Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
  • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
  • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
  • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

• Thrombotic microangiopathy is a post-transplant complication of hematopoietic stem cell transplant (HSCT) that may affect 10% to 35% of HSCT recipients (Dvorak et al., Front Pediatr. 2019;7: 133); Jodele et al., Blood Rev. 2015;29(3): 191-204; Seaby et al., Pediatr Nephrol. 2018;33(9): 1489-1500). It presents via endothelial injury and affects the kidney and other organs. It is estimated that 30% of patients with HSCT TMA will present with severe disease (Rosenthal et al., J. BloodMed.
• HSCT-TMA typically occurs early post allogeneic HSCT, with a median diagnosis at 35 to 47 days post-HSCT, and 88% to 92% occurring before Day +100.
• cases have been reported up to 2 years post-HSCT.
• Autologous recipients may develop HSCT TMA even earlier, with a median of 18 days post-HSCT (Dvorak et al., Front Pediatr. 2019;7: 133).
• Endothelial injury is fundamental to the pathogenesis of HSCT-TMA, with dysregulated complement activation likely to be a consequence of the endothelial damage.
• Risk factors associated with HSCT-TMA development that also initiate endothelial damage include calcineurin inhibitors (CNIs), infections, and conditioning regimens (high dose chemotherapy or total body irradiation) (Khosla, et al., Bone Marrow Transplant. 2018;53(2): 129-137; Masias, et al., Blood. 2017;129(21):2857-2863).
• CNIs calcineurin inhibitors
• infections infections
• conditioning regimens high dose chemotherapy or total body irradiation
• HSCT-TMA Currently, there are no approved therapies for the treatment of HSCT-TMA.
• Primary intervention for HSCT-TMA involves withdrawal of the offending agent (e.g, CNIs) and/or treatment of any trigger conditions (e.g., treatment for infections) (Dvorak, et al., Front Pediatr. 2019;7: 133); Seaby el al., Pediatr. Nephrol. 2018;33(9): 1489-1500).
• the offending agent and/or treatment of any associated trigger condition does not reverse the HSCT-TMA. Accordingly, it is an object of the present disclosure to provide improved methods for treating patients with HSCT-TMA.
• HSCT-TMA patients treated with ravulizumab according to a particular clinical dosage regimen e.g, at particular loading and maintenance dose amounts and according to a specific dosing schedule
• who received one or more transfusions e.g, platelet or red blood cell (RBC) transfusions
• RBC red blood cell
• a supplemental dosing simulation model the inventors have identified that delivery of a supplemental dose of ravulizumab to attain a mean (standard deviation) minimum and maximum plasma concentration of ravulizumab during a dosing interval that is between 474 (200) pg/mL and 1350 (430) pg/mL, respectively, provided a more effective treatment to HSCT-TMA patients who have undergone transfusion, e.g., RBC transfusion, during treatment.
• transfusion e.g., RBC transfusion
• HSCT patients with body weight >30 kg who received any (e.g, one, two, three, or more) RBC transfusions in the 4 weeks following a maintenance dose were administered a supplemental dose of ravulizumab 4 weeks after that maintenance dose.
• the supplemental ravulizumab dose regimen achieved immediate, complete, and sustained terminal complement inhibition.
• the supplemental dosing scheme was also applied to effectively treat HSCT-TMA patients in the lower body weight (e.g, ⁇ 30 kg) and particularly ultra-low body weight (e.g, ⁇ 20 kg, and particularly ⁇ 10 kg) cohorts.
• HSCT patients with body weight ⁇ 30 kg who received any (e.g, one, two, three, or more) RBC transfusions within a specified timeframe e.g, 2 w eeks for patients who are ⁇ 20 kg and 4 weeks for patients who are >20 kg (e.g, 20 kg ⁇ 30 kg; 30 kg ⁇ 40 kg; 40 kg ⁇ 60 kg; 60 kg ⁇ 100 kg; or > 100 kg)
• a maintenance dose were administered a supplemental dose of ravulizumab at the specified timeframe after that maintenance dose.
• the supplemental ravulizumab dose regimen achieved immediate, complete, and sustained terminal complement inhibition.
• HSCT-TMA in a particular patient sub-population
• a transfusion e.g., platelet or RBC transfusion
• a maintenance dose comprising administering to the patient an anti-C5 antibody, or antigen binding fragment thereof, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered (or is for administration) according to a particular clinical dosage regimen (e.g, at particular loading, maintenance, and one or more supplemental dose amounts, and according to a specific schedule).
• Also provided herein are methods for treating HSCT-TMA in a particular patient sub-population e.g., HSCT-TMA patients with body weight ⁇ 30 kg who received a transfusion (e.g, platelet or RBC transfusion) in the 2 weeks ( ⁇ 20 kg) or 4 weeks (>20 kg to 30 kg) following a maintenance dose), comprising administering to the patient an anti-C5 antibody, or antigen binding fragment thereof, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered (or is for administration) according to a particular clinical dosage regimen (e.g, at particular loading, maintenance, and one or more supplemental dose amounts, and according to a specific schedule).
• a transfusion e.g, platelet or RBC transfusion
• 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 antigen binding fragments and variants thereof.
• the antibody comprises the heavy and light chain complementarity determining regions (CDRs) or variable regions (VRs) of ravulizumab.
• 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.
• the antibody comprises CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively.
• the antibody comprises VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO: 8, respectively.
• the antibody comprises a heavy chain constant region as set forth in SEQ ID NO: 13.
• the antibody comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each according to the EU numbering convention.
• FcRn human neonatal Fc receptor
• the antibody comprises CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively and a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each according to the EU numbering convention.
• FcRn human neonatal Fc receptor
• the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the BNJ421 antibody (described in WO2015134894 and US Patent No. 9,079,949). In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the 7086 antibody (see US Patent Nos. 8,241,628 and 8,883,158). In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the 8110 antibody (see US Patent Nos. 8,241,628 and 8,883,158). In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the 305LO5 antibody (see US Patent No. 9,765,135). In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the SKY59 antibody. In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the REGN3918 antibody.
• the anti-C5 antibody is a biosimilar of eculizumab (SOLIRIS®).
• the anti-C5 antibody is, for example, ABP 959 antibody (manufactured by Amgen Inc., USA), ELIZARIA® (manufactured by Generium JNC, Russia), SB 12 (manufactured by Samsung Bioepis, Incheon, South Korea), ISU305 (eculizumab biosimilar from ISU Abxis, South Korea), ABLYZE® (eculizumab biosimilar from CinnaGen, Iran), BCD 148 (eculizumab biosimilar from Biocad Medical, Quebec, Canada), tesidolumab (manufactured by Novartis), Crovalimab (manufactured by Roche), CAN106 (manufactured by CanBridge Pharmaceuticals, China) or Pozelimab (manufactured by Regeneron).
• ABP 959 antibody manufactured by Amgen Inc., USA
• the antibody competes for binding with, and/or binds to the same epitope on C5 as any of the above-mentioned antibodies.
• the antibody has at least about 90% variable region amino acid sequence identity to any of the above-mentioned antibodies (e.g, at least about 90%, 95% or 99% variable region identity with SEQ ID NO: 12 or SEQ ID NO: 8)
• the antibody binds to human C5 at pH 7.4 and 25°C with an affinity dissociation constant (KD) that is in the range 0.1 nM ⁇ KD ⁇ 1 nM. In another embodiment, the antibody binds to human C5 at pH 7.4 and 25°C with an affinity dissociation constant (KD) of about 0.5 nM. In another embodiment, the antibody binds to human C5 at pH 6.0 and 25 °C with a KD > 10 nM. In another embodiment, the antibody binds to human C5 at pH 6.0 and 25°C with a KD of about 22 nM.
• KD affinity dissociation constant
• the [(KD of the antibody or antigen-binding fragment thereof for human C5 at pH 6.0 and at 25°C)/(KD of the antibody or antigen-binding fragment thereof for human C5 at pH 7.4 and at 25°C)] of the antibody is greater than 25.
• dosage regimens described herein provide an optimal desired response (e.g., an effective treatment).
• effective treatment comprises attaining an immediate, complete, and sustained terminal complement inhibition in the patient with HSCT-TMA.
• the anti-C5 antibody, or antigen binding fragment thereof is administered at a loading dose once on Day 1 (e.g., of the administration cycle), at a loading dose once on Day 5 (e.g., of the administration cycle), at a loading dose once on Day 10 (e.g., of the administration cycle), a maintenance dose every eight weeks thereafter starting at Day 15, along with a supplemental dose.
• a supplemental dose is administered to a patient who receives a red blood cell (RBC) transfusion within four w eeks of a maintenance dose, wherein the supplemental dose is administered four weeks after that maintenance dose.
• RBC red blood cell
• a supplemental dose is administered to a patient weighing > 30 kg who receives a RBC transfusion within four w eeks of a maintenance dose, wherein the supplemental dose is administered four weeks after that maintenance dose at a dose of: 2700 mg to a patient weighing > 30 to ⁇ 40 kg, 3000 mg to a patient weighing > 40 to ⁇ 60 kg, 3300 mg to a patient weighing > 60 to ⁇ 100 kg, or 3600 mg to a patient weighing > 100 kg.
• a method of treating a human patient with HSCT-TMA preferably an RBC-transfused HSCT-TMA patient, is provided, the method comprising administering to the patient an effective amount of ravulizumab, wherein ravulizumab is administered:
• the treatment results in a reduction in LDH levels to within normal levels or to within 50% below what is considered the ULN level (e.g., within 105-333 IU/L (international units per liter), a serum trough concentration of the anti-C5 antibody, or antigen binding fragment thereof, of at least 175 pg/mL or greater, and/or a free C5 concentration of 0.5 pg/mL or less (e.g., 0.4 pg/mL, 0.3 pg/rnL, 0.2 pg/mL, or 0.1 pg/mL or less).
• a method of treating a human patient with HSCT-TMA preferably an RBC-transfused HSCT-TMA patient, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody, or antigen binding fragment thereof, comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively, wherein the anti-C5 antibody, or antigen binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing 5 to ⁇ 10 kg:
• an anti-C5 antibody, or antigen binding fragment thereof comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively, wherein the anti-C
• a method of treating a human patient with HSCT-TMA preferably an RBC-transfused HSCT-TMA patient, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody, or antigen binding fragment thereof, comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively, wherein the anti-C5 antibody, or antigen binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing 5 to ⁇ 10 kg:
• an anti-C5 antibody, or antigen binding fragment thereof comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively, wherein the anti-C
• a supplemental dose of 400 mg to the patient who receives RBC transfusion within a specified timeframe of a maintenance dose, wherein the supplemental dose is administered at the specified timeframe following the maintenance dose, wherein the specified timeframe is two weeks.
• a method of treating a human patient with HSCT-TMA preferably an RBC-transfused HSCT-TMA patient, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody, or antigen binding fragment thereof, comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively, wherein the anti-C5 antibody, or antigen binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing 10 to ⁇ 20 kg:
• an anti-C5 antibody, or antigen binding fragment thereof comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively, wherein the anti-C
• a supplemental dose of 600 mg to the patient who receives RBC transfusion within a specified timeframe of a maintenance dose, wherein the supplemental dose is administered at the specified timeframe following the maintenance dose, wherein the specified timeframe is two weeks.
• a method of treating a human patient with HSCT-TMA preferably an RBC-transfused HSCT-TMA patient, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody, or antigen binding fragment thereof, comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively, wherein the anti-C5 antibody, or antigen binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing 10 to ⁇ 20 kg:
• a method of treating a human patient with HSCT-TMA preferably to RBC-transfused HSCT-TMA patient, the method comprising administering to the patient an effective amount of an anti-C5 anti body, or antigen binding fragment thereof, comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively, wherein the anti-C5 antibody, or antigen binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing 20 to ⁇ 30 kg:
• an anti-C5 anti body, or antigen binding fragment thereof comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively, wherein the anti-C5
• a method of treating a human patient with HSCT-TMA preferably RBC-transfused HSCT-TMA patent, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody, or antigen binding fragment thereof, comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively, wherein the anti-C5 antibody, or antigen binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing > 30 to
• the patient receives a post-transfusion supplemental dose of the anti-C5 antibody (e.g., ravulizumab) once only at the mid-way point between 2 maintenance doses. Since the maintenance doses are administered every eight weeks (Q8W), the supplemental dose of the anti-C5 antibody (e.g., ravulizumab) is administered after week 4, e.g., 28 days after the maintenance dose. In such embodiments, if the patient does not undergo any transfusions during the second maintenance dosing period, then no supplemental dose is needed during this maintenance dosing cycle.
• a post-transfusion supplemental dose of the anti-C5 antibody e.g., ravulizumab
• the treatment regimens described are sufficient to maintain particular serum trough concentrations of the anti-C5 antibody or antigen binding fragment thereof.
• the treatment regimen maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of 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,
• the treatment regimen maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of 100 pg/mL or greater, 150 pg/mL or greater, 200 pg/mL or greater, 250 pg/mL or greater, 300 pg/mL or greater, 350 pg/mL or greater, 400 pg/mL or greater, or 450 pg/mL or greater.
• the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of between 100 pg/mL and 700 pg/mL; preferably between 300 pg/mL and 600 pg/mL. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of about 475 pg/mL.
• the treatment regimen maintains a serum peak concentration of the anti-C5 antibody or antigen binding fragment thereof of less than about 1800, 1780, 1760, 1740, 1720, 1700, 1680, 1660, 1640, 1620, 1600, 1580, 1560, 1540, 1520, 1500, 1480, 1460, 1440, 1420, 1400, 1380, 1360, 1340, 1320, 1300, 1280, 1260, 1240, 1220, 1200, 1180, 1160, 1140, 1120, 1100, 1080, 1060, 1040, 1020, 1000, 980, 960, 940, 920, or 900 pg/mL, or less.
• the treatment maintains a peak serum concentration of the anti-C5 antibody or antigen binding fragment thereof of between 900 pg/mL and 1800 pg/mL; preferably between 1050 pg/mL and 1550 pg/mL. In another embodiment, the treatment maintains a peak serum concentration of the anti-C5 antibody or antigen binding fragment thereof of about 1350 pg/mL.
• the anti-C5 antibody is administered to the patient in an amount and with a frequency to maintain at least 50 pg, 55 pg, 60 pg, 65 pg, 70 pg, 75 pg, 80 pg, 85 pg, 90 pg, 95 pg, 100 pg, 105 pg, 1 10 pg, 115 pg, 120 pg, 125 pg, 130 pg, 135 pg, 140 pg, 145 pg, 150 pg, 155 pg, 160 pg, 165 pg,
• the anti-C5 antibody e.g., ravulizumab
• the anti-C5 antibody is administered to the patient in an amount and with a frequency to maintain a minimum and maximum plasma concentration ( ⁇ standard deviation) of the anti-C5 antibody (e.g., ravulizumab) during a dosing interval that is preferably between 474 ( ⁇ 200) pg/mL and 1350 ( ⁇ 430) pg/mL, respectively.
• the anti-C5 antibody is administered to the patient in an amount and with a frequency to maintain a minimum free C5 concentration.
• the anti-C5 antibody is administered to the patient in an amount and with a frequency to maintain a free C5 concentration of 0.5 pg/mL or less (e.g., 0.4 pg/mL, 0.3 pg/mL, 0.2 pg/mL, or 0.1 pg/mL or less).
• the anti-C5 antibodies, or antigen binding fragments thereof can be administered to a patient by any suitable means.
• the antibodies are formulated for intravenous administration.
• the efficacy of the treatment methods provided herein can be assessed using any suitable means.
• the treatment produces at least one therapeutic effect selected from the group consisting of: a reduction or cessation in microangiopathic hemolytic anemia, thrombocytopenia, endothelial injury, kidney damage, kidney failure, serositis, pulmonary hypertension, and multisystem organ failure compared to baseline.
• the treatment results in (a) platelet count > 50,000/mm 3 without transfusion support during the prior 7 days, (b) LDH ⁇ 1.5 x ULN, and (c) absence of schistocytes (if there were schistocytes present at baseline).
• the treatment results in (a) platelet count > 50,000/mm 3 without transfusion support during the prior 7 days, (b) LDH ⁇ 1.5 * ULN, (c) absence of schistocytes (if there were schistocytes present at baseline) and (d) at least 50% reduction of proteinuria from baseline.
• proteinuria is as protein/creatinine ratio > 0.5 mg/mg.
• the treatment results in a favorable hematological response.
• the treatment results in normalization of LDH, resolution of need for red cell and platelet transfusions, and disappearance of schistocytes.
• the treatment results in the patient’s ability to maintain hemoglobin > 8 g/dL without transfusion support. In another embodiment, the treatment results in hemoglobin > 8 g/dL without transfusion support.
• the treatment results in a decrease in LDH, an increase in platelets, and/or an increase in hemoglobin compared to baseline.
• the treatment results in normal levels of serum creatinine compared to baseline.
• the treatment results in an improvement in TMA-associated organ dysfunction in the renal, cardiovascular, pulmonary, CNS, and/or GI systems compared to baseline.
• the treatment results in terminal complement inhibition.
• the treatment produces a reduction in adverse events.
• the treatment produces a shift toward normal levels of biomarkers associated with vascular inflammation (e.g., shed tumor necrosis factor receptor 1 [TNF-R1]), endothelial damage and/or activation (e.g., thrombomodulin and shed vascular cell adhesion molecule 1 [VCAM-1]), renal injury' (e.g., Cystatin C), and/or complement proteins and complement activation pathway products.
• the treatment produces a shift toward normal levels of thrombomodulin (TM) and/or syndecan-1 (SYND1).
• the treatment produces a shift toward normal levels of complement factor Ba.
• the treatment produces a change from baseline in quality of life as assessed via a Quality of Life Assessment (e.g., a Quality of Life Inventory (PedsQL) Scale or an EQ-5D-5L questionnaire).
• a Quality of Life Assessment e.g., a Quality of Life Inventory (PedsQL) Scale or an EQ-5D-5L questionnaire.
• patients treated according to the disclosed methods experience an LDH percent change compared to baseline 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%.
• kits that include a pharmaceutical composition containing an anti-C5 antibody or antigen binding fragment thereof, such as ravulizumab, and a pharmaceutically acceptable carrier, in a therapeutically effective amount adapted for use in the methods described herein, e.g., for effective treatment of an HSCT-TMA patient who has undergone at least one transfusion, e.g., platelet or RBC transfusion.
• a pharmaceutical composition containing an anti-C5 antibody or antigen binding fragment thereof, such as ravulizumab, and a pharmaceutically acceptable carrier, in a therapeutically effective amount adapted for use in the methods described herein, e.g., for effective treatment of an HSCT-TMA patient who has undergone at least one transfusion, e.g., platelet or RBC transfusion.
• the kit comprises: (a) a dose of an anti-C5 antibody or antigen binding fragment thereof, comprising CDR1 , CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO: 8; and (b) instructions for using the anti-C5 antibody or antigen binding fragment thereof in the methods described herein.
• the kit comprises loading, maintenance, and supplemental doses of an anti-C5 antibody, or antigen binding fragment thereof, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered to a patient weighing 5 to ⁇ 10 kg:
• a supplemental dose of 400 mg with instructions that the supplemental dose is administered to a patient who receives RBC transfusion within 2 weeks of a maintenance dose, wherein the supplemental dose is administered two weeks after the maintenance dose.
• the kit comprises loading, maintenance, and supplemental doses of an anti-C5 antibody, or antigen binding fragment thereof, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered to a patient weighing 10 to ⁇ 20 kg:
• a supplemental dose of 600 mg with instructions that the supplemental dose is administered to a patient who receives RBC transfusion within 2 weeks of a maintenance dose, wherein the supplemental dose is administered two weeks after the maintenance dose.
• the kit comprises loading, maintenance, and supplemental doses of an anti-C5 antibody, or antigen binding fragment thereof, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered to a patient weighing 10 to ⁇ 20 kg:
• kits comprises loading, maintenance, and supplemental doses of an anti-C5 antibody, or antigen binding fragment thereof, wherein the anti-C5 antibody, or antigen binding fragment thereof is administered to a patient weighing 20 to ⁇ 30 kg:
• a supplemental dose of 2100 mg with instructions that the supplemental dose is administered to a patient who receives RBC transfusion within 4 weeks of a maintenance dose, wherein the supplemental dose is administered four weeks after the maintenance dose.
• the kit comprises loading, maintenance, and supplemental doses of an anti-C5 antibody, or antigen binding fragment thereof, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered to a patient weighing > 30 to ⁇ 40 kg:
• the kit comprises loading, maintenance, and supplemental doses of an anti-C5 antibody, or antigen binding fragment thereof, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered to a patient weighing > 40 to ⁇ 60 kg:
• the kit comprises loading, maintenance, and supplemental doses of an anti-C5 antibody, or antigen binding fragment thereof, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered to a patient weighing > 60 to ⁇ 100 kg:
• the kit comprises loading, maintenance, and supplemental doses of an anti-C5 antibody, or antigen binding fragment thereof, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered to a patient weighing > 100 kg:
• an anti-C5 antibody, or antigen-binding fragment thereof for use in treatment of an HSCT-TMA patient who has undergone RBC transfusion during a first half of a maintenance phase of treatment is provided, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered:
• anti-C5, antibody or antigen-binding fragment thereof e.g., ravulizumab (ULTOMIRIS®)
• ULTOMIRIS® ravulizumab
• FIG. 1 is a graph showing the ravulizumab pharmacokinetic (PK) profile for each patient. At Day 5 and Day 10, ravulizumab concentration was maintained above the 175 pg/mL threshold (dashed line).
• FIG. 2 is a graph showing free C5 concentration-time profile for each patient (i.e., pharmacodynamic (PD) profile). All patients demonstrated free C5 concentrations below the 0.5 pg/mL threshold (dashed line).
• FIG. 3 is a schematic depicting the clinical algorithm for assessing post-RBC supplemental dosing.
• the term “subject” or “patient” is a human patient (e.g., a patient having hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT- TMA)).
• HSCT- TMA hematopoietic stem cell transplant-associated thrombotic microangiopathy
• loading dose refers to the intial doses administered during an administration cycle (e.g., on Days 1, 5, and 10).
• supplemental dose refers to an additional dose administered to an HSCT-TMA patient (e.g., having a body weight >30 kg) who received a RBC transfusion in the 4 weeks following a maintenance dose.
• blood transfusion refers to a procedure in which whole blood or parts of blood are put into a patient’s bloodstream, e.g., through a vein. The blood may be donated by another person or it may have been taken from the patient and stored until needed.
• red blood cell (RBC) transfusion refers to a transfusion of red blood cells, i.e., concentrated ery throcytes obtained from donated whole blood or by donor apheresis, into a patient’s bloodstream, e.g., through a vein.
• the majonty of RBC transfusions are by infusion of packed RBCs that are prepared either by removing plasma from whole blood collection or by apheresis, followed by storage with additives to enhance cell viability and storage.
• serum trough level refers to the lowest level that the agent (e.g., the anti-C5 antibody, or antigen binding fragment thereof) or medicine is present in the serum.
• a “peak serum level,” refers to the highest level of the agent in the serum.
• the “average serum level,” refers to the mean level of the agent in the serum over time.
• This inhibition prevents the release of the proinflammatory mediator C5a and the formation of the cytolytic pore-forming membrane attack complex (MAC) C5b-9 while preserving the proximal or early components of complement activation (e.g., C3 and C3b) essential for the opsonization of microorganisms and clearance of immune complexes.
• MAC cytolytic pore-forming membrane attack complex
• the antibody comprises the heavy and light chain CDRs or variable regions of ravulizumab. Accordingly, in one embodiment, the antibody comprises the CDR1, CDR2 and CDR3 domains of the VH region of ravulizumab having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2 and CDR3 domains of the VL region of ravulizumab having the sequence set forth in SEQ ID NO: 8. In another embodiment, the antibody comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 19, 18 and 3, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:4, 5 and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO: 8, respectively.
• antibody BNJ421 comprising heavy and light chains having the sequences shown in SEQ ID NOs:20 and 11, respectively, or antigen binding fragments and variants thereof.
• BNJ421 also known as ALXN1211
• ALXN1211 is described in WO2015134894 and US Patent No.9,079,949, the entire teachings of which are hereby incorporated by reference.
• the antibody comprises the heavy and light chain CDRs or variable regions of BNJ421. Accordingly, in one embodiment, the antibody comprises the CDR1, CDR2 and CDR3 domains of the VH region of BNJ421 having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2 and CDR3 domains of the VL region of BNJ421 having the sequence set forth in SEQ ID NO: 8. In another embodiment, the antibody comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 19, 18 and 3, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:4, 5 and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO: 8, respectively.
• Another exemplary anti-C5 antibody is the SKY59 antibody (Fukuzawa, T. et al., Set. Rep., 7: 1080, 2017).
• the antibody comprises the heavy and light chain CDRs or variable regions of the SKY59 antibody.
• the antibody, or antigen binding fragment thereof comprises a heavy chain comprising SEQ ID NO:45 and a light chain comprising SEQ ID NO:46.
• the anti-C5 antibody is a biosimilar of eculizumab (SOLIRIS®).
• the anti-C5 antibody is, for example, ABP 959 antibody (eculizumab biosimilar manufactured by Amgen Inc., USA), ELIZ ARIA® (eculizumab biosimilar manufactured by Generium JNC, Russia), SB12 (eculizumab biosimilar manufactured by Samsung Bioepis, Incheon, South Korea), ISU305 (eculizumab biosimilar from ISU Abxis, South Korea), ABLYZE® (eculizumab biosimilar from CinnaGen, Iran), BCD 148 (eculizumab biosimilar from Biocad Medical, Quebec, Canada), tesidolumab (manufactured by Novartis), Crovalimab (manufactured by Roche), CAN106 (manufactured by CanBridge Pharmaceuticals, China), or Pozelimab (manufactured by Regeneron).
• ABP 959 antibody
• substitutions that enhance the binding affinity of an antibody Fc constant region for FcRn include, e.g., (1) the M252Y/S254T/T256E triple substitution (Dall’Acqua, W. et al., J. Biol. Chem., 281 :23514-24, 2006); (2) the M428L or T250Q/M428L substitutions (Hinton, P. et al., J. Biol. Chem., 279:6213-6. 2004; Hinton, P. et al., J. Immunol., 176:346-56, 2006); and (3) the N434A or T307/E380A/N434A substitutions (Petkova, S.
• the variant Fc constant region comprises no more than 30 (e.g., no more than 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 or 2) amino acid substitutions, insertions, or deletions relative to the native constant region from which it was derived.
• the variant Fc constant region comprises one or more amino acid substitutions selected from the group consisting of: M252Y, S254T, T256E, N434S, M428L, V259I, T250I and V308F.
• the substitution is selected from the group consisting of: methionine for glycine at position 237; alanine for proline at position 238; lysine for serine at position 239; isoleucine for lysine at position 248; alanine, phenylalanine, isoleucine, methionine, glutamine, serine, valine, tryptophan, or tyrosine for threonine at position 250; phenylalanine, tryptophan, or tyrosine for methionine at position 252; threonine for serine at position 254; glutamic acid for arginine at position 255; aspartic acid, glutamic acid, or glutamine for threonine at position 256; alanine, glycine, isoleucine, leucine, methionine, asparagine, serine, threonine, or valine for proline at position 257; histidine for
• the antibody binds to C5 at pH 7.4 and 25°C (and, otherwise, under physiologic conditions) with an affinity dissociation constant (KD) that is at least 0. 1 (e.g., at least 0.15, 0.175, 0.2, 0.25, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775, 0.8, 0.825, 0.85, 0.875, 0.9, 0.925, 0.95, or 0.975) nM.
• KD affinity dissociation constant
• the [(KD of the antibody for C5 at pH 6.0 at 25°C)/(KD of the antibody for C5 at pH 7.4 at 25C)] is greater than 21 (e.g., greater than 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500 or 8000)
• binding of an antibody to a protein antigen can be detected and/or quantified using a variety of techniques such as, but not limited to, Western blot, dot blot, surface plasmon resonance (SPR) detection (e.g., BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.), or enzyme-linked immunosorbent assay (ELISA; Benny K. C. Lo (2004) “Antibody Engineering: Methods and Protocols,” Humana Press (ISBN: 1588290921); Johne, B. et al., J.
• SPR surface plasmon resonance
• Colonies arising from single immortalized cells are screened for production of antibodies of the desired specificity and affinity for the antigen, and yield of the monoclonal antibodies produced by such cells may be enhanced by various techniques, including injection into the peritoneal cavity of a vertebrate host.
• compositions comprising an anti-C5 antibody or antigen binding fragment thereof.
• the composition comprises an anti-C5 antibody comprising the CDR1, CDR2 and CDR3 domains in a heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2 and CDR3 domains in a light chain variable region having the sequence set forth in SEQ ID NO: 8.
• the anti-C5 antibody comprises heavy and light chains having the sequences shown in SEQ ID NOs: 14 and 11, respectively.
• the anti-C5 antibody comprises heavy and light chains having the sequences shown in SEQ ID NOs:20 and 11, respectively.
• compositions can be formulated as a pharmaceutical solution, e.g, for administration to a subject for the treatment of HSCT-TMA.
• the pharmaceutical compositions generally include a pharmaceutically acceptable carrier.
• a “pharmaceutically acceptable carrier” refers to, and includes, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
• the compositions can include a pharmaceutically acceptable salt, e.g., an acid addition salt or a base addition salt, sugars, carbohydrates, polyols and/or tonicity modifiers.
• compositions can be formulated according to standard methods.
• Pharmaceutical formulation is an established art (see, for example, Gennaro (2000) “Remington: The Science and Practice of Pharmacy,” 20 th Edition, Lippincott, Williams & Wilkins (ISBN: 0683306472); Ansel et al. (1999) “Pharmaceutical Dosage Forms and Drug Delivery Systems,” 7 th Edition, Lippincott Williams & Wilkins Publishers (ISBN: 0683305727); and Kibbe (2000) “Handbook of Pharmaceutical Excipients American Pharmaceutical Association,” 3 rd Edition (ISBN: 091733096X)).
• a composition can be formulated, for example, as a buffered solution at a suitable concentration and suitable for storage at 2-8C (e.g., 4C). In some embodiments, a composition can be formulated for storage at a temperature below OC (e.g., -20C or -80C). In some embodiments, the composition can be formulated for storage 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 ! years or 2 years) at 2-8C (e.g, 4C). Thus, in some embodiments, the compositions described herein are stable in storage for at least 1 year at 2-8C (e.g., 4C).
• HSCT-TMA in a particular patient subpopulation
• a transfusion e.g., platelet or RBC transfusion
• a particular clinical dosage regimen e.g., at particular loading, maintenance, and one or more supplemental dose amounts, and according to a specific schedule.
• the dose of the anti-C5 antibody, or antigen binding fragment thereof is based on the weight of the patient.
• a 300 mg or 600 mg loading dose of the anti-C5 antibody, or antigen binding fragment thereof is administered to a patient weighing > 5 to ⁇ 10 kg.
• a 400 mg maintenance dose of the anti-C5 antibody, or antigen binding fragment thereof is administered to a patient weighing > 5 to ⁇ 10 kg.
• a 400 mg supplemental dose of the anti-C5 antibody, or antigen binding fragment thereof is administered to a patient weighing > 5 to ⁇ 10 kg.
• a 300 mg or 600 mg loading dose of the anti-C5 antibody, or antigen binding fragment thereof is administered to a patient weighing > 10 to ⁇ 20 kg.
• a 800 mg maintenance dose of the anti-C5 antibody, or antigen binding fragment thereof is administered to a patient weighing > 10 to ⁇ 20 kg.
• a 800 mg supplemental dose of the anti-C5 antibody, or antigen binding fragment thereof is administered to a patient weighing > 10 to
• a 300 mg or 900 mg loading dose of the anti-C5 antibody, or antigen binding fragment thereof is administered to a patient weighing > 20 to ⁇ 30 kg.
• a 2100 mg maintenance dose of the anti-C5 antibody, or antigen binding fragment thereof is administered to a patient weighing > 20 to ⁇ 30 kg.
• a 2100 mg supplemental dose of the anti-C5 antibody, or antigen binding fragment thereof is administered to a patient weighing > 20 to ⁇ 30 kg.
• a 300 mg or 1200 mg loading dose of the anti-C5 antibody, or antigen binding fragment thereof is administered to a patient weighing > 30 to
• a 2700 mg maintenance dose of the anti-C5 antibody, or antigen binding fragment thereof is administered to a patent weighing > 30 to ⁇ 40 kg.
• a 2700 mg supplemental dose of the anti-C5 antibody, or antigen binding fragment thereof is administered to a patient weighing > 30 to ⁇ 40 kg.
• a 600 mg or 2400 mg loading dose of the anti-C5 antibody, or antigen binding fragment thereof is administered to a patient weighing > 40 to ⁇ 60 kg.
• a 3000 mg maintenance dose of the anti-C5 antibody, or antigen binding fragment thereof is administered to a patient weighing > 40 to ⁇ 60 kg.
• a 3000 mg supplemental dose of the anti-C5 antibody, or antigen binding fragment thereof is administered to a patient weighing > 40 to ⁇ 60 kg.
• a 900 mg or 2700 mg loading dose of the anti-C5 antibody, or antigen binding fragment thereof is administered to a patent weighing > 60 to ⁇ 100 kg.
• a 3300 mg maintenance dose of the anti-C5 antibody, or antigen binding fragment thereof is administered to a patient weighing > 60 to ⁇ 100 kg.
• a 3300 mg supplemental dose of the anti-C5 antibody, or antigen binding fragment thereof is administered to a patient weighing > 60 to ⁇ 100 kg.
• a 900 mg or 3000 mg loading dose of the anti-C5 antibody, or antigen binding fragment thereof is administered to a patient weighing > 100 kg.
• a 3600 mg maintenance dose of the anti-C5 antibody, or antigen binding fragment thereof is administered to a patient weighing > 100 kg.
• a 3600 mg supplemental dose of the anti-C5 antibody, or antigen binding fragment thereof is administered to a patient weighing > 100 kg.
• the patient receives a post-transfusion supplemental dose of the anti-C5 antibody (e.g., ravulizumab) once only at the mid-way point between 2 maintenance doses.
• the maintenance doses are administered every four weeks (Q4W) for lower (e.g., ⁇ 20 kg) weight class and every eight weeks (Q8W) for higher (e.g., >20 kg) weight class
• the supplemental dose of the anti-C5 antibody is administered after week 2 ( ⁇ 20 kg patients) and after week 4 (>20 kg patients), e.g., 14 days or 28 days after the maintenance dose.
• a post-transfusion supplemental dose of the anti-C5 antibody, or antigen binding fragment thereof, is administered to the HSCT-TMA patient once only 4 weeks after the last maintenance dose, if any amount of RBC transfusion is provided to the patient within the 4 weeks after the last maintenance dose.
• the anti-C5 antibody, or antigen binding fragment thereof is administered for one or more administration cycles.
• the treatment e.g., administration cycle
• the treatment is 26 weeks.
• the anti-C5 antibody, or antigen binding fragment thereof is administered at a loading dose once on Day 1 (e.g., of the administration cycle), once on Day 5 (e.g., of the administration cycle), once on Day 10 (e.g, of the administration cycle).
• the anti-C5 antibody, or antigen binding fragment thereof is administered is administered a loading dose once on Day 1 (e.g., of the administration cycle), at a loading dose once on Day 5 (e.g, of the administration cycle), at a loading dose once on Day 10 (e.g, of the administration cycle) and a maintenance dose every eight weeks thereafter starting at Day 15.
• the anti-C5 antibody, or antigen binding fragment thereof is administered every eight weeks after treatment (e.g., an administration cycle) for an extension period up to two years (e.g., at a dose of 300 mg, 600 mg, 900 mg, 1200 mg, 2100 mg, 2400 mg, 2700 mg, 3000 mg, 3300 mg or 3600 mg).
• a supplemental dose is administered to a patient who receives a transfusion (e.g. , platelet or RBC transfusion) within two weeks or four weeks of a maintenance dose, wherein the supplemental dose is administered two weeks or four weeks after that maintenance dose.
• a supplemental dose is administered to a patient weighing ⁇ 20 kg who receives a RBC transfusion within two weeks of a maintenance dose, wherein the supplemental dose is administered two weeks after that maintenance dose at a dose of: 400 mg to a patient weighing > 5 to ⁇ 10 kg, 800 mg to a patient weighing > 10 to ⁇ 20 kg.
• a supplemental dose is administered to a patient weighing > 20 ⁇ 30 kg who receives a RBC transfusion within four weeks of a maintenance dose, wherein the supplemental dose is administered four weeks after that maintenance dose at a dose of: 2100 mg to a patient weighing > 20 ⁇ 30 kg.
• a supplemental dose is administered to a patient weighing > 30 kg who receives a RBC transfusion within four weeks of a maintenance dose, wherein the supplemental dose is administered four weeks after that maintenance dose at a dose of: 2700 mg to a patient w eighing > 30 to ⁇ 40 kg, 3000 mg to a patient weighing > 40 to ⁇ 60 kg, 3300 mg to a patient weighing > 60 to ⁇ 100 kg, or 3600 mg to a patient weighing > 100 kg.
• a method of treating a human patient with HSCT-TMA comprising administenng to the patient an effective amount of an anti-C5 antibody, or antigen binding fragment thereof, comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID N0s:4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen binding fragment thereof, is administered:
• a method of treating a human patient with HSCT-TMA comprising administering to the patient an effective amount of an anti-C5 antibody comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively and a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each according to the EU numbering convention, wherein the anti-C5 antibody is administered:
• a method of treating a human patient with HSCT-TMA comprising administering to the patient an effective amount of ravulizumab, wherein ravulizumab is administered:
• a maintenance dose of: 2100 mg to a patient weighing 20 to ⁇ 30 kg, 2700 mg to a patient weighing > 30 to ⁇ 40 kg, 3000 mg to a patient weighing > 40 to ⁇ 60 kg, 3300 mg to a patient weighing > 60 to ⁇ 100 kg, or 3600 mg to a patient weighing > 100 kg; and wherein a supplemental dose is administered: (i) to a patient weighing ⁇ 30 kg who receives RBC transfusion within a specified timeframe of a maintenance dose, wherein the supplemental dose is administered at the specified timeframe following the maintenance dose, at a dose of: a.
• the treatment results in a reduction in LDH levels to within normal levels or to within 50% below what is considered the ULN level (e.g., within 105-333 IU/L (international units per liter), a serum trough concentration of the anti-C5 antibody, or antigen binding fragment thereof, of at least 175 pg/mL or greater, and/or a free C5 concentration of 0.5 pg/mL or less (e.g., 0.4 pg/mL, 0.3 pg/mL, 0.2 pg/mL, or 0.1 pg/mL or less).
• a method of treating a human patient with HSCT-TMA comprising administering to the patient an effective amount of an anti-C5 antibody, or antigen binding fragment thereof, comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively, wherein the anti-C5 antibody, or antigen binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing 5 to ⁇ 10 kg:
• an anti-C5 antibody, or antigen binding fragment thereof comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively, wherein the anti-C5 antibody, or antigen binding fragment thereof (e.g., ravulizumab
• a supplemental dose of 400 mg to a patient who receives RBC transfusion within two weeks of a maintenance dose and wherein the supplemental dose is administered two weeks after the maintenance dose.
• a supplemental dose of 600 mg to a patient who receives RBC transfusion within two weeks of a maintenance dose and wherein the supplemental dose is administered two weeks after the maintenance dose.
• a method of treating a human patient with HSCT-TMA comprising administering to the patient an effective amount of an anti-C5 antibody, or antigen binding fragment thereof, comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively, wherein the anti-C5 antibody, or antigen binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing 10 to ⁇ 20 kg:
• an anti-C5 antibody, or antigen binding fragment thereof comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively, wherein the anti-C5 antibody, or antigen binding fragment thereof (e.g., ravulizumab
• a method of treating a human patient with HSCT-TMA comprising administering to the patient an effective amount of an anti-C5 antibody, or antigen binding fragment thereof, comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively, wherein the anti-C5 antibody, or antigen binding fragment thereof (e.g., ravulizumab), is administered to a patient weighing 20 to ⁇ 30 kg:
• an anti-C5 antibody, or antigen binding fragment thereof comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively, wherein the anti-C5 antibody, or antigen binding fragment thereof (e.g., ravulizumab
• a supplemental dose of 2100 mg to a patient who receives RBC transfusion within two weeks of a maintenance dose and wherein the supplemental dose is administered four weeks after the maintenance dose.
• the supplemental dose is administered if w arranted per a clinical algorithm as set forth in FIG. 3. In some embodiments, the supplemental dose is administered if warranted per a clinical algorithm as set forth in Table 7.
• a method of treating a human patient with HSCT-TMA comprising administering to the patient an effective amount of an anti-C5 antibody, or antigen binding fragment thereof, comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively, wherein the anti-C5 antibody, or antigen binding fragment thereof (e.g., ravulizumab), is administered to a patient w eighing > 30 to ⁇ 40 kg:
• the treatment results in (a) platelet count > 50,000/mm 3 without transfusion support during the prior 7 days, (b) LDH ⁇ 1.5 * ULN, (c) absence of schistocytes (if there were schistocytes present at baseline) and (d) at least 50% reduction of proteinuria from baseline.
• proteinuria is as protein/creatinine ratio > 0.5 mg/mg.
• the treatment results in a decrease in LDH, an increase in platelets, and/or an increase in hemoglobin compared to baseline.
• the treatment results in an improvement in TMA-associated organ dysfunction in the renal, cardiovascular, pulmonary, CNS, and/or GI systems compared to baseline.
• the treatment results in terminal complement inhibition.
• the treatment produces a reduction in adverse events.
• lactate dehydrogenase (LDH) levels can be used to evaluate responsiveness to a therapy.
• LDH is a marker of intravascular hemolysis (Hill, A. et al., Br. J. Haematol., 149:414-25, 2010; Hillmen, P. el 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 a correlation between cell-free hemoglobin and LDH concentration has been reported in vitro (Van Lente, F. et al., Clin.
• Examples include tissue removed for biopsy, tissue removed during resection, blood, urine, lymph tissue, lymph fluid, cerebrospinal fluid, mucous and stool samples.
• the sample used can vary based on the assay format, the detection method and the nature of the tumors, tissues, cells or extracts to be assayed. Methods for preparing samples are known in the art and can be readily adapted to obtain a sample that is compatible with the method utilized. In one embodiment, patients treated according to the disclosed methods experience reductions in LDH levels to normal levels or to within 10%, or within 20% above what is considered the normal level (e.g., within 105-333 IU/L).
• patients treated according to the disclosed methods experience an LDH percent change compared to baseline of 10%, 1 1 %, 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%.
• the treatment regimen maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of 100 pg/mL or greater, 150 pg/mL or greater, 200 pg/mL or greater, 250 pg/mL or greater, 300 pg/mL or greater, 350 pg/mL or greater, 400 pg/mL or greater, or 450 pg/mL or greater.
• the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of between 100 pg/mL and 700 pg/mL; preferably between 300 pg/mL and 600 pg/mL. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of about 475 pg/mL.
• the treatment regimen maintains a serum peak concentration of the anti-C5 antibody or antigen binding fragment thereof of less than about 1800, 1780, 1760, 1740, 1720, 1700, 1680, 1660, 1640, 1620, 1600, 1580, 1560, 1540, 1520, 1500, 1480, 1460, 1440, 1420, 1400, 1380, 1360, 1340, 1320, 1300, 1280, 1260, 1240, 1220, 1200, 1180, 1160, 1140, 1120, 1100, 1080, 1060, 1040, 1020, 1000, 980, 960, 940, 920, or 900 pg/mL, or less.
• the treatment maintains a peak serum concentration of the anti-C5 antibody or antigen binding fragment thereof of between 900 pg/mL and 1800 pg/mL; preferably between 1050 pg/mL and 1550 pg/mL. In another embodiment, the treatment maintains a peak serum concentration of the anti-C5 antibody or antigen binding fragment thereof of about 1350 pg/mL.
• the anti-C5 antibody is administered to the patient in an amount and with a frequency to maintain at least 50 pg, 55 pg, 60 pg, 65 pg, 70 pg, 75 pg, 80 pg, 85 pg, 90 pg, 95 pg, 100 pg, 105 pg, 110 pg, 115 pg, 120 pg, 125 pg, 130 pg, 135 pg, 140 pg, 145 pg, 150 pg, 155 pg, 160 pg, 165 pg,
• the anti-C5 antibody e.g., ravulizumab
• the anti-C5 antibody is administered to the patient in an amount and with a frequency to maintain a minimum and maximum plasma concentration ( ⁇ standard deviation) of the anti-C5 antibody (e.g, ravulizumab) during a dosing interval that is preferably between 474 ( ⁇ 200) pg/mL and 1350 ( ⁇ 430) pg/mL, respectively.
• patients treated according to the disclosed methods have a free C5 concentration of 0.5 pg/mL or less (e.g., 0.4 pg/mL, 0.3 pg/mL, 0.2 pg/mL, or 0.1 pg/mL or less).
• kits include multiple packages of the single-dose pharmaceutical compositions each containing an effective amount of the anti-C5 antibody, or antigen binding fragment thereof, for a single administration in accordance with the methods provided above.
• Instruments or devices necessary' for administering the pharmaceutical composition(s) also may be included in the kits.
• a kit may provide one or more pre-filled syringes containing an amount of the anti-C5 antibody or antigen binding fragment thereof.
• the kit comprises loading, maintenance, and supplemental doses of an anti-C5 antibody, or antigen binding fragment thereof, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered to a patient weighing 5 to ⁇ 10 kg:
• a supplemental dose of 800 mg with instructions that the supplemental dose is administered to a patient who receives RBC transfusion within 2 weeks of a maintenance dose, wherein the supplemental dose is administered two weeks after a maintenance dose.
• the kit comprises loading, maintenance, and supplemental doses of an anti-C5 antibody, or antigen binding fragment thereof, wherein the anti-C5 antibody, or antigen binding fragment thereof is administered to a patient weighing 20 to ⁇ 30 kg:
• a supplemental dose of 2100 mg with instructions that the supplemental dose is administered to a patient who receives RBC transfusion within 4 weeks of a maintenance dose, wherein the supplemental dose is administered four weeks after the maintenance dose.
• the kit comprises loading, maintenance, and supplemental doses of an anti-C5 antibody, or antigen binding fragment thereof, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered to a patient weighing > 100 kg:
• EXAMPLE 1 Ravulizumab Dose Confirmation Analysis in Global Phase 3 Study to Assess Pharinacokinetics/Pharmacodynamics in Adults and Adolescents Who Developed Thrombotic Microangiopathy After Hematopoietic Stem Cell Transplant
• PK-PD pharmacokinetic-pharmacodynamic
• DCA involved three steps.
• Step 1 PK and free C5 (primary PD) data were visualized. Previously established thresholds indicating complete C5 inhibition were used to empirically confirm that the dose regimen resulted in appropriate ravulizumab concentrations and was providing immediate, complete and sustained inhibition of free C5.
• Step 2 population pharmacokinetic (popPK) modeling of ravulizumab concentration-time data. Body weight and transfusions were applied to a previously developed aHUS popPK model to individualize the predicted exposure for each patient with HSCT-TMA and to assess the impact of these factors from a patient population level. Standard assessments were used for model qualification.
• Step 3 the qualified popPK model was used to perform simulations confirming/ adjusting the ravulizumab dose regimen, including transfusion-related supplemental doses. Monte Carlo simulation of concentration-time profiles was performed to assess if randomly generated exposures (based on population variability of PK parameters) would remain above the PK threshold, thus ensuring complete terminal complement inhibition.
• Example 2 the dose regimen set forth in Table 4 was confirmed for 7/9 patients (22%). However, it was determined that certain patients weighing ⁇ 30 kg with frequent RBC transfusions (e.g., high ravulizumab clearance” patients weighing ⁇ 30 kg) may not maintain target trough level (175 mcg/mL) and therefore, not achieve complete C5 inhibition. Therefore, this particular group of patients could benefit further from a revised dose regimen. Accordingly, a revised dosing regimen as set forth in Table 5 is assessed in this patient group, substantially according to the methods described in Examples 1-2 and WO/2022/036151, with the noted modifications.
• a post-RBC transfusion supplemental dose of ravulizumab is assessed when the patient reaches the mid-way point between maintenance doses as set forth in Table 6.
• a post-RBC transfusion supplemental dose is administered if the participant has received at least 1 RBC transfusion since the last maintenance dose.
• a clinical algorithm is followed to assess the need for post- RBC transfusion supplemental dosing Table 6: Timing of Post-RBC Transfusion Supplemental Dosing
• the supplemental dose is administered within the same window for each weight categories. If supplemental dosing is required at the same time as a scheduled study visit, the dosing can take place at that visit.
• the revised dosing regimen triggers a clinical algorithm when RBC transfusion day frequency exceeds >3.5 days /week (z.e.. the threshold for when >10% patients have trough level ⁇ 175 mcg/mL). Specifically, the clinical algorithm monitors the number of RBC transfusion days (the number of days with at least 1 RBC transfusion) and clinical worsening. Previously, the investigator assessed only whether the participant has received at least one RBC transfusion since the last maintenance dose. The revised dosing regimen is proposed to increase both maintenance and supplemental doses to mitigate issues.
• the clinical algorithm is set forth in FIG. 3 and summarized in Table 7.
• Supplemental doses of ravulizumab are allowed during the Treatment Period following administration of the first Maintenance Dose on Day 15 for patients who demonstrate clinical worsening.
• Clinical worsening is defined as meeting 2 or more of the following criteria:
• the minimum assessments to be performed during any supplemental dosing visit in which ravulizumab is administered include a urine pregnancy test, predose PK/PD blood sample collection, and vital signs.

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