody or its antigen-binding fragment) or drug present in the serum. In contrast, “peak serum level” refers to the highest level of an agonist in the serum. “Mean serum level” refers to the average level of an agonist in the serum over time.

[0053] The term "antibody" describes a polypeptide containing at least one antibody-inducible antigen-binding site (e.g., a VH / VL region or Fv, or CDR). Antibodies include known forms of antibodies, for example, an antibody may be a human antibody, a humanized antibody, a bispecific antibody, or a chimeric antibody. Antibodies may also be Fab, Fab'2, ScFv, SMIP, Affibody®, nanobody, or single-domain antibodies. Antibodies may be any or a combination of the following isotypes: IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD, IgE. Antibodies may be native antibodies or antibodies modified by protein manipulation techniques (e.g., by mutation, deletion, substitution, or conjugation to a non-antibody site). Antibodies may contain one or more variant amino acids (compared to native antibodies) that alter the properties of the antibody (e.g., functional properties). For example, many such modifications affecting half-life, effector function, and / or the immune response to the antibody in a patient are known in the art. The term antibody also includes artificial or modified polypeptide constructs that include at least one antibody-inducible antigen-binding site.

[0054] II. Anti-C5 antibody The anti-C5 antibodies described herein bind to complement component C5 (e.g., human C5) and inhibit the cleavage of C5 into fragments C5a and C5b. As described above, such antibodies also possess, for example, improved pharmacokinetic properties compared to other anti-C5 antibodies used for therapeutic purposes (e.g., eculizumab).

[0055] Anti-C5 antibodies (or VH / VL domains derived therefrom) suitable for use in the methods described herein can be produced using methods known in the art. Alternatively, anti-C5 antibodies recognized in this art can be used. Antibodies that compete with either the antibodies recognized in these art or the antibodies described herein for binding to C5 can also be used.

[0056] Exemplary anti-C5 antibodies include ravulizumab, or its antigen-binding fragments and variants, comprising heavy and light chains having the sequences shown in SEQ ID NOs. 14 and 11, respectively. Rabulizumab (also known as ULTOMIRIS®, BNJ441, and ALXN1210) is described in International Publication No. 2015134894 and U.S. Patent No. 9,079,949, the entire teaching of which is incorporated herein by reference. The terms ravulizumab, BNJ441, and ALXN1210 may be used interchangeably throughout this document, but all refer to the same antibody. Rabulizumab selectively binds to human complement protein C5, inhibiting its cleavage to C5a and C5b during complement activation. This inhibition prevents the release of the pro-inflammatory mediator C5a and the formation of cytolytic pore-forming membrane invasion complexes (MACs) C5b-9, while simultaneously preserving proximal or initial components (e.g., C3 and C3b) of complement activation essential for microbial opsonization and immune complex clearance.

[0057] In other embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of ravulizumab. Thus, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of ravulizumab having the sequence described in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of the VL region of ravulizumab having the sequence described in SEQ ID NO: 8. In another embodiment, the antibody comprises the heavy chain CDR1, CDR2, and CDR3 domains having the sequences described in SEQ ID NOs: 19, 18, and 3, respectively, and the light chain CDR1, CDR2, and CDR3 domains having the sequences described in SEQ ID NOs: 4, 5, and 6, respectively. In yet another embodiment, the antibody comprises the VH and VL regions having the amino acid sequences described in SEQ ID NO: 12 and SEQ ID NO: 8, respectively.

[0058] Another exemplary anti-C5 antibody is antibody BNJ421, which comprises a heavy chain and a light chain having the sequences shown in SEQ ID NOs. 20 and 11, respectively, or its antigen-binding fragment and variants. BNJ421 (also known as ALXN1211) is described in International Publication No. 2015134894 and U.S. Patent No. 9,079,949, the entire teaching of which is incorporated herein by reference.

[0059] 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 described in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of the VL region of BNJ421 having the sequence described in SEQ ID NO: 8. In another embodiment, the antibody comprises the heavy chain CDR1, CDR2, and CDR3 domains having the sequences described in SEQ ID NOs: 19, 18, and 3, respectively, and the light chain CDR1, CDR2, and CDR3 domains having the sequences described in SEQ ID NOs: 4, 5, and 6, respectively. In yet another embodiment, the antibody comprises the VH and VL regions having the amino acid sequences described in SEQ ID NOs: 12 and 8, respectively.

[0060] The precise boundaries of the CDR can be defined in various ways according to different methods. In some embodiments, the location of the CDR or framework region within the light chain or heavy chain variable domain is as defined by Kabat et al. [(1991) “Sequence of Proteins of Immunological Interest.” NIH Publication No. 91 3242, USD Department of Health and Human Services, Bethesda, MD]. In such cases, the CDR may also be called “Kabat CDR” (e.g., “Kabat LCDR2” or “Kabat HCDR1”). In some embodiments, the location of the CDR in the light chain or heavy chain variable region is as defined by Chothia et al. (Nature, 342:877-83, 1989). Thus, these regions may be called “Chothia CDR” (e.g., “Chothia LCDR2” or “Chothia HCDR3”). In some embodiments, the location of the CDR in the light chain and heavy chain variable region can be defined by a combined definition of Kabat and Chothia. In such embodiments, these regions may be referred to as “combined Kabat-Chothia CDRs.” Thomas, C. et al. (Mol.Immunol., 33:1389 401, 1996) illustrate the identification of CDR boundaries according to the Kabat and Chothia numbering scheme.

[0061] Another exemplary anti-C5 antibody is the 7086 antibody described in U.S. Patent No. 8,241,628 and U.S. Patent No. 8,883,158. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable region of the 7086 antibody (see U.S. Patent No. 8,241,628 and U.S. Patent No. 8,883,158). In another embodiment, the antibody, or its antigen-binding fragment, comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences described in SEQ ID NOs. 21, 22, and 23, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences described in SEQ ID NOs. 24, 25, and 26, respectively. In another embodiment, the antibody, or its antigen-binding fragment, comprises the VH region of the 7086 antibody having the sequence described in SEQ ID NO. 27, and the VL region of the 7086 antibody having the sequence described in SEQ ID NO. 28.

[0062] Another exemplary anti-C5 antibody is the 8110 antibody described in U.S. Patent No. 8,241,628 and U.S. Patent No. 8,883,158. In one embodiment, the antibody comprises the heavy chain and light chain CDR or variable region of the 8110 antibody. In another embodiment, the antibody, or its antigen-binding fragment, comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences described in SEQ ID NOs. 29, 30, and 31, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences described 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 described in SEQ ID NO. 35, and the VL region of the 8110 antibody having the sequence described in SEQ ID NO. 36.

[0063] 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 chain and light chain CDR or variable region of the 305LO5 antibody. In another embodiment, the antibody or its antigen-binding fragment comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences described in SEQ ID NOs. 37, 38 and 39, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences described in SEQ ID NOs. 40, 41 and 42, respectively. In yet another embodiment, the antibody comprises the VH region of the 305LO5 antibody having the sequence described in SEQ ID NO. 43, and the VL region of the 305LO5 antibody having the sequence described in SEQ ID NO. 44.

[0064] 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 chain and light chain CDR or variable region of the SKY59 antibody. In another embodiment, the antibody or its antigen-binding fragment comprises a heavy chain containing SEQ ID NO: 45 and a light chain containing SEQ ID NO: 46.

[0065] In some embodiments, the anti-C5 antibody comprises the heavy chain and light chain variable regions or the heavy chain and light chain 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 described in SEQ ID NO: 47 and the light chain variable region comprising the sequence described in SEQ ID NO: 48. In some embodiments, the anti-C5 antibody, or its antigen-binding fragment, comprises the heavy chain sequence described in SEQ ID NO: 49 and the light chain sequence described in SEQ ID NO: 50.

[0066] In some embodiments, the anti-C5 antibody described herein comprises a heavy chain CDR1 comprising or consisting of the following amino acid sequence: GHIFSNYWIQ (SEQ ID NO: 19). In some embodiments, the anti-C5 antibody described herein comprises a heavy chain CDR2 comprising or consisting of the following amino acid sequence: EILPGSGHTEYTENFKD (SEQ ID NO: 18). In some embodiments, the anti-C5 antibody described herein comprises the following amino acid sequence: [ka] It includes a heavy chain variable region.

[0067] In some embodiments, the anti-C5 antibody described herein has the following amino acid sequence: [ka] Includes a light chain variable region.

[0068] The anti-C5 antibodies described herein, in some embodiments, include a variant human Fc constant region that binds to a human neonatal Fc receptor (FcRn) having a higher affinity than the native human Fc constant region, from which the variant human Fc constant region is derived. The Fc constant region includes, for example, one or more (e.g., 2, 3, 4, 5, 6, 7, or 8 or more) amino acid substitutions from the native human Fc constant region, from which the variant human Fc constant region is derived. The substitutions can increase the binding affinity of the IgG antibody containing the variant Fc constant region to FcRn at pH 6.0, while maintaining the pH dependence of the interaction. Methods for testing whether one or more substitutions in the Fc constant region of an antibody increase the affinity of the Fc constant region to 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. For example, see International Publication No. 2015134894 and U.S. Patent No. 9,079,949, the entirety of which is incorporated herein by reference.

[0069] Substitutions that enhance the binding affinity of the antibody Fc constant region to FcRn are known in the art, for example, (1) the triple substitution of M252Y / S254T / T256E (Dall'Acqua, W. et al., J. Biol. Chem., 281:23514-24, 2006); (2) the substitution of M428L or T250Q / M428L (Hinton, P. et al., J. Biol. Chem., 279:6213-6, 2004; Hinton, P. et al., J. Immunol., 176:346-56, 2006); and (3) the substitution of N434A or T307 / E380A / N434A (Petkova, S. et al., Int. Immunol., 18:1759-69, 2006). Further substitution combinations, the entirety of which is incorporated herein by reference, include P257I / Q311I, P257I / N434H, and D376V / N434H (Datta Mannan, A. et al., J. Biol. Chem., 282:1709-17, 2007).

[0070] In some embodiments, the variant constant region has a substitution of valine at EU amino acid position 255. In some embodiments, the variant constant region has a substitution of asparagine at EU amino acid position 309. In some embodiments, the variant constant region has a substitution of isoleucine at EU amino acid position 312. In some embodiments, the variant constant region has a substitution of EU amino acid position 386.

[0071] In some embodiments, the variant Fc constant region contains 30 or fewer amino acid substitutions, insertions, or deletions (e.g., 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 or fewer) relative to the derived native constant region. 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, respectively, of the native human IgG Fc constant region in EU numbering. In some embodiments, the variant Fc steady-state region includes, for example, the 428L / 434S double substitution described in U.S. Patent No. 8,088,376.

[0072] In some embodiments, the precise locations of these mutations may be shifted from the natural human Fc constant region for antibody manipulation. For example, when used in IgG2 / 4 chimeric Fc, the 428L / 434S double substitution may correspond to 429L and 435S, as well as the M429L and N435S variants found in ravulizumab, as described in U.S. Patent No. 9,079,949, the entire disclosure of which is incorporated herein by reference.

[0073] In some embodiments, the variant constant region includes 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 natural human Fc constant region. In some embodiments, the substitutions include: substituting glycine with methionine at position 237; substituting proline with alanine at position 238; substituting serine with lysine at position 239; substituting lysine with isoleucine at position 248; substituting threonine with alanine, phenylalanine, isoleucine, methionine, glutamine, serine, valine, tryptophan, or tyrosine at position 250; substituting methionine with phenylalanine, tryptophan, or tyrosine at position 252; substituting serine with threonine at position 254; substituting arginine with glutamic acid at position 255; substituting threonine with aspartic acid, glutamic acid, or glutamine at position 256; substituting proline with alanine, glycine, isoleucine, leucine, methionine, asparagine, serine, threonine, or valine at position 257; and substituting glutamic acid with phenylalanine at position 258. Substitute with stidine; substitute aspartic acid with alanine at position 265; substitute aspartic acid with phenylalanine at position 270; substitute asparagine with alanine or glutamic acid at position 286; substitute threonine with histidine at position 289; substitute asparagine with alanine at position 297; substitute serine with glycine at position 298; substitute valine with alanine at position 303; substitute valine with alanine at position 305; substitute threonine with alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, valine, tryptophan, or tyrosine at position 307; substitute valine with alanine, phenylalanine, isoleucine, leucine, methionine, proline, glutamine, or threonine at position 308;Substitute leucine or valine with alanine, aspartic acid, glutamic acid, proline, or arginine at position 309; substitute glutamine with alanine, histidine, or isoleucine at position 311; substitute aspartic acid with alanine or histidine at position 312; substitute leucine with lysine or arginine at position 314; substitute asparagine with alanine or histidine at position 315; substitute lysine with alanine at position 317; substitute asparagine with glycine at position 325; substitute isoleucine with valine at position 332; substitute lysine with leucine at position 334; substitute lysine with histidine at position 360; substitute aspartic acid with alanine at position 376; substitute glutamic acid with alanine at position 380; substitute glutamic acid with alanine at position 382; substitute asparagine or serine with alanine at position 384; position The group is selected from the following: substitution of glycine with aspartic acid or histidine at position 385; substitution of glutamine with proline at position 386; substitution of proline with glutamic acid at position 387; substitution of asparagine with alanine or serine at position 389; substitution of serine with alanine at position 424; substitution of methionine with alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, asparagine, proline, glutamine, serine, threonine, valine, tryptophan, or tyrosine at position 428; substitution of histidine with lysine at position 433; substitution of asparagine with alanine, phenylalanine, histidine, serine, tryptophan, or tyrosine at position 434; and substitution of tyrosine or phenylalanine with histidine at position 436 (all EU numbered).

[0074] In some embodiments, an anti-C5 antibody suitable for use in the method described herein comprises a heavy chain polypeptide containing the amino acid sequence described in SEQ ID NO: 14 and / or a light chain polypeptide containing the amino acid sequence described in SEQ ID NO: 11. Alternatively, in some embodiments, an anti-C5 antibody used in the method described herein comprises a heavy chain polypeptide containing the amino acid sequence described in SEQ ID NO: 20 and / or a light chain polypeptide containing the amino acid sequence described in SEQ ID NO: 11.

[0075] In one embodiment, the antibody binds to C5 at pH 7.4 and 25°C (and otherwise under physiological conditions), and the affinity dissociation constant (K D ) is at least 0.1 (e.g., at least 0.15, 0.175, 0.2, 0.25, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775, 0.8, 0.825, 0.85, 0.875, 0.9, 0.925, 0.95, or 0.975) nM. In some embodiments, the K D of the anti-C5 antibody or its antigen-binding fragment is 1 or less (e.g., 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, or 0.2 or less) nM.

[0076] In other embodiments, [(K D of the antibody for C5 at pH 6.0, 25°C) / (K D of the antibody for C5 at pH 7.4, 25°C)] 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).

[0077] Methods for determining whether an antibody binds to a protein antigen, and / or the affinity of an antibody to a protein antigen, are known in the art. The binding of antibodies to protein antigens can be detected and / or quantified using a variety of techniques, including, but not limited to, Western blotting, dot blotting, surface plasmon resonance (SPR) detection (e.g., BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ), or enzyme immunoassay (ELISA; Benny KCLo (2004) “Antibody Engineering: Methods and Protocols,” Humana Press (ISBN: 1588290921); Johne, B. et al., J. Immunol. Meth., 160:191-8, 1993; Jonsson, U. et al., Ann. Biol. Clin., 51:19-26, 1993; Jonsson, U. et al., Biotechniques, 11:620-7, 1991). Furthermore, methods for measuring affinity (e.g., dissociation and association constants) are described in the examples of the work.

[0078] The term "k" used herein a The term "k" refers to the rate constant of antibody association with an antigen. d The term "K" refers to the rate constant of antibody dissociation from antibody / antigen complexes. D The term "equilibrium dissociation constant" refers to the equilibrium dissociation constant of antibody-antigen interaction. The equilibrium dissociation constant is the ratio of the kinetic rate constants, K D =k a / k d This is estimated from the following. Such a determination 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 using an anti-Fc capture method to immobilize the antibody via SPR in a BIAcore3000 instrument.

[0079] In one embodiment, an anti-C5 antibody or its antigen-binding fragment blocks the cleavage of C5 to C5a and C5b. Through this blocking action, for example, the pro-inflammatory effect of C5a and the production of the C5b-9 membrane invasion complex (MAC) on the cell surface are inhibited.

[0080] Methods for determining whether the specific antibodies described herein inhibit C5 cleavage are known in the art. Inhibition of human complement component C5 may reduce the cytolytic capacity of complement in the body fluid of interest. Such reduction in the cytolytic capacity of complement present in body fluids can be measured by methods known in the art, such as conventional hemolysis assays (Kabat and Mayer (eds.), Experimental Immunochemistry, 2nd Edition, 135-240, Springfield, IL, CC Thomas (1961), pages 135-139), or by conventional variations of assays such as chicken erythrocyte hemolysis (Hillmen, P. et al., N.Engl. J.Med., 350:552-9, 2004). Methods for determining whether a candidate compound inhibits the cleavage of human C5 into C5a and C5b forms are known in the art (Evans, M. et al., Mol.Immunol., 32:1183-95, 1995). The concentrations and / or physiological activities of C5a and C5b in body fluids can be measured, for example, by methods known in the art. For C5b, hemolysis assays or assays for soluble C5b-9, as described herein, can be used. Other assays known in the art can also be used. Candidate agonists capable of inhibiting human complement component C5 can be screened using these, or other suitable types of assays.

[0081] Immunological techniques such as ELISA can be used to measure the protein concentration of C5 and / or its split product, and to determine the ability of an anti-C5 antibody or its antigen-binding fragment to inhibit the conversion of C5 to a bioactive product. In some embodiments, C5a production is measured. In some embodiments, MAC formation is detected using a C5b-9 neoepitope-specific antibody.

[0082] A hemolysis assay can be used to determine the inhibitory activity of an anti-C5 antibody or its antigen-binding fragment against complement activation. To determine the effect of an anti-C5 antibody or its antigen-binding fragment against classical complement pathway-mediated hemolysis in a serum test solution in vitro, for example, hemolysin-coated sheep erythrocytes or chicken erythrocytes sensitized with an anti-chicken erythrocyte antibody are used as target cells. The percentage of lysis is normalized by considering 100% lysis, which is equivalent to lysis occurring in the absence of the inhibitor. In some embodiments, the classical complement pathway is activated by a human IgM antibody, for example, as used in the Wieslab® Classical Pathway Complement Kit (Wieslab® COMPL CP310, Euro Diagnostica, Sweden). Briefly, the test serum is incubated with the anti-C5 antibody or its antigen-binding fragment in the presence of the human IgM antibody. The amount of C5b-9 produced is measured by contacting a mixture of 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 anti-C5 antibody or its antigen-binding fragment. In some embodiments, the test serum is C5-deficient serum reconstituted with C5 polypeptide.

[0083] To determine the effect of an anti-C5 antibody or its antigen-binding fragment on alternative pathway-mediated hemolysis, unsensitized rabbit or guinea pig erythrocytes can be used as target cells. In some embodiments, the serum test solution is C5-deficient serum reconstituted with C5 polypeptide. The percentage of lysis is normalized by considering 100% lysis, which is equivalent to lysis occurring in the absence of the inhibitor. In some embodiments, the complement-activated secondary pathway is activated by a lipopolysaccharide molecule, for example, as used in the Wieslab® Alternative Pathway Complement Kit (Wieslab® COMPL AP330, Euro Diagnostica, Sweden). Briefly, the test serum is incubated with the anti-C5 antibody or its antigen-binding fragment in the presence of lipopolysaccharide. The amount of C5b-9 produced is measured by contacting a mixture of the 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 anti-C5 antibody or its antigen-binding fragment.

[0084] In some embodiments, the CH50eq assay is used to quantify C5 activity or its inhibition. The CH50eq assay is a method for measuring the total activity of classical complement in serum. This test is lytic, and the amount required to obtain 50% lysis (CH50) is determined using antibody-sensitized erythrocytes as activators of the classical complement pathway and various dilutions of the test serum. The hemolysis percentage can be determined, for example, using a spectrophotometer. Since TCCs themselves are the direct cause of the hemolysis being measured, the CH50eq assay provides an indirect measure of terminal complement complex (TCC) formation. The assay is well known and commonly performed by those skilled in the art. Briefly, to activate the classical complement pathway, an undiluted serum sample (e.g., a reconstituted human serum sample) is added to a well of a microassay containing antibody-sensitized erythrocytes, thereby producing TCCs. The activated serum is then diluted in a microassay well coated with a capture reagent (e.g., an antibody that binds to one or more components of TCCs). TCCs present in the activated sample bind to a monoclonal antibody coating the surface of the microassay wells. The wells are washed, and a detection reagent that recognizes the bound TCCs, which has been detected by labeling, is added to each well. The detectable labeling may be, for example, fluorescent or enzymatic. The assay results are expressed in units of CH50 equivalents per milliliter (CH50 U Eq / mL).

[0085] For example, if it relates to terminal complement activity, the inhibition includes a reduction of at least 5% (e.g., at least 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60%) of terminal complement activity compared to a control antibody (or its antigen-binding fragment) under similar conditions and equimolar concentrations in, for example, a hemolysis assay or a CH50eq assay. Substantial inhibition as used herein means inhibition of a given activity (e.g., terminal complement activity) of at least 40% (e.g., at least 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% or more). In some embodiments, the anti-C5 antibodies described herein contain one or more amino acid substitutions to the CDR of eculizumab (i.e., SEQ ID NOs: 1-6) and further 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 CH50eq assay.

[0086] The anti-C5 antibodies described herein have a human serum half-life of at least 20 days (for example, at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 days). In another embodiment, the anti-C5 antibodies described herein have a human serum half-life of at least 40 days. In another embodiment, the anti-C5 antibodies described herein have a human serum half-life of about 43 days. In another embodiment, the anti-C5 antibodies described herein have a human serum half-life of 39 to 48 days. Methods for measuring the serum half-life of an antibody are known in the art. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof described herein has a serum half-life that is at least 20% (e.g., at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250, 300, 400, or 500%) higher than the serum half-life of eculizumab as measured in one of the mouse model systems described in the Working Examples (e.g., C5-deficient / NOD / SCID mouse or hFcRn gene-transformed mouse model systems).

[0087] In one embodiment, an antibody competes for binding to the same epitope on C5 as the antibody described herein, and / or binds to the same epitope. The term “binding 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 predetermined method. Techniques for determining whether an antibody binds to the same epitope on C5 using the antibodies described herein include, for example, epitope mapping, e.g., X-ray diffraction of the antigen:antibody complex crystal, and hydrogen / deuterium exchange mass spectrometry (HDXMS). Other methods monitor binding to peptide antigen fragments or variants of antigens, where loss of binding due to modification of amino acid residues in the antigen sequence is often considered an indicator of the epitope component. Furthermore, combinatorial calculation methods for epitope mapping can also be used. These methods depend on the ability of the antibody in question to isolate specific short peptides from combinatorial phage display peptide libraries by affinity. Antibodies having the same VH and VL sequences, or the same CDR1, CDR2, and CDR3 sequences, are expected to bind to the same epitope.

[0088] An antibody that "competes with another antibody for binding to a target" means an antibody that (partially or completely) inhibits the binding of another antibody to the target. Whether two antibodies compete with each other for binding to a target, that is, whether one antibody inhibits the binding of the other antibody to the target, and to what extent, can be determined using known competition experiments. In certain embodiments, an antibody competes with the binding of another antibody to the target and inhibits the binding of the other antibody to the target by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. The level of inhibition or competition may vary depending on which antibody is the "blocking antibody" (i.e., the antibody that is first incubated with the target). A competing antibody may bind to, for example, the same epitope, a duplicate epitope, or an adjacent epitope (e.g., demonstrated by steric hindrance).

[0089] The anti-C5 antibodies or antigen-binding fragments thereof used in the methods described herein are obtained by various techniques well known to those skilled in the art. Briefly, spleen cells from animals immunized with the antigen of interest are usually immortalized by fusion with myeloma cells (Kohler, G. & Milstein, C., Eur. J. Immunol., 6:5119, 1976). Methods of immortalization include transformation with Epstein-Barr virus, oncogenes, or retroviruses, or methods known in the art. Colonies resulting from single immortalized cells are screened for the production of antibodies of the desired specificity and affinity of the antigen, and the yield of monoclonal antibodies produced by such cells can be enhanced by various techniques, such as intraperitoneal injection into a vertebrate host. Alternatively, DNA sequences encoding monoclonal antibodies or their binding fragments can be isolated by screening DNA libraries from human B cells (Huse, W. et al., Science, 246:1275-81, 1989).

[0090] III. Composition Compositions comprising an anti-C5 antibody or an antigen-binding fragment thereof are also provided herein. In one embodiment, the composition comprises an anti-C5 antibody comprising CDR1, CDR2, and CDR3 domains in a heavy chain variable region having the sequence described in SEQ ID NO: 12, and CDR1, CDR2, and CDR3 domains in a light chain variable region having the sequence described 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 yet 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.

[0091] For example, a composition may be formulated as a drug solution administered to a subject for the treatment or prevention of complement-related disorders. Drug compositions generally contain a pharmaceutically acceptable carrier. As used herein, “pharmaceutically acceptable carrier” means and includes any and all physiologically compatible solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic and absorption retardants, etc. The composition may contain pharmaceutically acceptable salts, e.g., acid addition salts or base addition salts, sugars, carbohydrates, polyols and / or tonic modifiers.

[0092] The composition can be formulated according to standard methods. Pharmaceutical formulation is an established technique (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,” 3rd Edition (ISBN: 091733096X)). In some embodiments, the composition can be formulated as a buffer solution, for example, at an appropriate concentration and suitable storage at 2–8°C (e.g., 4°C). In some embodiments, the composition can be formulated for storage at temperatures below 9°C (e.g., -20°C or -80°C). In some embodiments, the compositions may be formulated for storage at 2-8°C (e.g., 4°C) for up to 2 years (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 1.5 years, or 2 years). Therefore, in some embodiments, the compositions described herein are stable for storage at 2-8°C (e.g., 4°C) for at least 1 year.

[0093] Pharmaceutical compositions can take various forms. These forms include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and injectable solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The preferred form depends in part on the intended mode of administration and therapeutic use. Compositions containing a composition intended for systemic or topical delivery may, for example, take the form of an injectable or injectable solution. Thus, compositions can be formulated for parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection). As used herein, “parenteral administration,” “administered parenterally,” and other grammatically equivalent phrases mean, but are not limited to, intravenous, intranasal, intraocular, transpulmonary, intramuscular, intraarterial, intrathecal, intra-articular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, intratracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intrathecal, epidural, intracerebral, intracranial, carotid, and intrasternal injections and infusions.

[0094] IV. Method A method for treating PNH in human pediatric patients is provided herein, comprising administering an anti-C5 antibody or an antigen-binding fragment thereof to the patient, wherein the anti-C5 antibody or the antigen-binding fragment is administered (or intended for administration) according to a specific clinical dosing plan (e.g., in a specific dose and according to a specific dosing plan).

[0095] In one embodiment, the dose of anti-C5 antibody or its antigen-binding fragment is based on the patient's body weight. In one embodiment, for example, 300 mg of anti-C5 antibody or its antigen-binding fragment is administered to a patient weighing 5 kg or more but less than 10 kg. In another embodiment, for example, 600 mg of anti-C5 antibody or its antigen-binding fragment is administered to a patient weighing 10 kg or more but less than 20 kg. In another embodiment, 900 mg or 2100 mg of anti-C5 antibody or its antigen-binding fragment is administered to a patient weighing 20 kg or more but less than 30 kg. In another embodiment, 1200 mg or 2700 mg of anti-C5 antibody or its antigen-binding fragment is administered to a patient weighing 30 kg or more but less than 40 kg. In another embodiment, 2400 mg or 3000 mg of C5 antibody or its antigen-binding fragment is administered to a patient weighing 40 kg or more but less than 60 kg. In another embodiment, 2700 mg or 3300 mg of C5 antibody or its antigen-binding fragment is administered to patients weighing 60 kg or more but less than 100 kg. In yet another embodiment, 3000 mg or 3600 mg of C5 antibody or its antigen-binding fragment is administered to patients weighing 100 kg or more. In a particular embodiment, the dosing regimen is adjusted to provide the optimal desired response (e.g., an effective response).

[0096] In another embodiment, the anti-C5 antibody or its antigen-binding fragment is administered in one or more administration cycles. In one embodiment, the treatment (e.g., administration cycle) is 26 weeks. In one embodiment, the anti-C5 antibody or its antigen-binding fragment is administered once on day 1 (e.g., of the administration cycle), once on day 15 (e.g., of the administration cycle), and thereafter every 4 weeks. In another embodiment, the anti-C5 antibody or its antigen-binding fragment is administered once on day 1 (e.g., of the administration cycle), once on day 15 (e.g., of the administration cycle), and thereafter every 8 weeks. In another embodiment, an anti-C5 antibody or its antigen-binding fragment is administered every 4 or 8 weeks after treatment (e.g., in doses of 300 mg, 600 mg, 900 mg, 1200 mg, 2100 mg, 2400 mg, 2700 mg, 3000 mg, 3300 mg, or 3600 mg) for an extension period of up to 2 years.

[0097] In another embodiment, a method is provided for treating a human patient having PNH, the method comprising administering to the patient an effective amount of an anti-C5 antibody or its antigen-binding fragment, comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs: 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs: 4, 5, and 6, respectively (e.g., during a dosing cycle), wherein the anti-C5 antibody or its antigen-binding fragment is administered once on day 1 at a dose of 600 mg for patients weighing 5 kg to less than 10 kg, 600 mg for patients weighing 10 kg to less than 20 kg, 900 mg for patients weighing 20 kg to less than 30 kg, and 1200 mg for patients weighing 30 kg to less than 40 kg, and 4 (b) On day 15 and every four weeks thereafter, patients weighing 5 kg and under 10 kg shall be given a dose of 300 mg, or patients weighing 100 kg and under 100 kg shall be given a dose of 300 mg, or patients weighing 10 kg and under 20 kg shall be given a dose of 600 mg, or on day 15 and every eight weeks thereafter, patients weighing 20 kg and under 30 kg shall be given a dose of 2100 mg, patients weighing 30 kg and under 40 kg shall be given a dose of 2700 mg, patients weighing 40 kg and under 60 kg shall be given a dose of 3000 mg, patients weighing 60 kg and under 100 kg shall be given a dose of 3300 mg, or patients weighing 100 kg and under 100 kg shall be given a dose of 3600 mg.

[0098] In another embodiment, a method is provided for treating a human patient having PNH, the method comprising administering to the patient (e.g., during a dosing cycle) an effective amount of an anti-C5 antibody or its antigen-binding fragment, comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs: 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs: 4, 5, and 6, respectively, the anti-C5 antibody or its antigen-binding fragment is administered once on day 1 to patients weighing between 5 kg and 10 kg. (b) For patients weighing 10 kg or more but less than 20 kg, the dose is 600 mg; for patients weighing 20 kg or more but less than 30 kg, the dose is 900 mg; for patients weighing 30 kg or more but less than 40 kg, the dose is 1200 mg; for patients weighing 40 kg or more but less than 60 kg, the dose is 2400 mg; for patients weighing 60 kg or more but less than 100 kg, the dose is 2700 mg; or for patients weighing 100 kg or more, the dose is 3000 mg; (b) On the 15th day and every 4 weeks thereafter, for patients weighing 5 kg or more but less than 10 kg The drug was administered at a dose of 300 mg, or 600 mg for patients weighing 10 kg to less than 20 kg; or on day 15 and every 8 weeks thereafter, at a dose of 2100 mg for patients weighing 20 kg to less than 30 kg, 2700 mg for patients weighing 30 kg to less than 40 kg, 3000 mg for patients weighing 40 kg to less than 60 kg, 3300 mg for patients weighing 60 kg to less than 100 kg, or 3600 mg for patients weighing 100 kg or more, and as a result of treatment, the levels were brought within the normal range, or U The LDH level is reduced to a level within 50% of the LN level (for example, a value considered to be 105-333 IU / L (International Units / liter)), resulting in a serum trough concentration of at least 175 μg / mL or higher of anti-C5 antibody or its antigen-binding fragment, and / or a free C5 concentration of 0.5 μg / mL or lower (for example, 0.4 μg / mL, 0.3 μg / mL, 0.2 μg / mL, or 0.1 μg / mL or lower). In another embodiment, the treatment eliminates breakthrough hemolysis (BTH).

[0099] In another embodiment, a method is provided for treating a human patient having PNH, the method comprising administering to the patient (e.g., during an administration cycle) an effective amount of an anti-C5 antibody or its antigen-binding fragment comprising the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs: 19, 18, and 3, respectively, the CDR1, CDR2, and CDR3 light chain sequences described 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 is a natural human IgG, each conforming to the EU numbering rules. The anti-C5 antibody or its antigen-binding fragment contains Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 in the Fc constant region, and is administered once on day 1 at doses of 600 mg for patients weighing 5 kg or more but less than 10 kg, 600 mg for patients weighing 10 kg or more but less than 20 kg, 900 mg for patients weighing 20 kg or more but less than 30 kg, 1200 mg for patients weighing 30 kg or more but less than 40 kg, 2400 mg for patients weighing 40 kg or more but less than 60 kg, and 2700 mg for patients weighing 60 kg or more but less than 100 kg, or (b) On day 15 and every four weeks thereafter, patients weighing 5 kg or more are given a dose of 300 mg, or patients weighing 10 kg or more but less than 20 kg are given a dose of 600 mg; or on day 15 and every eight weeks thereafter, patients weighing 20 kg or more but less than 30 kg are given a dose of 2100 mg, patients weighing 30 kg or more but less than 40 kg are given a dose of 2700 mg, patients weighing 40 kg or more but less than 60 kg are given a dose of 3000 mg, patients weighing 60 kg or more but less than 100 kg are given a dose of 3300 mg, or patients weighing 100 kg or more are given a dose of 3600 mg.

[0100] In another embodiment, an anti-C5 antibody or its antigen-binding fragment is administered to patients weighing between 5 kg and 10 kg: (a) once on day 1 at a dose of 600 mg; and (b) on day 15 and every 4 weeks thereafter at a dose of 300 mg.

[0101] In another embodiment, the anti-C5 antibody is administered to patients weighing between 10 kg and 20 kg in doses: (a) once on day 1 at a dose of 600 mg; and (b) on day 15 and every 4 weeks thereafter at a dose of 600 mg.

[0102] In another embodiment, the anti-C5 antibody is administered to patients weighing between 20 kg and less than 30 kg: (a) once on day 1 at a dose of 900 mg; and (b) on day 15 and every 8 weeks thereafter at a dose of 2100 mg.

[0103] In another embodiment, the anti-C5 antibody is administered to patients weighing 30 kg or more but less than 40 kg: (a) once on day 1 at a dose of 1200 mg; and (b) on day 15 and every 8 weeks thereafter at a dose of 2700 mg.

[0104] In another embodiment, the anti-C5 antibody is administered to patients weighing between 40 kg and 60 kg: (a) once on day 1 at a dose of 2400 mg; and (b) on day 15 and every 8 weeks thereafter at a dose of 3000 mg.

[0105] In another embodiment, the anti-C5 antibody is administered to patients weighing between 60 kg and less than 100 kg: (a) once on day 1 at a dose of 2700 mg; and (b) on day 15 and every 8 weeks thereafter at a dose of 3300 mg.

[0106] In another embodiment, an anti-C5 antibody is administered to patients weighing 100 kg or more: (a) once on day 1 at a dose of 3000 mg; and (b) on day 15 and every 8 weeks thereafter at a dose of 3600 mg.

[0107] In one embodiment, the patient has not been previously treated with eculizumab. In another embodiment, the patient has been previously treated with eculizumab. In yet another embodiment, the patient has been previously treated with eculizumab, and day 1 (e.g., of the administration cycle) is two weeks or more since the patient's last dose of eculizumab.

[0108] V. Results A method for treating PNH in a patient is provided herein, comprising administering an anti-C5 antibody to the patient. Symptoms of PNH include, but are not limited to, pallor, fatigue (e.g., exhaustion, difficulty performing daily activities, difficulty concentrating, dizziness, weakness), pain (e.g., stomach pain, leg pain or swelling, chest pain, back pain), dark urine, shortness of breath, difficulty swallowing, yellowing of the skin and / or eyes, anemia, cytopenia, erectile dysfunction, blood clots, kidney disease, organ damage, stroke or heart attack.

[0109] Patients treated according to the methods disclosed herein will experience improvement in at least one sign of PNH. Such treatment may produce at least one therapeutic effect selected from the group consisting of, for example, reduction or cessation of pallor, fatigue, jaundice, anemia, cytopenia, abdominal pain, dyspnea, dysphagia, chest pain, or erectile dysfunction.

[0110] In one embodiment, the improvement is measured by terminal complement inhibition.

[0111] In another embodiment, the efficacy of therapy can be evaluated using lactate dehydrogenase (LDH) levels (for example, a reduction in hemolysis as assessed by lactate dehydrogenase (LDH) levels indicates improvement in at least one sign of PNH). 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 the correlation between cell-free hemoglobin and LDH concentration has been reported both 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). Hemolysis results are unrelated to anemia (Hill, A. et al., Haematologica, 93(s1):359 Abs.0903, 2008; Kanakura, Y. et al., Int. J. Hematol., 93:36-46, 2011). LDH concentration obtained at baseline and then continuously throughout the treatment period is an important measure of hemolysis. Baseline levels of cell-free plasma hemoglobin are very high in patients with PNH who have LDH levels of 1.5 or higher (LDH ≥ 1.5 × ULN), and there is a significant correlation between LDH and cell-free plasma hemoglobin (Hillmen, P. et al., N. Engl. J. Med., 355:1233-43, 2006). The normal LDH range is 105–333 IU / L (International Units / liter).

[0112] LDH levels can be measured using any appropriate test or assay, such as those described in Ferri FF, ed., Ferri's Clinical Advisor 2014. Philadelphia: Pa: Elsevier Mosby; 2014: Section IV - Laboratory test and interpretation of results. LDH concentrations can be measured in various samples obtained from patients, particularly serum samples. As used herein, the term “sample” means a biological substance from a subject. While serum LDH concentration is of interest, samples may be derived from other sources, such as single cells, multiple cells, tissues, tumors, biological fluids, biomolecules or supernatants, or extracts of any of the aforementioned. Examples include tissues excised for biopsy, tissues removed during excision, blood, urine, lymphoid tissue, lymph fluid, cerebrospinal fluid, mucous membranes, and fecal samples. The samples used may vary depending on the assay type, detection method, and the nature of the tumor, tissue, cell, or extract being assayed. Methods for preparing samples are known in the art and can be readily adapted to obtain samples compatible with the method used.

[0113] In one embodiment, a patient treated according to the method of the present disclosure experiences a reduction in LDH levels to normal levels, or to levels that are within 10% or 20% above levels considered normal (e.g., within 105-333 IU / L). For example, a patient treated according to the method of the present disclosure experiences a reduction in LDH levels to normal levels, or to levels that are within 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, The patient experiences a reduction in LDH levels to within 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or below 50%. In one embodiment, the patient's LDH level is 1.5 times or more ULN before initiating treatment (LDH ≥ 1.5 × ULN).

[0114] In one embodiment, a patient treated according to the method of the present disclosure experiences an LDH% change of 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% compared to baseline.

[0115] In one embodiment, a patient treated according to the method of the present disclosure maintains a serum trough concentration of at least 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 205, 210, 215, 220, 225, 230, 240, 245, 250, 255, 260, 265, 270, 280, 290, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 μg / mL or higher of anti-C5 antibody or its antigen-binding fragment. In one embodiment, a patient treated according to the method of the present disclosure maintains a serum trough concentration of at least 175 μg / mL or higher of anti-C5 antibody or its antigen-binding fragment.

[0116] In one embodiment, a patient treated according to the method of the present disclosure 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).

[0117] In one embodiment, patients treated according to the method of this disclosure do not experience breakthrough hemolysis (BTH).

[0118] In another embodiment, the treatment causes a shift to normal levels of hemolysis-related hematological biomarkers selected from the group consisting of free hemoglobin, haptoglobin, reticulocyte count, PNH red blood cell (RBC) clones, and D-dimer.

[0119] In another embodiment, the treatment reduces the need for blood transfusions compared to baseline.

[0120] In another embodiment, the treatment reduces major vascular adverse events (MAVEs; e.g., thrombophlebitis / deep vein thrombosis, pulmonary embolism, myocardial infarction, transient ischemic attack, unstable angina, renal vein thrombosis / renal artery thrombosis / glomerulostomy, renal infarction, acute peripheral vascular occlusion, mesenteric / visceral vein / arterial thrombosis or infarction, hepatic / portal vein thrombosis, cerebral arterial occlusion / cerebrovascular disorder, cerebral vein occlusion, renal artery thrombosis, or polyinfarct dementia).

[0121] In another embodiment, the treatment causes a shift to normal levels of estimated glomerular filtration rate (eGFR) and chronic disease-related biomarkers selected from the group consisting of spot urine:albumin:creatinine and plasma brain natriuretic peptide (BNP).

[0122] In another embodiment, treatment results in a change in quality of life from baseline, as assessed by the Functional Assessment of the Fatigue Scale, Version 4, of the Treatment for Chronic Disease (FACIT) and the European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire Core 30 Scale.

[0123] VI. Kits and Unit Dosage Forms Also provided herein are kits containing a therapeutically effective dose of a drug composition comprising an anti-C5 antibody such as ravulizumab or BNJ421, or an antigen-binding fragment thereof, and a drug-acceptable carrier, suitable for use in the manner described above. The kit may optionally include instructions, such as an administration schedule, enabling a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to a patient having PNH. The kit may also include a syringe.

[0124] Optionally, the kit comprises multiple packages of single-dose drug compositions, each containing an effective amount of anti-C5 antibody or its antigen-binding fragment for single-dose administration according to the method provided above. Apparatus or devices necessary for administering the drug composition may also be included in the kit. For example, the kit may provide one or more pre-filled syringes containing a certain amount of anti-C5 antibody or its antigen-binding fragment.

[0125] In one embodiment, a kit for treating PNH in human pediatric patients comprises: (a) a dose of an anti-C5 antibody or its antigen-binding fragment comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 8; and (b) instructions for using the anti-C5 antibody or its antigen-binding fragment according to any of the methods described herein.

[0126] In one embodiment, the kit comprises a dose of an anti-C5 antibody or its antigen-binding fragment, which is administered to patients weighing 5 kg or more but less than 10 kg in doses of (a) 600 mg once on day 1, and (b) 300 mg on day 15 and every 4 weeks thereafter.

[0127] In one embodiment, the kit comprises a dose of an anti-C5 antibody or its antigen-binding fragment, which is administered to patients weighing 10 kg or more but less than 20 kg in doses of (a) 600 mg once on day 1, and (b) 600 mg on day 15 and every 4 weeks thereafter.

[0128] In another embodiment, the kit comprises a dose of an anti-C5 antibody or its antigen-binding fragment, which is administered to patients weighing 20 kg or more but less than 30 kg in doses of (a) 900 mg once on day 1, and (b) 2100 mg on day 15 and every 8 weeks thereafter.

[0129] In another embodiment, the kit comprises a dose of an anti-C5 antibody or its antigen-binding fragment, which is administered to patients weighing 30 kg or more but less than 40 kg in doses of (a) 1200 mg once on day 1, and (b) 2700 mg on day 15 and every 8 weeks thereafter.

[0130] In another embodiment, the kit comprises a dose of an anti-C5 antibody or its antigen-binding fragment, which is administered to patients weighing 40 kg or more but less than 60 kg in doses of (a) 2400 mg once on day 1, and (b) 3000 mg on day 15 and every 8 weeks thereafter.

[0131] In another embodiment, the kit comprises a dose of an anti-C5 antibody or its antigen-binding fragment, which is administered to patients weighing 60 kg or more but less than 100 kg in doses of (a) 2700 mg once on day 1, and (b) 3300 mg on day 15 and every 8 weeks thereafter.

[0132] In another embodiment, the kit comprises a dose of an anti-C5 antibody or its antigen-binding fragment, which is administered to patients weighing 100 kg or more in doses of (a) 3000 mg once on day 1, and (b) 3600 mg on day 15 and every 8 weeks thereafter.

[0133] The following examples are merely illustrative and should not be construed as limiting the scope of this disclosure, as many variations and equivalents will be apparent to those skilled in the art upon reading this disclosure. All references, Genbank registrations, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference. [Examples]

[0134] Example 1: Phase 3, open-label trial of ravulizumab in children and adolescents with paroxysmal nocturnal hemoglobinuria (PNH). In this Phase 3, open-label trial, the pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety of ravulizumab will be evaluated in pediatric patients with progressive neuropathy (PNH).

[0135] 1. Purpose The primary objective of the trial is to evaluate the pharmacokinetics, disease progression, safety, and efficacy of ravulizumab in pediatric patients with PNH.

[0136] 2. Endpoint The primary endpoint is PK / PD parameters (trough and peak) at baseline and at weeks 2, 10, 18, and 26. PK parameters are defined as the maximum serum concentration (C). max ), trough serum concentration (measured at the end of the dosing interval in steady state; C trough), and accumulation ratio are included. PD parameters include measurement of changes in free C5 concentration and chicken erythrocyte (cRBC) hemolytic activity over time.

[0137] Secondary outcome measures include the evaluation of the following parameters: Percentage change in LDH from baseline up to day 183 (week 26); Transfusion avoidance (TA) is defined as the percentage of patients who maintain a transfusion-free state and do not require transfusions up to day 183 (week 26). Changes in quality of life (QoL) from baseline, as measured by the pediatric functional assessment of the Fatigue Inventory for Chronic Disease Treatment (FACIT) (patients aged 5 years and older) up to day 183 (week 26); The percentage of patients with stable hemoglobin, defined as avoiding a decrease of 2 g / dL or more from baseline in the absence of blood transfusions up to day 183 (week 26); Percentage change in free hemoglobin from baseline up to day 183 (week 26); As follows: For patients participating in the trial without prior complement inhibitor treatment, the proportion of patients with high LDH ≥ 2 × upper limit of normal after LDH has been reduced to < 1.5 × ULN with treatment; for patients participating in the trial after being stabilized with eculizumab treatment, the proportion of patients with high LDH ≥ 2 × ULN, in the presence of high LDH, defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia, major vascular adverse events [including MAVE, thrombosis], dysphagia, or erectile dysfunction).

[0138] Regarding safety endpoints, the safety and tolerability of ravulizumab will be assessed from baseline, up to week 26, and throughout the extension period, based on physical examination, vital signs, physical growth (height, weight, and head circumference [the latter only in patients aged 3 years or younger]), electrocardiogram (ECG), experimental assessment, and the number of adverse events (AEs) and serious adverse events (SAEs). The proportion of patients developing anti-drug antibodies (ADAs) will also be assessed.

[0139] 3. Examination Design This is a phase 3, open-label, single-arm, multicenter clinical trial to evaluate the pharmacokinetic / pathogenic disease progression (PK / PD), safety, and efficacy of ravulizumab administered intravenously (IV) in pediatric patients (under 18 years of age) with progressive nodule syndrome (PNH). The trial consists of a 4-week screening period, a 26-week primary endpoint period, and an extension period.

[0140] Patients who have given their consent will be screened for study eligibility up to four weeks prior to day 1. Patients who meet all inclusion and exclusion criteria will be enrolled in the primary endpoint and will receive a weight-based loading dose of ravulizumab on day 1, followed by weight-based maintenance therapy with ravulizumab for a total of 26 weeks: once on day 15 and every eight weeks thereafter (q8w) for patients weighing 20 kg or more, or once every four weeks (q4w) for patients weighing less than 20 kg. For patients participating in the study with eculizumab therapy, day 1 of the study treatment will take place two weeks after the last dose of eculizumab for patients receiving eculizumab.

[0141] Preliminary analyses of data such as ravulizumab PK and free C5 levels will be conducted after four patients weighing between 5 kg and 40 kg have completed administration up to day 71. Patient enrollment will continue without interruption while the analysis is underway. The safety and PK / PD data obtained will be evaluated to confirm that ravulizumab treatment is well-tolerated and provides appropriate complement inhibition. Furthermore, an independent Data Monitoring Committee (DMC) will formally review the safety data from the trial.

[0142] After all evaluations are completed on day 183, all patients will enter an extension period and continue receiving ravulizumab according to an appropriate weight-based dosing plan. The extension period will continue until the product is registered or approved (according to country-specific regulations), or for up to two years, whichever comes first. The end of the study will be defined as the last visit of the last patient in the extension period.

[0143] 4. Evaluation Schedule The evaluation schedule is outlined in Table 1 for the screening and primary evaluation periods, and in Table 2 for the extension period.

[0144] Additional (unscheduled) visits outside of designated appointments are permitted at the discretion of the researcher. Procedures, tests, and evaluations are conducted at the discretion of the researcher. All tests, procedures, or evaluations performed during unscheduled visits are recorded in the electronic case report form.

[0145] Furthermore, if an event suspected of being a breakthrough hemolysis occurs, LDH, PK, and PD parameters are analyzed at the central laboratory. If a suspected breakthrough event does not occur during a scheduled visit, an unscheduled visit is made for patient evaluation and collection of necessary LDH, PK, and PD parameters. For the purpose of defining breakthrough hemolysis, LDH evaluation is based on values ​​from the central laboratory.

[0146] [Table 1-1]

[0147] [Table 1-2]

[0148] [Table 2-1]

[0149] [Table 2-2]

[0150] 5. Clinical trial population Pediatric patients (under 18 years of age) with a proven diagnosis of PNH will be enrolled and treated with ravulizumab worldwide at approximately 40 study sites. Approximately 12 patients will be enrolled to ensure that at least 10 evaluable patients complete 26 weeks. Individuals who do not meet the criteria for participation in this trial (screening dropouts) may be rescreened once.

[0151] A patient is eligible to enroll in the clinical trial only if they meet all of the following criteria and do not meet any of the exclusion criteria: 1. Male and female patients who are under 18 years of age and weigh 5 kg or more at the time of giving consent. 2. Definitive diagnosis of PNH confirmed by high-sensitivity flow cytometry evaluation of red blood cells (RBCs) and white blood cells (WBCs) along with granulocyte or monocyte clone size of 5% or more (Borowitz, M. et al., Cytometry B Clin. Cytom., 78:211-30, 2010). 3. For patients not currently being treated with eculizumab, the following PNH-related signs or symptoms within 3 months of screening: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia, a history of major vascular adverse events (such as thrombosis), dysphagia, or erectile dysfunction; or a history of pRBC transfusion due to PNH. 4. The LDH values ​​are as follows: a. For patients not currently being treated with eculizumab, LDH level ≥ 1.5 × ULN. b. For patients currently receiving eculizumab, LDH ≤ 1.5 × ULN (a sample must be taken on the scheduled eculizumab administration day [i.e., at the trough level of eculizumab] before administration and analyzed by the central laboratory). 5. To reduce the risk of meningococcal infection, all patients must be vaccinated against meningococcal infection within three years prior to or at the time of initiation of the investigational drug. Patients who begin investigational drug treatment less than two weeks after meningococcal vaccination must receive appropriate prophylactic antibiotic treatment within two weeks of vaccination. Patients who cannot receive vaccination must receive antibiotic prophylaxis for the entire duration of treatment and for eight months after the last dose. 6. Patients must be vaccinated against Haemophilus influenzae type B (Hib) and Streptococcus pneumoniae, in accordance with national and local vaccination schedule guidelines as appropriate. 7. Female patients of childbearing potential (i.e., those who have reached menarche) and male patients with female partners of childbearing potential should follow the protocol-specified guidance for avoiding pregnancy during treatment and for 8 months after the last dose of the investigational drug.

[0152] The patient's legal guardian will submit written informed consent, and the patient will submit written informed consent and follow the clinical trial visit schedule.

[0153] Patients will be excluded from clinical trial registration if they meet any of the following criteria: 1. Platelet count calculated during screening: <30,000 / mm³ 3 (30×10 9 / L). 2. Screening showed an absolute neutrophil count <500 / μL (0.5 × 10⁻¹⁰). 9 / L). 3. History of bone marrow transplantation. 4. History of meningococcal infection. 5. History of recurrent infections of unknown origin 6. Active systemic bacterial, viral, or fungal infection within 14 days prior to administration of the investigational drug on day 1. 7. A history of malignant disease of the neck within the past five years, excluding well-treated non-melanoma skin cancer or carcinoma in situ. 8. A history of or ongoing major cardiac, pulmonary, renal, endocrine, or hepatic disease (e.g., active hepatitis) that, in the opinion of the researcher or sponsor, would exclude the patient from participation in the clinical trial. 9. Unstable medical conditions that make it less likely to withstand the protocol requirements (e.g., myocardial ischemia, active gastrointestinal bleeding, severe congestive heart failure, anticipated need for major surgery within 6 months of screening, coexistence of chronic anemia unrelated to PNH). 10.1 If a stable administration plan is not in place, concomitant use of anticoagulants is prohibited at least two weeks prior to day 10.1. 11. A history of hypersensitivity to any component of the investigational drug, such as hypersensitivity to mouse proteins. 12. Women who are planning to become pregnant, are currently pregnant, or are breastfeeding. 13. A woman of childbearing potential who has a positive pregnancy test result on day 11 of screening. 14. Participation in another study or clinical trial, or use of any experimental therapy, within 30 days prior to initiating the investigational drug on day 1 of this clinical trial, or within 5 half-lives of the investigational product. 15. A known or suspected history of drug or alcohol abuse or dependence within one year prior to the start of screening. 16. Any known medical condition, psychological state, or risk factor that, in the opinion of the researcher or sponsor, could hinder the patient's full participation in the clinical trial, impose additional risks on the patient, or interfere with the patient's evaluation or the outcome of the clinical trial.

[0154] 6. Clinical Trial Therapies Labulizumab is a humanized anti-C5 mAb produced in Chinese hamster cells. The labulizumab drug is supplied to clinical studies as a preservative-free 10 mg / mL sterile solution in disposable vials and is designed for administration by dilution in commercially available saline (0.9% sodium chloride injection; national pharmacopoeia) via IV infusion (see Table 3).

[0155] [Table 3]

[0156] Rabulizumab is packaged in a United States Pharmacopeia / European Pharmacopeia Type 1 borosilicate glass vial, sealed with a butyl rubber stopper, aluminum overseal, and flip-off cap. The investigational drug is supplied in a kit.

[0157] Upon arrival of the investigational drug kits at the clinical trial site, a pharmacist or designated person shall promptly remove the kits from the transport cooler and store them in their original cartons under refrigerated storage conditions of 2-8°C (35-47°F), protected from light. Rabulizumab is not frozen. The investigational drugs are stored in a secure, restricted-access storage area, and their temperature is monitored daily.

[0158] The mixed pharmaceutical product should be at room temperature before administration. Its materials should not be heated by anything other than ambient air temperature (e.g., not using microwaves or other heat sources).

[0159] Rabulizumab is not administered as an intravenous (IV) push or bolus infusion. The investigational drug infusion is prepared using sterile techniques. The patient's required dose of ravulizumab is further diluted in commercially available saline (0.9% sodium chloride; national pharmacopoeia) in the volumes specified in Table 4. The ravulizumab mixture is administered to the patient using an IV tube infusion set with an infusion pump. The use of a 0.2 micron filter is required during ravulizumab infusion.

[0160] [Table 4]

[0161] The investigational drug dosage will only be prepared and administered by qualified clinical trial staff. The investigational drug will only be administered to registered patients who have been confirmed as eligible to participate. Once the investigational drug has been prepared for a patient, it will only be administered to that patient. Each investigational drug vial will be used only once, and any remaining drug in the vial will not be used for other patients. Any drug remaining in the infusion tube or infusion bag will not be used for other patients.

[0162] As shown in Table 5, patients receive a loading dose of ravulizumab on day 1, followed by maintenance doses of ravulizumab on day 15 and every 8 weeks thereafter (q8w) for patients weighing 20 kg or more, or every 4 weeks (q4w) for patients weighing less than 20 kg. With the agreement of the medical monitor, a loading dose of 600 mg may be administered to patients weighing 5 kg or more but less than 10 kg as two separate infusions administered no more than 24 hours apart. In addition, the administration of additional doses of ravulizumab is permitted. The dosage is based on the patient's weight recorded on the day of administration or the most recently recorded weight. For patients entering the eculizumab therapy trial, day 1 of the investigational treatment takes place two weeks after the patient's last eculizumab dose.

[0163] [Table 5]

[0164] After the primary evaluation period, all patients will roll over to the extension period, and, whichever occurs first, they will continue to receive a weight-based maintenance dose of ravulizumab on day 183 and every 8 weeks thereafter (q8w) for patients weighing 20 kg or more, or every 4 weeks for patients weighing less than 20 kg, until the product is registered or approved, or for up to 2 years.

[0165] The actual time of all dose administrations, including doses administered as additional doses or two separate infusions, will be recorded. Due to its mechanism of action, the use of ravulizumab increases the patient's morbidity with meningococcal disease (N. meningitidis). To reduce the risk of meningococcal disease, all patients will be vaccinated against meningococcal disease within three years prior to the start of the investigational drug, or at the time of the start of the investigational drug. Patients starting investigational drug treatment less than two weeks after meningococcal vaccination will receive treatment with appropriate prophylactic antibiotics within two weeks after vaccination. Where available, vaccines against serotypes A, C, Y, W135, and B are recommended to prevent common pathogenic meningococcal serotypes. Patients will be vaccinated or revaccinated in accordance with current national immunization guidelines or local practices for the use of immunization with eculizumab. Vaccination may not be sufficient to prevent meningococcal disease. This will be considered in accordance with official guidance and local practices regarding the appropriate use of antimicrobial agents and immunizations. All patients will be monitored for early signs of meningococcal infection, immediately evaluated if infection is suspected, and treated with appropriate antibiotics if necessary. Patients will also be vaccinated against Hib and Streptococcus pneumoniae in accordance with national and local immunization schedule guidelines.

[0166] 7. Evaluation of effectiveness The administration of packed red blood cell (pRBC) transfusions, including the hemoglobin results and symptoms that triggered the transfusion, as well as the number of units transfused, are recorded in the electronic case report form (eCRF).

[0167] Blood and urine samples will be collected at the designated times in the Schedule of Assessments.

[0168] The following disease-related experimental parameters will be measured during the trial: LDH, free hemoglobin, occult blood, urine, total C5, haptoglobin, reticulocyte count, PNH RBC clone size as assessed by high-sensitivity flow cytometry, and estimated glomerular filtration rate (calculated using Schwartz's formula).

[0169] The researcher or designated person shall record for each patient the following signs and symptoms of PNH: fatigue, chest pain, hemoglobinuria, abdominal pain, dyspnea, dysphagia, erectile dysfunction, and the presence or absence of red / dark urine or hemoglobinuria.

[0170] The Pediatric FACIT Fatigue Scale is a 13-item questionnaire that assesses fatigue over the preceding 7 weeks and its impact on daily activities and function. Each item is scored on a 5-point scale, with a total score ranging from 0 to 52. A higher score indicates a higher quality of life (QoL). The questionnaire is self-reported by patients who were 8 years of age or older at the time of enrollment, and by caregivers for patients who were 5 to under 8 years of age at the time of enrollment. Patients under 5 years of age are evaluated. The Pediatric FACIT Fatigue Scale is shown in Table 6.

[0171] [Table 6]

[0172] Major vascular adverse events (MAVEs) are evaluated as part of the planned assessment of adverse events (AEs). Details of MAVEs, such as diagnostic method (e.g., magnetic resonance imaging, ultrasound, angiography), date of diagnosis, and date of recovery (or ongoing), are collected in the eCRF as part of the patient's medical history (prior to baseline). MAVEs are defined as follows: thrombophlebitis / deep vein thrombosis, transpulmonary embolism, myocardial infarction, transient ischemic attack, unstable angina, renal venous thrombosis, acute peripheral vascular occlusion, mesenteric / visceral venous thrombosis or infarction, mesenteric / visceral artery thrombosis or infarction, hepatic / portal vein thrombosis (Budd-Chiari syndrome), cerebral arterial occlusion / cerebrovascular disorder, cerebral venous occlusion, renal artery thrombosis, gangrene (non-traumatic; non-diabetic), amputation (non-traumatic; non-diabetic), and cutaneous thrombosis.

[0173] 8. Safety Evaluation Demographic parameters such as age, sex, race, and ethnicity are reviewed. A complete medical history is taken and recorded. Weight and height are recorded. Head circumference is recorded for patients under 3 years of age. The patient's PNH history, including PNH symptoms, date of diagnosis, PNH clone size, and history of pRBC transfusions and any MAVE, is recorded during the screening visit.

[0174] The patient's medical history, including previous and co-existing symptoms / diseases and history of blood transfusions, will be recorded during the screening visit. Medication use (prescription or over-the-counter medications, including vitamins and / or herbal supplements) within 28 days prior to the start of screening will also be recorded. Details of previous treatment with eculizumab, including dose level and frequency, will be gathered. Meningococcal vaccination within 3 years prior to the first administration of the investigational drug, and vaccination history for Hib and Streptococcus pneumoniae since birth will also be recorded.

[0175] The physical examination includes the following assessments: overall appearance; skin; head, ears, eyes, nose, and throat; neck; lymph nodes; chest; heart; abdominal cavity; limbs; central nervous system; and musculoskeletal system. The brief physical examination consists of body system-related assessments based on the researcher's judgment and the patient's symptoms. Physical growth (height, weight, and head circumference [the latter only in patients aged 3 years or younger]) is assessed.

[0176] After the patient has rested for at least 5 minutes, vital signs should be measured, including systolic and diastolic blood pressure (BP; millimeters of mercury [mmHg]), heart rate (beats / min), respiratory rate (respiratory rate / min), and body temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]).

[0177] Serum pregnancy tests, hematological, chemical, coagulation, and urinalysis samples are collected at designated points in the evaluation schedule. Specific laboratory evaluations are shown in Table 7. Samples for laboratory evaluation are collected before administration of each investigational drug. For infants with insufficient blood volume, an alternative blood sampling schedule must be used. In the event of a suspected breakthrough, an unscheduled hospital visit will be made for analysis of LDH, PK, and PD parameters by the central laboratory, with samples being collected at that time.

[0178] [Table 7]

[0179] Some laboratory values ​​are expected to be outside the normal range due to the underlying disease. Researchers should use their medical judgment when assessing the clinical significance of these values. Clinical significance is defined as any variation in a laboratory measurement that has medical relevance and consequently alters treatment. If a clinically significant laboratory change from baseline is noted, the change will be recorded as an adverse event. Researchers will also assess the relevance of all clinically significant out-of-range values ​​to the investigational treatment. Researchers will monitor patients through additional laboratory assessments until (1) the value returns to the normal range or baseline level, or (2) the out-of-range value is no longer associated with the administration of the investigational drug or other protocol-specific procedures, in the researcher's judgment.

[0180] For women of childbearing potential (i.e., those who have reached menarche), serum or urine pregnancy tests (beta-human chorionic gonadotropin [beta-hCG]) are performed according to the evaluation schedule.

[0181] Blood samples are analyzed for the hematological parameters shown in Table 7. Indirect bilirubin is calculated from total bilirubin and direct bilirubin values. Therefore, if direct bilirubin is below the quantification limit, the indirect bilirubin result is unavailable.

[0182] Chemical evaluation will be performed at designated points in the evaluation schedule. Estimated glomerular filtration rate will be calculated using the Schwarz formula for all visits when serum chemistry is collected. Blood samples will also be analyzed for coagulation parameters as shown in Table 7.

[0183] Urine samples are analyzed for the parameters shown in Table 7. If the macroscopic analysis is abnormal, a microscopic examination of the urine sample is performed.

[0184] For each patient, a single 12-lead digital electrocardiogram (ECG) is collected according to the evaluation schedule. Patients are in a supine position for approximately 5–10 minutes prior to ECG collection and maintain this position during ECG collection (but remain awake). The ECG is evaluated to determine whether it falls within the normal range and to determine the clinical significance of the result.

[0185] Blood samples are collected to test for the presence and titer of anti-drug antibodies against ravulizumab in serum prior to administration of the investigational drug, as outlined in the evaluation schedule. Further characterization of the antibody response, including binding and neutralizing antibodies, PK / PD, and the safety and activity of ravulizumab, will be performed as appropriate.

[0186] An adverse event is any undesirable medical occurrence that occurs in a patient receiving a drug for which there is no causal relationship with the treatment in question. Therefore, whether or not it is considered drug-related, an adverse event may be any sign (e.g., an abnormal laboratory finding), symptom, or disease that is temporarily associated with the use of a drug and has a poor prognosis or is unintended.

[0187] The absence of undesirable medical events (e.g., hospitalization for elective surgery if planned before the start of the trial, hospitalization for social or convenience reasons) and predictable daily fluctuations of pre-existing diseases or conditions present or detectable at the start of the trial that do not worsen are not considered adverse events. Blood transfusions are treated as efficacy endpoints. Blood transfusions administered in a patient or outpatient setting should not be considered adverse events or serious adverse events unless identified as such. Since the objective of clinical trials is to establish drug action, the absence of drug action is not considered an adverse event in clinical trials.

[0188] Medication errors (intentional misuse, abuse, and overdose of the drug) or use other than that defined in the protocol will not be considered adverse events unless an undesirable medical event occurs as a result of the medication error.

[0189] Cases of pregnancy occurring during maternal or paternal exposure to the investigational drug product are reported by the researcher / site within 24 hours of recognition. Data on fetal outcomes and breastfeeding are collected for reporting to regulatory authorities and for safety assessment.

[0190] The severity of adverse events is graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 or later. A grading scale (severity) is provided for each adverse event term. Each CTCAE term is a lower-level term (LLT) in accordance with the ICH Medical Dictionary for Regulatory Activities (MedDRA®). Each LLT is coded in a MedDRA base term (PT). The grade represents the severity of the adverse event. As shown in Table 8, CTCAE assigns grades 1 through 5 to each adverse event, along with a clinical description of its severity.

[0191] [Table 8]

[0192] Severity and seriousness are distinct terms. Severity describes the intensity of an adverse event, while the term serious refers to an adverse event that meets specific criteria for a serious adverse event. Causal assessments (unrelated, unlikely, possible, likely, or certain) are provided for all adverse events (both serious and non-serious) based on the researcher's medical judgment and the confirmed symptoms associated with the event as shown in Table 9.

[0193] [Table 9]

[0194] A SAE is any undesirable medical event that results in death, is life-threatening (i.e., the patient was at risk of death at the time of the event), requires hospitalization or extension of existing hospitalization, results in a persistent or significant disability / incapacity, or is a birth defect / absence.

[0195] A significant medical event that, based on appropriate medical judgment, requires intervention to endanger the patient or prevent one of the above consequences, and which does not result in death, is not immediately life-threatening, or requires hospitalization, is considered a serious adverse event.

[0196] A suspected, unpredictable, serious adverse event (SUSAR) is a serious event that is not described in the researcher's brochure and that the researcher identifies as being related to the investigational drug product or procedure.

[0197] All adverse events will be collected from the time of signing the Informed Consent Form (ICF) until 56 days after the last administration of the drug to the end-test patient, or until 56 days after the last administration of the drug to the patient completing the trial. All adverse events will be recorded in the eCRF as soon as their occurrence is noticed. Researchers will be instructed to report serious adverse events, including their assessment (e.g., severity, severity, and potential association with the investigational drug).

[0198] 9. Pharmacokinetics (PK) and Pharmacodynamics (PD) Blood samples for determining serum drug concentration and evaluating pharmacokinetics (PK / PD) are collected before and after administration of the investigational drug at the designated points in the evaluation schedule. The actual date and time (24-hour clock time) of each sample is recorded. Additional PK / PD samples are required in the event of breakthrough hemolysis.

[0199] The final blood sample for PK and PD evaluation is taken from the arm opposite to the one used for drug injection. PK / PD evaluation is performed as follows: serum ravulizumab concentration over time, free and total C5 concentrations over time, and cRBC hemolytic activity over time.

[0200] 10. Statistical methods and planned analysis The Clinical Trial Report (CSR) is prepared based on efficacy, safety, pharmacokinetic (PK), disease progression (PD), and immunogenicity data collected throughout the 26-week primary endpoint period (day 183). The final CSR, summarizing long-term efficacy, safety, PK, PD, and immunogenicity data, is prepared at the completion of the trial.

[0201] This study is inherently descriptive, and power for hypothesis testing has not been calculated due to the rarity of the disease in pediatric patients. Approximately 12 patients will be enrolled to ensure that at least 10 evaluable patients complete 26 weeks. A sample size of 10 is expected to adequately account for PK / PD in pediatric patients with PNH. Efficacy analysis will be performed in the largest analysis population (FAS). The FAS will include all patients who have received at least one dose of ravulizumab and have at least one post-baseline evaluation.

[0202] Safety analysis will be conducted in the Safety Set, which is defined as all patients receiving at least one dose of ravulizumab.

[0203] Pharmacokinetic and disease progression (PD) analyses will be performed in all patients who receive at least one dose of ravulizumab and have evaluable PK and PD data.

[0204] Patient demographic and baseline characteristics, including medical history and transfusion history, are compiled for the Clinical Study Report (FAS) and the safety analysis population. All patients are included in the patient faculties summary, which explains the frequency and percentage of patients who discontinued the trial, along with the reasons for screening, treatment, and completion of the trial, or withdrawal from the trial.

[0205] The number of patients receiving treatment, discontinuing treatment (with reasons for discontinuation), completing or discontinuing the primary evaluation period (with reasons for discontinuation), entering an extension period, and completing or discontinuing the extension period (with reasons for discontinuation) is summarized in the table.

[0206] Previous and concurrent drug use for each patient is coded using the World Health Organization Drug Dictionary, and the percentage of concurrently used drugs is summarized. Drug applications are summarized by anatomical therapeutic chemistry classification and generic name, using the frequency and percentage of patients in the safety analysis population. The number of infusions administered per patient is summarized in tables for the FAS and the safety analysis population. Efficacy analysis is performed using the FAS. Continuous variables are summarized using explanatory statistics such as observation count, mean, SD, median, minimum, and maximum. Categorical variables are summarized by patient frequency count and percentage. Analysis is performed separately for untreated patients and patients previously treated with eculizumab.

[0207] The following definitions apply to adverse events: A pre-treatment adverse event is any adverse event that occurs after informed consent has been given but before the first infusion of the investigational drug. A treatment-induced adverse event is any adverse event that occurs during or after the first infusion of the investigational drug. A serious treatment-induced adverse event is a serious AE (TEAE) that occurs under treatment.

[0208] The number of TEAEs, TEAEs leading to withdrawal from the trial, TEAEs leading to discontinuation of treatment, TEAEs during investigational drug administration, severe TEAEs, and SAEs are summarized. All adverse events are coded using MedDRA version 18 or later and grouped by system organ class and basic terminology. Detailed patient lists are provided for TEAEs, SAEs, related TEAEs, TEAEs during investigational drug administration, TEAEs leading to withdrawal from the trial, and TEAEs leading to discontinuation of treatment.

[0209] Adverse changes from baseline in physical examination findings are classified as adverse events and analyzed accordingly.

[0210] Vital signs are described descriptively at baseline, post-baseline, and in terms of changes from baseline by treatment group.

[0211] Height, weight, and head circumference (the latter only for patients aged 3 years or younger) are descriptively summarized at baseline, after baseline, and as changes from baseline by treatment group.

[0212] Changes in clinical chemistry, hematological, and urinalysis from baseline to baseline trial time are descriptively summarized. A shift table over time is provided for all central laboratory values, where applicable, using normal low or high values ​​based on the normal range. A list of patients with abnormal results is provided. A list of patient data for ECG parameters is provided. Changes from baseline in electrocardiogram intervals (PR, RR, QT, and QTcF) are provided. The QT interval is corrected for heart rate using Fridericia's formula (QTcF).

[0213] The incidence and titer of anti-drug antibodies (ADAs) against rabulizumab are summarized in a table. Using individual serum concentration data for all patients who received at least one dose of rabulizumab and have evaluable PK data, pharmacokinetic parameters for rabulizumab are derived.

[0214] A graph of the mean serum concentration-time profile is created. Graphs of serum concentration-time profiles for individual patients are also provided. Actual dose administration and sampling times are used in all calculations. Descriptive statistics are calculated for serum concentration data at each sampling time, as appropriate. Assessment of population pharmacokinetics is expected to use data from this trial or in conjunction with data from other studies.

[0215] PD analysis will be performed for all patients who have received at least one dose of ravulizumab and have evaluable PK data.

[0216] Descriptive statistics are presented for all ravulizumab PD endpoints at each sampling time. Where appropriate, the PD effect of IV-administered ravulizumab is evaluated by assessing the absolute values, changes, and percentage changes from baseline in total and free C5 serum concentrations, as well as the change from baseline in cRBC hemolysis, over time.

[0217] The evaluation of the rabulizumab PK / PD relationship will be considered using data from this clinical trial or in conjunction with data from other studies. The analysis will be performed separately for treatment-naive patients and patients previously treated with eculizumab.

[0218] If the assessment on day 1 is missing, the screening assessment will be used as the baseline assessment.

[0219] Example 2: Interim results from a Phase 3, open-label trial of ravulizumab in children and adolescents with PNH. An open-label trial of ravulizumab in a pediatric patient population with PNH was conducted substantially in accordance with the ravulizumab trial described in Example 1, and its pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy were evaluated.

[0220] A. Experimental Design The study design is shown in Figure 1. Thirteen patients were enrolled, and 12 were included in this preliminary analysis. All patients were vaccinated against Haemophilus influenzae type B (Hib) and Streptococcus pneumoniae. Screening revealed that patients who received eculizumab had LDH < 1.5 × ULN, while patients who did not receive eculizumab had LDH ≥ 1.5 × ULN. Patients had granulocyte or monocyte PNH clone size > 5%.

[0221] No patients discontinued treatment during the primary evaluation period. A summary of patient predispositions is shown in Figure 2. Baseline patient demographics are shown in Figure 3, and baseline disease characteristics are shown in Figure 4.

[0222] B. Results In pediatric patients with PNH, following body weight-based ravulizumab administration, C max C-trough, free C5, and cRBC hemolytic activity were consistent with previous pharmacological studies of ravulizumab at weeks 2, 10, 18, and 26.

[0223] Figures 5 and 6 show the time-course serum and mean serum concentrations of ravulizumab in patients who were treatment-naive and those who had previously received eculizumab treatment, respectively. During the trial, all C-trough levels were >175 μg / mL except for one patient. The excluded treatment-naive patient experienced SAE (Severe Acute Embolism) and MAVE (Severe Acute Embolism) during the trial, received multiple pRBC transfusions, and had two C-trough levels below 175 μg / mL. Despite subthermal concentrations, free C5 control was maintained in this patient throughout the primary endpoint period.

[0224] Figure 7 shows the time-dependent results for free C5 and CRBC in treatment-naive patients and patients with prior eculizumab treatment. Figures 8 and 9 show the mean cRBC and mean free C5 over time for both patient groups. All serum free C5 levels were <0.5 μg / mL (i.e., the threshold for complete terminal complement inhibition). For both cohorts, mean cRBC hemolytic activity was less than 20% at all time points (i.e., the threshold for complete hemolysis inhibition). No anti-drug antibodies (ADAs) were detected under treatment.

[0225] Regarding efficacy, descriptive statistics of the endpoints demonstrated the efficacy of ravulizumab in pediatric PNH patients who were treatment-naive and those treated with eculizumab. No patients experienced breakthrough hemolysis (BTH). The overall efficacy results are shown in Figure 12. For the purposes of this study, the following definitions were used: LDH% change from baseline (LDH-PCHG) is defined as the percentage change in LDH from baseline to day 183. Transfusion avoidance (TA) is defined as the proportion of patients who remained transfusion-free and did not require transfusions up to day 183 according to protocol-specific guidelines. Treatment of chronic disease (FACIT) is defined as the change in quality of life (QoL) from baseline to day 183, as assessed by the pediatric functional assessment of the Treatment of Chronic Disease (FACIT) fatigue scale. The proportion of patients with stable hemoglobin (HGB-S) is defined as avoidance of a decrease of ≥2 g / dL in hemoglobin level from baseline to day 183 in the absence of transfusions. The percentage change in free hemoglobin from baseline (free HGB-PCHG) is defined as the percentage change in free hemoglobin from baseline to day 183. The proportion of patients with breakthrough hemolysis is defined as the presence of at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin <10 g / dL], major vascular adverse events [including MAVE, thrombosis], dysphagia, or erectile dysfunction) in the presence of high LDH, after LDH has been pre-reduced to <1.5 × ULN with treatment for patients participating in the trial who are treatment-naive to complement inhibitor therapy; or high LDH ≥ 2 × ULN for patients participating in the trial who are stabilized with eculizumab therapy.

[0226] Figures 10 and 11 show the mean change from baseline pediatric FACIT fatigue score and the mean FACIT fatigue score over time for treatment-naive patients and patients with prior eculizumab treatment, respectively. Figures 13 and 14 show the mean (95% CI)% change and mean LDH over time for both patient groups. The mean (SD) % change in LDH from baseline for treatment-naive patients was -42.09 (58.992), and for patients with prior eculizumab treatment it was 4.65 (44.702).

[0227] Rabulizumab administration in pediatric PNH patients was safe and well-tolerated. A summary of key safety points is shown in Figure 15. Serious adverse events (TESAES) that occurred during treatment are summarized in Figure 16. The most frequent adverse events (AEs) were abdominal pain and nasopharyngitis (2 patients each). No meningococcal infections, AE-related discontinuations, or deaths were observed during the primary evaluation period. One patient experienced a major vascular adverse event (MAVE).

[0228] In short, the pharmacokinetics (PK) / pharmacodynamics (PD), efficacy, and safety of ravulizumab in pediatric patients who were treatment-naive and those who had previously received eculizumab treatment were consistent with previous study results (i.e., the ALXN1210-PNH-301 (clinical trial ID: NCT02946463) and ALXN1210-PNH-302 (clinical trial ID: NCT03056040) trials).

[0229] It should be understood that all maximum limits shown throughout this specification include all lower limits, as if such lower limits were clearly stated herein. All minimum limits shown throughout this specification include all higher limits, as if such higher limits were clearly stated herein. All numerical ranges shown throughout this specification include all narrower numerical ranges that fall within such wider numerical ranges, as if all such narrower numerical ranges were clearly stated herein.

[0230] Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this disclosure pertains. Methods and materials used herein are described herein; other suitable methods and materials known in the art may also be used. Materials, methods, and examples are illustrative and not intended to limit. All patent publications, patent applications, patents, sequences, database entries (e.g., PUBMED, NCBI, UNIPROT, clinical trial acceptance numbers), and other references mentioned herein are incorporated by reference in their entirety. In case of any conflict, this specification shall prevail, including definitions.

[0231] While specific embodiments of this disclosure are illustrated and described, it will be apparent to those skilled in the art that various other modifications and modifications may be made without departing from the spirit and scope of this disclosure. Therefore, all such modifications and modifications within the scope of this disclosure are intended to be incorporated into the appended claims.

[0232] [Table 10]

[0233] [Table 11]

[0234] [Table 12]

[0235] [Table 13]

Claims

Claim 1: A composition for use in a method for treating paroxysmal nocturnal hemoglobinuria (PNH) in a human pediatric patient, said composition comprising an anti-C5 antibody or antigen-binding fragment thereof, said antibody or antigen-binding fragment comprising a heavy chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO:14, and a light chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO:11, said method comprising administering said anti-C5 antibody or antigen-binding fragment thereof to said patient, wherein said anti-C5 antibody or antigen-binding fragment thereof is: (a) administered intravenously once on day 1 at a dose of 600 mg to patients weighing 5 kg or more but less than 10 kg, 600 mg to patients weighing 10 kg or more but less than 20 kg, 900 mg to patients weighing 20 kg or more but less than 30 kg, 1200 mg to patients weighing 30 kg or more but less than 40 kg, 2400 mg to patients weighing 40 kg or more but less than 60 kg, 2700 mg to patients weighing 60 kg or more but less than 100 kg, or 3000 mg to patients weighing 100 kg or more; (b) on day 15 and every four weeks thereafter, at a dose of 300 mg to patients weighing 5 kg or greater but less than 10 kg, or at a dose of 600 mg to patients weighing 10 kg or greater but less than 20 kg; or on day 15 and every eight weeks thereafter, at a dose of 2100 mg to patients weighing 20 kg or greater but less than 30 kg, at a dose of 2700 mg to patients weighing 30 kg or greater but less than 40 kg, at a dose of 3000 mg to patients weighing 40 kg or greater but less than 60 kg, at a dose of 3300 mg to patients weighing 60 kg or greater but less than 100 kg, or at a dose of 3600 mg to patients weighing 100 kg or greater.

2. A composition for use in a method for treating paroxysmal nocturnal hemoglobinuria (PNH) in a human pediatric patient, said composition comprising an anti-C5 antibody or antigen-binding fragment thereof, said antibody comprising a heavy chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 14, and a light chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 11, and a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), said method comprising administering said anti-C5 antibody or antigen-binding fragment thereof to said patient, said variant human Fc constant region comprising Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, in EU numbering of native human IgG Fc constant region, said anti-C5 antibody or antigen-binding fragment thereof (a) administered intravenously once on day 1 at a dose of 600 mg to patients weighing 5 kg or more but less than 10 kg, 600 mg to patients weighing 10 kg or more but less than 20 kg, 900 mg to patients weighing 20 kg or more but less than 30 kg, 1200 mg to patients weighing 30 kg or more but less than 40 kg, 2400 mg to patients weighing 40 kg or more but less than 60 kg, 2700 mg to patients weighing 60 kg or more but less than 100 kg, or 3000 mg to patients weighing 100 kg or more; (b) on day 15 and every four weeks thereafter, at a dose of 300 mg to patients weighing 5 kg or greater but less than 10 kg, or at a dose of 600 mg to patients weighing 10 kg or greater but less than 20 kg; or on day 15 and every eight weeks thereafter, at a dose of 2100 mg to patients weighing 20 kg or greater but less than 30 kg, at a dose of 2700 mg to patients weighing 30 kg or greater but less than 40 kg, at a dose of 3000 mg to patients weighing 40 kg or greater but less than 60 kg, at a dose of 3300 mg to patients weighing 60 kg or greater but less than 100 kg, or at a dose of 3600 mg to patients weighing 100 kg or greater.

3. The anti-C5 antibody has a K Ｄ Affinity dissociation constants (K) in the range of ≦1 nM Ｄ 3. The composition according to claim 1, wherein the composition binds to human C5 at pH 7.4 and 25°C.

4. The anti-C5 antibody is Ｄ The composition of any one of claims 1 to 3, which binds to human C5 at ≥ 10 nM at pH 6.0 and 25°C.

5. The anti-C5 antibody is administered to a patient weighing 5 kg or more and less than 10 kg: (a) at a dose of 600 mg once on day 1; and (b) at a dose of 300 mg on day 15 and every 4 weeks thereafter The composition according to any one of claims 1 to 4, characterized in that it is administered.

6. The anti-C5 antibody is administered to a patient weighing 10 kg or more and less than 20 kg: (a) at a dose of 600 mg once on day 1; and (b) at a dose of 600 mg on day 15 and every 4 weeks thereafter The composition according to any one of claims 1 to 5, characterized in that it is administered.

7. The anti-C5 antibody is administered to a patient weighing 20 kg or more and less than 30 kg: (a) at a dose of 900 mg once on day 1; and (b) at a dose of 2100 mg on day 15 and every 8 weeks thereafter The composition according to any one of claims 1 to 6, characterized in that it is administered.

8. The anti-C5 antibody is administered to a patient weighing 30 kg or more and less than 40 kg: (a) at a dose of 1200 mg once on day 1; and (b) at a dose of 2700 mg on day 15 and every 8 weeks thereafter The composition according to any one of claims 1 to 7, characterized in that it is administered.

9. The anti-C5 antibody is administered to a patient weighing 40 kg or more and less than 60 kg: (a) at a dose of 2400 mg once on day 1; and (b) at a dose of 3000 mg on day 15 and every 8 weeks thereafter The composition according to any one of claims 1 to 8, characterized in that it is administered.

10. The anti-C5 antibody is administered to a patient weighing 60 kg or more and less than 100 kg: (a) at a dose of 2700 mg once on day 1; and (b) at a dose of 3300 mg on day 15 and every 8 weeks thereafter The composition according to any one of claims 1 to 9, characterized in that it is administered.

11. The anti-C5 antibody is administered to a patient weighing 100 kg or more: (a) at a dose of 3000 mg once on day 1; and (b) at a dose of 3600 mg on day 15 and every 8 weeks thereafter The composition according to any one of claims 1 to 10, characterized in that it is administered.

12. The composition of any one of claims 1 to 11, wherein the treatment maintains a serum trough concentration of the anti-C5 antibody of 100 μg / mL or greater.

13. The composition of any one of claims 1 to 12, wherein the treatment maintains a serum trough concentration of the anti-C5 antibody of 200 μg / mL or greater.

14. The composition of any one of claims 1 to 13, wherein the anti-C5 antibody is formulated for intravenous administration.

15. The composition of any one of claims 1 to 14, wherein the treatment is a dosing cycle comprising a total of 26 weeks of treatment.

16. The composition of any one of claims 1 to 15, wherein the treatment results in terminal complement inhibition.

17. 17. The composition of any one of claims 1 to 16, wherein the treatment results in a reduction in hemolysis as assessed by lactate dehydrogenase (LDH) levels compared to baseline.

18. 18. The composition of any one of claims 1-17, wherein the treatment produces at least one therapeutic effect selected from the group consisting of a reduction or cessation of abdominal pain, dyspnea, dysphagia, chest pain, and erectile dysfunction compared to baseline.

19. 19. The composition of any one of claims 1 to 18, wherein the treatment results in a shift to normal levels of at least one hemolysis-associated hematological biomarker selected from the group consisting of free hemoglobin, haptoglobin, reticulocyte count, PNH red blood cell (RBC) clone, and D-dimer.

20. 20. The composition of any one of claims 1 to 19, wherein the treatment reduces the need for blood transfusions compared to baseline.

21. 21. The composition of any one of claims 1 to 20, wherein said treatment reduces major adverse vascular events (MAVE).

22. 22. The composition of any one of claims 1 to 21, wherein the treatment results in a shift in estimated glomerular filtration rate (eGFR) or spot urine: albumin: creatinine and plasma brain natriuretic peptide (BNP) to normal levels.

23. 23. The composition of any one of claims 1-22, wherein the treatment results in a change from baseline in quality of life as assessed by the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue scale, version 4 and the European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire Core 30 scale compared to baseline.

24. 24. The composition of any one of claims 1 to 23, wherein the treatment results in a reduction in free C5 levels or a reduction in red blood cell (RBC) hemolysis in the patient; in particular, the treatment results in a free C5 level of 0.5 μg / mL or less and / or RBC hemolysis of 20% or less compared to an untreated patient.

25. The composition of any one of claims 1 to 24, wherein the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof in the patient of at least 175 µg / mL or greater.

26. 26. The composition of any one of claims 1 to 25, wherein the treatment results in an improvement in at least one clinical parameter selected from: (a) lactate dehydrogenase (LDH) percent change from baseline (LDH-PCHG); (b) transfusion avoidance (TA); (c) pediatric FACIT fatigue (FACIT); (d) hemoglobin stabilization (HGB-S); (e) free hemoglobin percent change from baseline (free HGB-PCHG); and (f) breakthrough hemolysis (BTH) or a combination thereof; preferably, the treatment results in a reduction in breakthrough hemolysis (BTH).

27. 27. The composition of any one of claims 1-26, wherein the patient has previously been treated with eculizumab, and day 1 of the treatment is 2 weeks or more since the patient's last dose of eculizumab.

28. 1. A kit for treating paroxysmal nocturnal hemoglobinuria (PNH) in a human pediatric patient, comprising: (a) a dose of an anti-C5 antibody or antigen-binding fragment thereof comprising a heavy chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 14 and a light chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 11; and (b) Instructions for using the anti-C5 antibody or antigen-binding fragment thereof in the method of claim 1 or 2. A kit comprising:

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