Dosage regimens for the treatment or prevention of C5-related diseases

Abstract

To provide pharmaceutical formulations for treating or preventing C5-related diseases. [Solution] A pharmaceutical formulation for use in a method of treating CD55 deficiency accompanied by complement hyperactivation, vascular thrombosis, and protein-losing enteropathy (CHAPLE disease) in a subject, wherein the pharmaceutical formulation comprises an antibody or antigen-binding fragment thereof that specifically binds to C5 and includes three heavy chain complementarity-determining regions of a heavy chain variable region (HCVR) containing a specific amino acid sequence, and three light chain complementarity-determining regions of a light chain variable region (LCVR) containing a specific amino acid sequence, wherein the subject has hypoalbuminemia and is determined to have a CD55 loss-of-function mutation by genetic analysis.

Description

[Technical Field]

[0001] This application claims the interests of U.S. Provisional Patent Application No. 62 / 926,213 filed on 25 October 2019; U.S. Provisional Patent Application No. 62 / 992,330 filed on 20 March 2020; and U.S. Provisional Patent Application No. 63 / 019,533 filed on 4 May 2020; each of these is incorporated herein by reference in whole for all purposes.

[0002] The sequence listing for this application is submitted electronically as an ASCII-formatted sequence listing with the filename "seqlist10673P2", created on March 20, 2020, and with a size of 165 KB. This submitted sequence listing is part of this specification and is incorporated herein by reference in its entirety.

[0003] The present invention relates to a method for administering an antagonist anti-C5 antibody to treat or prevent C5-related disorders. [Background technology]

[0004] Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, progressive, fatal, multisystem disorder. It is typically characterized by uncontrolled complement activation, leading to intravascular hemolysis of red blood cells (RBCs) (Non-Patent Literature 1) and an increased risk of thrombosis in white blood cells (WBCs) and platelets. The estimated incidence of PNH is 1.3 cases per million people per year, and the estimated prevalence is 15.9 cases per million people per year (Non-Patent Literature 2).

[0005] Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, and fatal blood disorder. Red blood cells with PNH defects are highly susceptible to premature destruction by a specific part of the body's own immune system called the complement system. The disease is characterized by red blood cell destruction (hemolytic anemia), blood clots (thrombi), and bone marrow dysfunction.

[0006] CD55-deficient protein-losing enteropathy (CD55-deficient PLE), also known as complement hyperactivation, angiopathic thrombosis, protein-losing enteropathy (CHAPLE disease), is a rare disease that can be treated by C5 blockade (Non-Patent Document 3; Non-Patent Document 4). CD55-deficient PLE / CHAPLE disease is caused by bi-allelic loss-of-function mutations in the CD55 gene. The absence of CD55 causes overactivation of the complement system, resulting in the production of various complement products, including anaphylatoxins and the membrane attack complex. In CD55-deficient PLE, isolated germ line loss of CD55 expression in all tissues manifests in the GI tract, such as primary intestinal lymphangiectasia, causing PLE. Most patients suffer from early-onset GI symptoms, including bloody diarrhea, vomiting, and abdominal pain, and sometimes develop partial or complete intestinal obstruction and intestinal failure.

Prior Art Documents

Non-Patent Documents

[0007]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0008] Eculizumab is an antibody against C5, which blocks the formation of MAC-C5b-9 and thus protects PNH RBCs from complement-mediated intravascular hemolysis. However, not all patients receive optimal therapeutic effects. For example, 25% of patients still require repeated transfusions, albeit infrequently. Up to 20% of patients during eculizumab therapy require a substantial increase in dose or dosing frequency due to breakthrough hemolysis secondary to incomplete inhibition of C5 (Nakayama et al., Eculizumab Dosing Intervals Longer than 17 Days May Be Associated with Greater Risk of Breakthrough Hemolysis in Patients with Paroxysmal Nocturnal Hemoglobinuria. Biol Pharm Bull 2016;39(2):285-288) (Hill et al., Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 2013;121(25):4985-4996) (Peffault de Latour et al., Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab. Blood 2015;125(5):775-83). Furthermore, intravenous (IV) administration of eculizumab every two weeks (Q2W) is described as a burden for patients. Rabulizumab is also an anti-C5 antibody that treats conditions such as PNH. However, some patients using rabulizumab still experience some degree of hemolytic breakthrough. Moreover, IV-administered rabulizumab does not offer the significant convenience and burden reduction of subcutaneous (SC) self-administration (first approved by the US FDA). The subcutaneous rabulizumab administration regimen requires 7 ml infusions in two separate injections over 10 minutes. Alexion: Investor Presentation (Slides), March 20, 2019. [Means for solving the problem]

[0009] The present invention provides a method for administering an antagonist antigen-binding protein (e.g., REGN3918) or a pharmaceutical formulation thereof that specifically binds to C5 to a subject suffering from a C5-related disease (e.g., PNH, aHUS, MG, or CHAPLE), comprising the steps of: introducing approximately 30 mg / kg of the antagonist antigen-binding protein that specifically binds to C5 into the subject's body intravenously one or more times; and optionally introducing the antagonist antigen-binding protein or a pharmaceutical formulation thereof that specifically binds to C5 subcutaneously one or more times.

[0010] The present invention also relates to a dosage regimen for administering an antagonist antigen-binding protein (e.g., REGN3918) that specifically binds to C5 to a subject (e.g., a human), comprising the steps of (i) introducing approximately 30 mg / kg of anti-C5 antigen-binding protein intravenously (IV) once or multiple times into the subject's body, and then (ii) introducing approximately 800 mg of anti-C5 antigen-binding protein subcutaneously (SC) once or multiple times (for example, starting approximately 7 days after the initial dose and administered weekly). The administration regimen also includes the steps of (a) introducing approximately 30 mg / kg of anti-C5 antigen-binding protein intravenously (IV) once or more times, and then (b) administering it subcutaneously once or more times based on body weight, as follows: 125 mg for body weight (BW) < 10 kg, 200 mg for BW ≥ 10 kg and < 20 kg, 350 mg for BW ≥ 20 kg and < 40 kg, 500 mg for BW ≥ 40 kg and < 60 kg, and 800 mg for BW ≥ 60 kg. For example, in one embodiment of the present invention, the subcutaneous administration is given once a week (weekly, q1w or qw). In one embodiment of the present invention, the weekly administration is given approximately every 7 days, every 7 days (+1 day), every 7 days (+2 days), or every 7 days (+3 days) after the most recent administration. For example, if the first dose is given on day 1, the next weekly dose is given around day 8, and thereafter every 7 days. In one embodiment of the present invention, the subject suffers from a C5-related disease (e.g., PNH, CHAPLE, aHUS, or MG).

[0011] The present invention further provides a method for treating or preventing CHAPLE disease in a subject by administering to the subject an antagonist antigen-binding protein that specifically binds to C5 as described herein, for example, REGN3918 (in a therapeutically effective amount thereof).

[0012] The present invention also provides a method for treating or preventing C5-related disease or reducing C5 complement activity (for example, by a CH50 assay, for example, measuring the lysis of sheep red blood cells, for example, by about 99 or 100%) in a subject (for example, a human subject), the method comprising administering to the subject an antagonist antigen-binding protein (for example, REGN3918) that specifically binds to C5, according to the administration regimens discussed herein. In one embodiment of the present invention, C5-related diseases include: adult respiratory distress syndrome; age-related macular degeneration (AMD); allergies; Alport syndrome; Alzheimer's disease; amyotrophic lateral sclerosis (ALS); antiphospholipid syndrome (APS); asthma; atherosclerosis; atypical hemolytic uremic syndrome (aHUS); autoimmune diseases; autoimmune hemolytic anemia (AIHA); balloon angiogenesis; bronchoconstriction; bullous pemphigoid; burns; C3 glomerulosis; capillary leak syndrome; cardiovascular disorders; fulminant antiphospholipid syndrome (CAPS); cerebrovascular disorders; CHAPLE's disease (complement CD55 deficiency with hyperactivation, vasotoxic thrombosis, and protein-losing enteropathy); chemical damage; chronic obstructive pulmonary disease (COPD); cold agglutinin disease (CAD); corneal and / or retinal tissue; Crohn's disease; Degos disease; dense deposit disease (DDD); dermatomyositis; diabetes mellitus; diabetic vasculopathy; diabetic macular edema (DME); diabetic nephropathy; diabetic retinopathy; dilated cardiomyopathy; impaired inappropriate or undesirable complement activation; dyspnea; eclampsia; emphysema; epidermolysis bullosa; epilepsy; fibrogenic pneumoconiosis (fibrogenic pneumoconiosis). Dust disease; frostbite; geographic atrophy (GA); glomerulonephritis; glomerulopathy; Goodpasture syndrome; Graves' disease; Guillain-Barré syndrome; Hashimoto's thyroiditis; complications of hemodialysis; hemolysis, elevated liver enzymes, thrombocytopenia (HELLP) syndrome; hemolytic anemia; hemoptysis; Henoch-Schönlein purpura nephritis; hereditary angioedema; hyperacute allograft rejection; hypersensitivity pneumonitis; idiopathic thrombocytopenic purpura (ITP); IgA nephropathy; immune complex disorder; immune complex vasculitis; immune complex-associated inflammation; infection; inflammation due to autoimmune disease; inflammatory disorders; hereditary CD59 deficiency; damage from inert dust and / or inorganic substances; interleukin-2 induced toxicity during IL-2 therapy; ischemia-reperfusion injury; Kawasaki disease; lung disease or disorder; lupus nephritis;Membranoproliferative glomerulonephritis; membranoproliferative glomerulonephritis; mesenteric artery reperfusion after aortic reconstruction; mesenteric / intestinal circulatory disorders; multifocal motor neuropathy (MMN); multiple sclerosis; myasthenia gravis; myocardial infarction; myocarditis; neuropathy; neuromyelitis optica; obesity; intraocular neovascularization; intraocular neovascularization affecting the choroid; organoconstriction; parasitic diseases; Parkinson's disease; paroxysmal nocturnal hemoglobinuria (PNH); microimmune vasculitis; pemphigus; percutaneous transluminal coronary angioplasty (PTCA); peripheral (e.g., musculoskeletal) vascular disorders; pneumonia; post-ischemic reperfusion; post-pump syndrome in cardiopulmonary bypass; post-pump syndrome in renal bypass; preeclampsia; progressive renal failure; proliferative kidney; Inflammation; proteinuria; psoriasis; pulmonary embolism; pulmonary fibrosis; pulmonary infarction; pulmonary vasculitis; recurrent miscarriage; renal impairment; renal ischemia; renal ischemia-reperfusion injury; renal vascular disease; restenosis after stent placement; rheumatoid arthritis (RA); rotational atherosclerosis; schizophrenia; sepsis; septic shock; SLE nephritis; smoke damage; spinal cord injury; spontaneous miscarriage; stroke; systemic inflammatory response to sepsis; systemic lupus erythematosus (SLE); systemic lupus erythematosus-associated vasculitis; Takayasu's arteriovenous arthritis; burns; thrombotic thrombocytopenic purpura (TTP); traumatic brain injury; type 1 diabetes mellitus; typical hemolytic uremic syndrome (tHUS); uveitis; vasculitis; vasculitis associated with rheumatoid arthritis; venous gas embolism (VGE); and / or xenograft rejection.

[0013] The present invention also provides a method for establishing and / or maintaining over time concentrations (e.g., trough concentrations) of an antagonist antigen-binding protein (e.g., REGN3918) that specifically binds to C5 in the serum of a subject (e.g., a human) of at least about 100 mg / L, 150 mg / L, 400 mg / L, 600 mg / L, 700 mg / L or 600-700 mg / L, and / or achieving suppression of at least 80% (e.g., 81, 82, 93, 84, 85, 90, 95% or more) of hemolysis in the serum of the subject (e.g., as measured by AH50 and / or CH50 assays), the method comprising the step of administering the anti-C5 antigen-binding protein to the subject according to the dosing regimens discussed herein.

[0014] The present invention also provides a method for reducing serum lactate dehydrogenase (LDH) levels, intravascular hemolysis, and / or the need for red blood cell transfusions in a subject (e.g., a human) suffering from paroxysmal nocturnal hemoglobinuria (PNH), comprising the steps of administering an antagonist antigen-binding protein (e.g., REGN3918) that specifically binds to C5 to the subject in accordance with the administration regimen discussed herein (e.g., (i) approximately 30 mg / kg of antigen-binding protein administered intravenously (IV) once or more times; then (ii) approximately 800 mg of antigen-binding protein administered subcutaneously (SC) once or more weeks).

[0015] In one embodiment of the present invention, in a subject taking an antagonist antigen-binding protein that specifically binds to C5 as discussed herein (e.g., REGN3918) (e.g., suffering from PNH), (i) the subject has a serum lactate dehydrogenase (LDH) level ≥ 2 × upper limit of normal (ULN); (ii) the subject has > 10% PNH granulocytes (polymorphonuclear [PMN]); (iii) the subject has hypoalbuminemia ≤ 3.2 g / dL; (iv) the subject suffers from diarrhea; (v) the subject suffers from vomiting; (vi) the subject has abdominal (vii) The subject has pain; (viii) The subject has an episode of infection or a thromboembolic event complicated with hypogammaglobulinemia; (ix) The subject has fatigue; (x) The subject has hemoglobinuria; (xi) The subject has shortness of breath (dyspnea); (xii) The subject has anemia; (xiii) The subject has a history of a major adverse vascular event; (xiv) The subject has dysphagia; and / or (xv) The subject has erectile dysfunction.

[0016] The present invention also provides a method for normalizing and / or increasing serum albumin or reducing therapeutic intervention in a subject suffering from CD55-deficient protein-losing enteropathy, comprising the step of administering to the subject a C5-specific antagonist antigen-binding protein (e.g., REGN3918) by a method according to the administration regimen described herein, wherein the therapeutic intervention is one or more selected from the group consisting of: (i) administration of corticosteroids; (ii) administration of immunoglobulins; (iii) administration of albumin; (iv) administration of antitumor necrosis factor alpha therapeutic agents; (v) administration of immunomodulators; (vi) administration of micronutrients; (vii) administration of enteral or parenteral supplementation; (viii) administration of anticoagulants; (ix) administration of antibiotics; and (x) administration of antiplatelet agents.

[0017] In one embodiment of the present invention, a subject (e.g., suffering from CHAPLE) taking an antagonist antigen-binding protein (e.g., REGN3918) that specifically binds to C5 as discussed herein, wherein (i) the subject has a biallelelic loss-of-function mutation in CD55; (ii) the subject has a biallelelic loss-of-function mutation in CD55 that is a frameshift mutation; a missense mutation, a splice site mutation or a nonsense mutation; (iii) the subject has hypoalbuminemia with serum albumin less than 3.2 g / dL; (iv) the subject suffers from diarrhea; (v) the subject suffers from vomiting; (vi) the subject suffers from abdominal pain; (vii) the subject suffers from peripheral edema or facial edema; (viii) the subject has had an episode of infection complicated with hypogammaglobulinemia; and / or (ix) the subject has had a thrombotic event.

[0018] In one embodiment of the present invention, the antagonist antigen-binding protein that specifically binds to C5 as discussed herein is an antibody such as REGN3918 (pozelimab) or an antigen-binding fragment thereof. In one embodiment of the present invention, the antagonist antigen-binding protein (e.g., an antibody or its antigen-binding fragment) that specifically binds to C5 as discussed herein is: (1) the heavy chain variable region (HCVR) containing the amino acid sequence described in SEQ ID NO: 2 or its HCDR1, HCDR2, and HCDR3, and the light chain variable region (LCVR) containing the amino acid sequence described in SEQ ID NO: 10 or its LCDR1, LCDR2, and LCDR3; (2) the HCVR containing the amino acid sequence described in SEQ ID NO: 18 or its HCDR1, HCDR2, and HCDR3, and the LCVR containing the amino acid sequence described in SEQ ID NO: 26 or its LCDR1, LCDR2, and LCDR3; (3) the HCVR containing the amino acid sequence described in SEQ ID NO: 34 or its HCDR1, HCDR2, and HCDR3, and the LCVR containing the amino acid sequence described in SEQ ID NO: 42 or its LCDR1, LCDR2, and LCDR3; (4) the sequence described in SEQ ID NO: 50 (5) HCVRs containing the amino acid sequence described or its HCDR1, HCDR2, and HCDR3, and LCVRs containing the amino acid sequence described in SEQ ID NO: 58 or its LCDR1, LCDR2, and LCDR3; (6) HCVRs containing the amino acid sequence described in SEQ ID NO: 66 or its HCDR1, HCDR2, and HCDR3, and LCVRs containing the amino acid sequence described in SEQ ID NO: 74 or its LCDR1, LCDR2, and LCDR3; (7) HCVRs containing the amino acid sequence described in SEQ ID NO: 82 or its HCDR1, HCDR2, and HCDR3, and LCVRs containing the amino acid sequence described in SEQ ID NO: 90 or its LCDR1, LCDR2, and LCDR3;(8) HCVR containing the amino acid sequence described in SEQ ID NO: 98 or its HCDR1, HCDR2 and HCDR3, and LCVR containing the amino acid sequence described in SEQ ID NO: 114 or its LCDR1, LCDR2 and LCDR3; (9) HCVR containing the amino acid sequence described in SEQ ID NO: 122 or its HCDR1, HCDR2 and HCDR3, and LCVR containing the amino acid sequence described in SEQ ID NO: 106 or its LCDR1, LCDR2 and LCDR3; (10) HCVR containing the amino acid sequence described in SEQ ID NO: 98 or its HCDR1, HCDR2 and HCDR3, and LCVR containing the amino acid sequence described in SEQ ID NO: 130 or its LCDR1, L LCVR containing CDR2 and LCDR3; (11) HCVR containing HCDR1, HCDR2 and HCDR3 of the amino acid sequence described in SEQ ID NO: 138, and LCVR containing HCDR1, HCDR2 and HCDR3 of the amino acid sequence described in SEQ ID NO: 106; (12) HCVR containing HCDR1, HCDR2 and HCDR3 of the amino acid sequence described in SEQ ID NO: 146, and LCVR containing HCDR1, HCDR2 and HCDR3 of the amino acid sequence described in SEQ ID NO: 106; (13) HCVR containing HCDR1, HCDR2 and HCDR3 of the amino acid sequence described in SEQ ID NO: 122, and in SEQ ID NO: 130; LCVR containing the amino acid sequence described or its LCDR1, LCDR2 and LCDR3; (14) HCVR containing the amino acid sequence described in SEQ ID NO: 146 or its HCDR1, HCDR2 and HCDR3, and LCVR containing the amino acid sequence described in SEQ ID NO: 114 or its LCDR1, LCDR2 and LCDR3; (15) HCVR containing the amino acid sequence described in SEQ ID NO: 146 or its HCDR1, HCDR2 and HCDR3, and LCVR containing the amino acid sequence described in SEQ ID NO: 130 or its LCDR1, LCDR2 and LCDR3; (16) HCVR containing the amino acid sequence described in SEQ ID NO: 138 or its HCDR1, HCDR2 and HCDR3, and LCVR containing the amino acid sequence described in SEQ ID NO: 130 or its LCDR1, LCDR2 and LCDR3; (17) HCVR containing the amino acid sequence described in SEQ ID NO: 154 or its HCDR1, HCDR2 and HCDR3, and LCVR containing the amino acid sequence described in SEQ ID NO: 162 or its LCDR1 , LCVR including LCDR2 and LCDR3; (18) HCVR containing the amino acid sequence described in SEQ ID NO: 170 or its HCDR1, HCDR2 and HCDR3, and LCVR containing the amino acid sequence described in SEQ ID NO: 178 or its HCDR1, LCDR2 and LCDR3; (19) HCVR containing the amino acid sequence described in SEQ ID NO: 186 or its HCDR1, HCDR2 and HCDR3, and LCVR containing the amino acid sequence described in SEQ ID NO: 194 or its HCDR1, LCDR2 and LCDR3; (20) HCVR containing the amino acid sequence described in SEQ ID NO: 202 or its HCDR1, HCDR2 and HCDR3, and LCVR containing the amino acid sequence described in SEQ ID NO: 210 or its HCDR1, LCDR2 and LCDR3; (21) HCVR containing the amino acid sequence described in SEQ ID NO: 218 or its HCDR1, HCDR2 and HCDR3, and LCVR containing the amino acid sequence described in SEQ ID NO: 226 or its HCDR1, LCDR2 and LCDR3;(22) HCVR containing the amino acid sequence described in SEQ ID NO: 234 or its HCDR1, HCDR2 and HCDR3, and LCVR containing the amino acid sequence described in SEQ ID NO: 242 or its LCDR1, LCDR2 and LCDR3; (23) HCVR containing the amino acid sequence described in SEQ ID NO: 250 or its HCDR1, HCDR2 and HCDR3, and LCVR containing the amino acid sequence described in SEQ ID NO: 258 or its LCDR1, LCDR2 and LCDR3; (24) HCVR containing the amino acid sequence described in SEQ ID NO: 266 or its HCDR1, HCDR2 and HCDR3, and LCVR containing the amino acid sequence described in SEQ ID NO: 258 or its LCDR1, LCDR2 and LCDR3; (25) HCVR containing the amino acid sequence described in SEQ ID NO: 274 or its HCDR1, HCDR2 and HCDR3, and LCVR containing the amino acid sequence described in SEQ ID NO: 282 or its LCDR1, LCDR2 and LCDR3; (26) HCVR containing the amino acid sequence described in SEQ ID NO: 290 or its HC HCVR containing DR1, HCDR2, and HCDR3, and LCVR containing the amino acid sequence described in SEQ ID NO: 298 or its LCDR1, LCDR2, and LCDR3; (27) HCVR containing the amino acid sequence described in SEQ ID NO: 306 or its LCDR1, HCDR2, and HCDR3, and LCVR containing the amino acid sequence described in SEQ ID NO: 314 or its LCDR1, LCDR2, and LCDR3; (28) HCVR containing the amino acid sequence described in SEQ ID NO: 322 or its LCDR1, HCDR2, and HCDR3, and LCVR containing the amino acid sequence described in SEQ ID NO: 330 or its LCDR1, LCDR2, and LCDR3; and / or (29) HCVR containing the amino acid sequence described in SEQ ID NO: 338 or its LCDR1, HCDR2, and HCDR3, and LCVR containing the amino acid sequence described in SEQ ID NO: 346 or its LCDR1, LCDR2, and LCDR3; or competing for binding to C5 with antigen-binding proteins selected from the group consisting of (1) to (29);Alternatively, it binds to the same C5 epitope as the antigen-binding protein selected from the group consisting of (1) to (29).

[0019] In one embodiment of the present invention, a subject taking the C5-specific antagonist antigen-binding protein described herein has previously taken tesidorumab, eculizumab, or ravulizumab. In one embodiment of the present invention, the C5-specific antagonist antigen-binding protein described herein is a further therapeutic agent; for example, cemdisiran, oligonucleotides, anticoagulants, warfarin, aspirin, heparin, phenindione, fondaparinux, hydraparinax, thrombin inhibitors, argatroban, repiridine, bivalirudine, dabigatran, anti-inflammatory drugs, corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), antihypertensive drugs, angiotensin-converting enzyme inhibitors, immunosuppressants, vincristine, cyclosporine A, or methotrexate, fibrinolytic agents. Anklod, E-aminocaproic acid, anti-plasmin-α1, prostacyclin, defibrotide, lipid-lowering agents, hydroxymethylglutaryl-CoA reductase inhibitors, anti-CD20 agents, rituximab, anti-TNF-alpha agents, infliximab, anticonvulsants, magnesium sulfate, C3 inhibitors, antithrombotic agents, antibiotics, penicillin, erythromycin, vaccines, meningococcal vaccines, antifungal agents, antiviral agents, corticosteroids, erythropoietin, immunosuppressants, anticoagulants, iron supplements, folic acid, acetaminophen, aspirin, ibuprofen, or administered in combination with hormone replacement therapy. In one embodiment of the present invention, further therapeutic agents are oligonucleotides which are DNA oligonucleotides, RNA oligonucleotides, single-stranded DNA oligonucleotides, single-stranded RNA oligonucleotides, double-stranded DNA oligonucleotides, or double-stranded RNA oligonucleotides; optionally, the oligonucleotides are conjugated to sugars.

[0020] The present invention also provides a dosage regimen for administering an antagonist antigen-binding protein (e.g., REGN3918) that specifically binds to C5 to a subject (e.g., a human), wherein the subject's body... (i) a step of introducing approximately 30 mg / kg of anti-C5 antigen-binding protein intravenously (IV) once or multiple times, and / or (ii) The process of subcutaneously administering approximately 800 mg of anti-C5 antigen-binding protein once or multiple times (for example, starting approximately 7 days after the initial dose and being administered weekly); or (a) A step of introducing approximately 30 mg / kg of anti-C5 antigen-binding protein intravenously (IV) once or multiple times, and / or (b) The administration regimen is also provided which includes a step of subcutaneous administration once or more times based on body weight (for example, starting about 7 days after the first dose and given weekly), as follows: 125 mg for body weight (BW) < 10 kg, 200 mg for BW ≥ 10 kg and < 20 kg, 350 mg for BW ≥ 20 kg and < 40 kg, 500 mg for BW ≥ 40 kg and < 60 kg, and 800 mg for BW ≥ 60 kg. As described above, (i) and (ii) may be in either order, and (a) and (b) may be in either order. For example, in one embodiment of the present invention, the subcutaneous administration is given once a week (weekly, q1w or qw). In one embodiment of the present invention, the once-weekly administration is given about 7 days, 7 days (+1 day), 7 days (+2 days), or 7 days (+3 days) after the most recent dose. For example, if the first dose is given on day 1, the next weekly dose is given on approximately day 8, and thereafter every 7 days. In one embodiment of the present invention, the subject suffers from a C5-related disorder (e.g., PNH, CHAPLE, aHUS, or MG). Methods for treating or preventing C5-related disorders, including the aforementioned administration method, are within the scope of the present invention. [Brief explanation of the drawing]

[0021] [Figure 1] This figure illustrates a cohort in a clinical trial of REGN3918 in patients with paroxysmal nocturnal hemoglobinuria (PNH). [Figure 2] This graph shows the mean (±SE) serum concentration of total REGN3918 against nominal time in each treatment group (1 mg / kg IV, single dose; 3 mg / kg IV, single dose; 300 mg SC, single dose; 10 mg / kg IV, single dose; 600 mg SC, single dose; 30 mg / kg IV, single dose; or 15 mg / kg IV followed by 400 mg q1w × 4 weeks of SC administration, repeated four times) in healthy human volunteers. [Figure 3] This graph shows the mean (±SE) percentage change (%) of CH50 from baseline relative to nominal time in each treatment group (1 mg / kg IV, single dose; 3 mg / kg IV, single dose; 300 mg SC, single dose; 10 mg / kg IV, single dose; 600 mg SC, single dose; 30 mg / kg IV, single dose; or 15 mg / kg IV followed by 400 mg q1w × 4 weeks of SC administration, repeated four times) in healthy human volunteers. [Figure 4-1] Figure 4(A-I) shows graphs illustrating in vitro alternative pathway (AP) and classical pathway (CP) hemolysis in the presence of various concentrations of pozelimab (REGN3918), eculizumab, rabulizumab, or isotype control antibody (REGN1945). Figure 4A shows the AP hemolysis assay in the presence of 10% normal human serum (NHS). Figure 4B shows the AP hemolysis assay in the presence of 25% NHS. Figure 4C shows the AP hemolysis assay in the presence of 48% NHS. Figure 4D shows the CP hemolysis assay in the presence of 5% NHS. Figure 4E shows the CP hemolysis assay in the presence of 10% NHS. Figure 4F shows the CP hemolysis assay in the presence of 25% NHS. Figure 4G shows the AP hemolysis assay in the presence of 25% NHS and 1 mM MgCl2. Figure 4H is a graph showing the AP hemolysis assay in the presence of 25% NHS and 1.5 mM MgCl2. Figure 4I is a graph showing the AP hemolysis assay in the presence of 25% NHS and 2 mM MgCl2. [Figure 4-2] Continuation of Figure 4-1. [Figure 5] This graph shows the time course of lactate dehydrogenase (LDH) (X ULN) in six patients (410001001F; 410001002F; 410004001F; 410004002M; 410005001F; and 410005002M) on a standard scale. The upper limit of normal LDH (ULN) and 1.5×ULN are displayed. [Figure 6] This graph shows the time course of lactate dehydrogenase (LDH) (X ULN) in six patients, on a semi-logarithmic scale. The upper limit of normal LDH (ULN) and 1.5×ULN are displayed. [Figure 7] This graph shows the mean lactate dehydrogenase (LDH) (X ULN) levels over time for six patients, using a standard scale. The upper limit of normal LDH (ULN) and 1.5×ULN are displayed. [Figure 8] This graph shows the mean lactate dehydrogenase (LDH) (X ULN) levels over time for six patients, on a semi-logarithmic scale. The upper limit of normal LDH (ULN) and 1.5×ULN are displayed. [Figure 9A] Figure 9A is a graph showing the individual normal scale concentrations (mg / L) of total serum REGN3918 as a percentage of nominal time in six patients who had not received prior PNH treatment. [Figure 9B] Figure 9B is a graph showing the individual semi-logarithmic scale concentrations (mg / L) of total serum REGN3918 as a percentage of nominal time in six patients who had not received prior PNH treatment. [Figure 9C] Figure 9C is a graph showing the median-normal scale concentration (mg / L) of total serum REGN3918 as a percentage of nominal time in six first-time PNH-naive patients. Figure 9D is a graph showing the median-semi-logarithmic scale concentration (mg / L) of total serum REGN3918 as a percentage of nominal time in six first-time PNH-naive patients. [Figure 9D] Figure 9D is a graph showing the median semi-logarithmic scale concentration (mg / L) of total serum REGN3918 as a percentage of nominal time in six patients who had not received prior PNH treatment. [Figure 10A] Figure 10A is a graph showing the individual normal scale concentrations (mg / L) of total serum REGN3918 as a percentage of nominal time, broken down by sex, in six patients who had not previously received PNH treatment. [Figure 10B] Figure 10B is a graph showing, by sex, the individual semi-logarithmic scale concentration (mg / L) of total serum REGN3918 as a percentage of nominal time in six patients who had not received prior PNH treatment. [Figure 10C] Figure 10C is a graph showing the median-normal scale concentration (mg / L) of total serum REGN3918 as a percentage of nominal time, broken down by sex, for six patients who had not previously received PNH treatment. [Figure 10D] Figure 10D is a graph showing the median semi-logarithmic scale concentration (mg / L) of total serum REGN3918 as a percentage of nominal time, broken down by sex, for six patients who had not previously received PNH treatment. [Figure 11A] Figure 11A is a graph showing the individual concentrations (mg / L) of total plasma C5 against nominal time in six patients who had not previously received PNH treatment. [Figure 11B] Figure 11B is a graph showing the median plasma total C5 concentration (mg / L) as a percentage of nominal time in six patients who had not previously received PNH treatment. [Figure 12A] Figure 12A is a graph showing the individual concentrations (mg / L) of total plasma C5 as a percentage of nominal time, broken down by sex, in six patients who had not previously received PNH treatment. [Figure 12B] Figure 12B is a graph showing the median plasma C5 concentration (mg / L) as a percentage of nominal time, broken down by sex, for six patients who had not previously received PNH treatment. [Figure 13A] Figure 13A is a graph showing individual ratios to baseline total plasma C5 for nominal time in six patients who had not received prior PNH treatment. [Figure 13B] Figure 13B is a graph showing the median ratio to baseline total plasma C5 for nominal time in the first six PNH treatment-naive patients. [Figure 14A] Figure 14A is a graph showing the individual ratios to baseline total plasma C5 observed in the first six PNH treatment-naive patients, broken down by nominal time and sex. [Figure 14B] Figure 14B is a graph showing the median ratio to baseline total plasma C5 for nominal time and by sex in six patients who were the first PNH treatment-naive patients. [Figure 15] This graph shows the mean (±SD) plasma total C5 concentration (mg / L) as a function of nominal time in six patients who had not previously received PNH treatment. [Figure 16] This graph shows the individual concentrations of total REGN3918 (TOR3918; triangle) and total C5 (TOC5; circle) against nominal time in six patients (A, B, C, D, E, and F). [Figure 17] This graph shows LDH(X ULN) levels for six patients, including those from day 57 onwards (female LDH ULN = 330 U / L, and male LDH ULN = 281 U / L). [Figure 18] This graph shows the semi-logarithmic scale LDH(X ULN) for six patients, including those from day 57 onwards (female LDH ULN = 330 U / L, and male LDH ULN = 281 U / L). [Figure 19] This graph shows the average LDH(X ULN) for 6 patients, including those from day 57 onwards (female LDH ULN = 330 U / L, and male LDH ULN = 281 U / L). [Figure 20] This graph shows the mean LDH(X ULN) on a semi-logarithmic scale for six patients, including those from day 57 onwards (female LDH ULN = 330 U / L, and male LDH ULN = 281 U / L). [Figure 21] This graph shows LDH(X ULN) levels for nine patients, including those from day 57 onwards (female LDH ULN = 330 U / L, and male LDH ULN = 281 U / L). [Figure 22]This graph shows LDH(X ULN) on a semi-logarithmic scale for nine patients, including those from day 57 onwards (female LDH ULN = 330 U / L, and male LDH ULN = 281 U / L). [Figure 23] This graph shows the average LDH (X ULN) for 9 patients, including those from day 57 onwards (female LDH ULN = 330 U / L, and male LDH ULN = 281 U / L). [Figure 24] This graph shows the mean LDH(X ULN) on a semi-logarithmic scale for 9 patients, including those from day 57 onwards. [Figure 25] This figure shows an overview of a clinical trial treating previously nascent PNH patients with ALXN1210 (ravulizumab) or eculizumab. [Figure 26A] This graph shows that switching from eculizumab to REGN3918 administration normalizes serum C5 concentration and maintains suppression of hemolytic activity. Figure 26A shows the total hIgG concentration measured by Gyros in serum collected from C5hu / hu mice that received three doses of REGN3918 alone (black circles), three doses of eculizumab alone (squares), or one dose of eculizumab followed by two doses of REGN3918 (switch, white circles). The arrows on the y-axis and the vertical gray dashed lines indicate the administration time. [Figure 26B] This graph shows that switching from eculizumab to REGN3918 administration normalizes serum C5 concentration and maintains suppression of hemolytic activity. Figure 26B shows the total serum C5 concentration measured from mice collected throughout the clinical trial period, in C5hu / hu mice administered REGN3918 alone (black circles), eculizumab alone (squares), or switched from eculizumab to REGN3918 (switch, white circles). [Figure 26C]This graph shows that switching from eculizumab to REGN3918 administration normalizes serum C5 concentration and maintains suppression of hemolytic activity. Figure 26C is a graph showing that serum collected from the final blood sampling of C5hu / hu mice administered with REGN3918 alone (black circles), eculizumab alone (squares), or a switch between eculizumab and REGN3918 (white circles) was supplemented with hC3, and that the percentage of CP-mediated hemolysis was evaluated using an ex vivo assay. [Figure 26D] This graph shows that switching from eculizumab to REGN3918 normalizes serum C5 concentration and maintains suppression of hemolytic activity. Figure 26D shows the total serum C5 and hIgG concentrations used to calculate the C5:mAb ratio at the indicated time points. The data are plotted as mean ± SEM. [Figure 27] This graph shows that REGN3918 and eculizumab bind to different sites on C5 and, when all three are present under conditions designed to mimic dose switching, form a complex primarily containing 1-2 molecules of C5. The eculizumab:C5 complex was analyzed by asymmetric flow field-flow fractionation coupled with multi-angle laser light scattering (A4F-MALLS). Fractograms obtained from individual samples of eculizumab, C5, and REGN3918 are also superimposed. Relative UV absorption at 215 nm as a function of retention time is shown for each sample, and molar mass measurements of the separated peaks are also shown. [Figure 28A] This figure shows the serum albumin levels of four CHAPLE patients over time. Figure 28A is a graph showing the serum albumin levels of four CHAPLE patients during the treatment period. [Figure 28B] This figure shows the serum albumin levels of four CHAPLE patients over time. Figure 28B is a graph showing the serum albumin level of the first of the four CHAPLE patients before treatment. [Figure 28C]This figure shows the serum albumin levels of four CHAPLE patients over time. Figure 28C is a graph showing the second serum albumin level of the four CHAPLE patients before treatment. [Figure 28D] This figure shows the serum albumin levels of four CHAPLE patients over time. Figure 28D is a graph showing the third serum albumin level of the four CHAPLE patients before treatment. [Figure 28E] This figure shows the serum albumin levels of four CHAPLE patients over time. Figure 28E is a graph showing the fourth serum albumin level of the four CHAPLE patients before treatment. The lower limit of normal (LLN) is shown for both male and female patients. [Figure 29] This graph shows the total serum protein levels for four CHAPLE patients over time, starting from baseline. The lower limit of normal (LLN) and upper limit of normal (ULN) are displayed. [Figure 30] This graph shows the time-course vitamin B12 levels in each of the four CHAPLE patients during the treatment period, starting from baseline. [Figure 31] This graph shows the time-series platelet counts for each of the four CHAPLE patients during the treatment period, starting from baseline. [Figure 32] This graph shows the time-course fecal alpha-1-antitrypsin concentration in four CHAPLE patients during the treatment period, starting from baseline. The upper limit of normal (ULN) is indicated. [Figure 33] This graph shows the time-course facial edema grade in four CHAPLE patients before and during treatment. [Figure 34] This graph shows the time-course plot of peripheral edema grade in four CHAPLE patients before and during treatment. [Figure 35] This graph shows the average number of bowel movements per day for each of the four CHAPLE patients, plotted on a weekly basis. [Modes for carrying out the invention]

[0022] A simple REGN3918 (pozelimab) administration regimen including a subcutaneous component has been developed for the treatment of C5-related disorders such as PNH in humans. Subcutaneous administration provides patients with the option of home administration and therefore offers the advantage of better patient compliance compared to IV administration regimens of eculizumab and ravulizumab. This administration regimen has been shown to be highly effective in controlling hemolysis and reducing breakthrough hemolysis in human patients receiving antibodies. REGN3918 administered via SC at 30 mg / kg IV followed by 800 mg once weekly (REGN3918-30+800 regimen) showed robust inhibition of intravascular hemolysis and normalization of LDH in human PNH patients. REGN3918 is known to bind to C5 (R885H / C) with high affinity, and it has been shown to effectively normalize LDH in human PNH patients receiving the REGN3918-30+800 regimen. The data presented herein demonstrate the efficacy of the REGN3918-30+800 dosing regimen in human patients with C5 variants who were previously resistant to eculizumab therapy. The REGN3918-30+800 dosing regimen also demonstrated clinical benefits over eculizumab and ravulizumab. Treatment with REGN3918 resulted in a rapid, robust, and sustained reduction of LDH up to day 57 of the study; LDH in all six patients decreased on day 3 (48 hours after the first dose), reached LDH ≤ 1.5 × ULN (upper limit of normal) on day 14, and normalized LDH (≤ 1.0 × ULN) on day 29, achieving control of intravascular hemolysis. In contrast, evidence suggests that only about half of patients treated with ravulizumab and eculizumab achieved LDH normalization. In fact, 25% of PNH patients treated with eculizumab still require repeated transfusions, albeit less frequently; and up to 20% of patients require a significant increase in dose or frequency due to breakthrough hemolysis secondary to incomplete inhibition of C5. (Nakayama et al., Eculizumab Dosing Intervals Longer than 17 Days) May Be Associated with Greater Risk of Breakthrough Hemolysis in Patients with See also Paroxysmal Nocturnal Hemoglobinuria. Biol Pharm Bull 2016;39(2):285-288; Hil et al., Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 2013;121(25):4985-4996; and Peffault de Latour et al., Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab. Blood 2015;125(5):775-7883. The comparative ex vivo hemolysis assay presented herein suggests that pozerimab is more effective than ravulizumab and eculizumab in inhibiting AP complement-mediated hemolysis, and superior to ravulizumab in inhibiting CP complement-mediated hemolysis.

[0023] Discussions of administration regimens including the administration of A and, if applicable, B, refer to regimens including the administration of A alone, as well as regimens including the administration of A and, if applicable, B.

[0024] Antagonist antigen-binding protein that specifically binds to C5 The present invention provides a method for using a pharmaceutical formulation comprising an antagonist antigen-binding protein (e.g., an antibody and its antigen-binding fragment) that specifically binds to C5 as expressed herein, and a pharmaceutically acceptable carrier.

[0025] In one embodiment of the present invention, an antagonist antigen-binding protein that specifically binds to C5 binds to the beta chain, alpha chain, or both of the C5 molecule at residues 591-599 and / or 775-794, for example, NMATGMDSW (SEQ ID NO: 353) and / or WEVHLVPRRKQLQFALPDSL (SEQ ID NO: 354). In one embodiment of the present invention, the anti-C5 antigen-binding protein does not bind to C5a.

[0026] In one embodiment of the present invention, the antagonist antigen-binding protein that specifically binds to C5 is bound at the residue KDMQLGRLHMKTLLPVSK (SEQ ID NO: 355).

[0027] In one embodiment of the present invention, an antagonist antigen-binding protein that specifically binds to C5 binds the beta chain of its C5 at, for example, residues 332-398, 332-378, 332-364, 332-348, 350-420, 369-409, 379-398 and / or 386-392.

[0028] In one embodiment of the present invention, an antagonist antigen-binding protein that specifically binds to C5 binds C5a, for example, with the residues NDETCEQRA (SEQ ID NO: 356) and / or SHKDMQL (SEQ ID NO: 357).

[0029] In one embodiment of the present invention, the antagonist antigen-binding protein that specifically binds to C5 binds to the beta chain of C5, for example, residues 19-180. In one embodiment of the present invention, binding to C5 is Reduced by E48A, D51A, and / or K109A C5 mutations.

[0030] The immunoglobulin polypeptides of antagonist antigen-binding proteins (e.g., antibodies or their antigen-binding fragments) that specifically bind to C5 and are used in the method of the present invention are listed in Table A.

[0031] [Table 1]

[0032] The polynucleotides encoding the chains listed in Table A are shown in Table B below.

[0033] [Table 2]

[0034] H2M11683N HCVR Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Asp Asp Gly Asn Asn Ile Asn Tyr Ser Asp Ser Val 50 55 60 Lys Gly Arg Phe Ile Ile Ser Arg Asp Asn Ser Arg Lys Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Gly Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ala Pro Ile Ala Pro Val Pro Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 (SEQ ID NO:2)

[0035] LCVR Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Lys Ala Ser Ser Leu Asp Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Thr Tyr Ser Tyr 85 90 95 Thr Phe Gly Leu Gly Thr Lys Leu Glu Ile Lys 100 105 (SEQ ID NO:10)

[0036] H2M11686N HCVR Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser Gly Asn Thr Ile Lys Tyr Ala Asp Ser Met 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Phe 65 70 75 80 Val Glu Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Lys Ser Ser Ser Asp Tyr Phe Asp His Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 (SEQ ID NO: 18)

[0037] LCVR Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Arg Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Ala Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln Ser Gly Asn Trp Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 (SEQ ID NO: 26)

[0038] H4H12159P HCVR Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Gly Ala Ser Gly Phe Thr Phe Ser Thr Tyr<> 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Asp Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Glu Val Ala Pro Val Gly Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 (SEQ ID NO: 34)

[0039] LCVR Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Ile Cys Arg Ala Ser Gln Ser Ile Asn Arg Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Asp Asp Phe Ala Ala Tyr Tyr Cys Gln Gln Tyr Asn Asp Tyr Ser Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 (SEQ ID NO: 42)

[0040] H4H12161P HCVR Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp His 20 25 30 Tyr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Asp Trp Ile 35 40 45 Gly Arg Ile Arg Asn Lys Ala Asn Ala Tyr Asn Thr Glu Tyr Ala Ala 50 55 60 Ser Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Asn Leu 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Asp Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Val Arg Val Trp Asn Tyr Ala Tyr Phe Ala Met Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 (SEQ ID NO: 50)

[0041] LCVR Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Asn Ile Gly Ile Phe 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Glu Ala Pro Asn Leu Leu Ile 35 40 45 Ser Ala Ala Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Gly Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Tyr Asn Thr Ile Phe 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105 (SEQ ID NO: 58)

[0042] H4H12163P HCVR Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Gly Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Leu Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Lys Glu Gly Glu Gln Leu Val Tyr Trp Tyr Phe Asp Leu Trp Gly 100 105 110 Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 (SEQ ID NO: 66)

[0043] LCVR Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile Ser Asn Phe 20 25 30 Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ser Thr Tyr Phe Cys Gln Gln Ser Tyr Thr Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 (SEQ ID NO: 74)

[0044] H4H12164P HCVR Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Ser Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Arg Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Ser Ser Thr Tyr Tyr Thr Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser Val Asp 65 70 75 80 Leu Gln Met His Ser Leu Arg Val Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Gly Thr Thr Val Thr Thr Gly Tyr Gly Met Asp Val Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 (SEQ ID NO: 82)

[0045] LCVR Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Phe Thr Cys Gln Ala Ser Gln Asp Ile Thr Asn Ser 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Tyr Leu Lys Ala Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asp Leu Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 (SEQ ID NO: 90)

[0046] H4H12166P HCVR Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Val Ser Ser Ser 20 25 30 Tyr Trp Thr Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Tyr Ser Gly Ser Ser Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Glu Gly Asn Val Asp Thr Thr Met Ile Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 (SEQ ID NO: 98)

[0047] LCVR Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ala Gly 50 55 60 Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Phe Asn Tyr Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 (SEQ ID NO: 106)

[0048] H4H12166P2 HCVR Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Val Ser Ser Ser 20 25 30 Tyr Trp Thr Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Tyr Ser Gly Ser Ser Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Glu Gly Asn Val Asp Thr Thr Met Ile Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 (SEQ ID NO: 98)

[0049] LCVR Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ala Gly 50 55 60 Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Asp Phe Asn Tyr Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 (SEQ ID NO: 114)

[0050] H4H12166P3 HCVR Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Val Ser Ser Ser 20 25 30 Tyr Trp Thr Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Tyr Ser Gly Ser Ser Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Glu His Asn Val Asp Thr Thr Met Ile Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 (SEQ ID NO: 122)

[0051] LCVR Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ala Gly 50 55 60 Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Phe Asn Tyr Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 (SEQ ID NO: 106)

[0052] H4H12166P4 HCVR Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Val Ser Ser Ser 20 25 30 Tyr Trp Thr Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Tyr Ser Gly Ser Ser Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Glu Gly Asn Val Asp Thr Thr Met Ile Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 (SEQ ID NO: 98)

[0053] LCVR Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ala Gly 50 55 60 Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Phe Asn Tyr Pro Trp 85 90 95 His Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 (SEQ ID NO: 130)

[0054] H4H12166P5 HCVR Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Val Ser Ser Ser 20 25 30 Tyr Trp Thr Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Tyr Ser Gly Ser Ser Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Glu Gly Asn Val Asp Thr Thr Met Ile His Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 (SEQ ID NO: 138)

[0055] LCVR Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ala Gly 50 55 60 Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Phe Asn Tyr Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 (SEQ ID NO: 106)

[0056] H4H12166P6 HCVR Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Val Ser Ser Ser 20 25 30 Tyr Trp Thr Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Tyr Ser Gly Ser Ser Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Glu Gly Asn Val Asp His Thr Met Ile Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 (SEQ ID NO: 146)

[0057] LCVR Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ala Gly 50 55 60 Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Phe Asn Tyr Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 (SEQ ID NO: 106)

[0058] H4H12166P7 HCVR Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Val Ser Ser Ser 20 25 30 Tyr Trp Thr Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Tyr Ser Gly Ser Ser Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Glu His Asn Val Asp Thr Thr Met Ile Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 (SEQ ID NO: 122)

[0059] LCVR Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ala Gly 50 55 60 Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Phe Asn Tyr Pro Trp 85 90 95 His Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 (SEQ ID NO: 130)

[0060] H4H12166P8 HCVR Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Val Ser Ser Ser 20 25 30 Tyr Trp Thr Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Tyr Ser Gly Ser Ser Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Glu Gly Asn Val Asp His Thr Met Ile Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 (SEQ ID NO: 146)

[0061] LCVR Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ala Gly 50 55 60 Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Asp Phe Asn Tyr Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 (SEQ ID NO: 114)

[0062] H4H12166P9 HCVR Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Val Ser Ser Ser 20 25 30 Tyr Trp Thr Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Tyr Ser Gly Ser Ser Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Glu Gly Asn Val Asp His Thr Met Ile Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 (SEQ ID NO: 146)

[0063] LCVR Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ala Gly 50 55 60 Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Phe Asn Tyr Pro Trp 85 90 95 His Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 (SEQ ID NO: 130)

[0064] H4H12166P10 HCVR Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Val Ser Ser Ser 20 25 30 Tyr Trp Thr Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Tyr Ser Gly Ser Ser Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Glu Gly Asn Val Asp Thr Thr Met Ile His Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 (SEQ ID NO: 138)

[0065] LCVR Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ala Gly 50 55 60 Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Phe Asn Tyr Pro Trp 85 90 95 His Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 (SEQ ID NO: 130)

[0066] H4H12167P HCVR Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Ser Tyr Ile Gly Ser Ser Gly Asn Thr Phe Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Asn Asn Leu Leu Tyr 65 70 75 80 Leu Gln Met Thr Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Glu Gly Asp Phe Trp Ser Ala Val Asp Ser Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 (SEQ ID NO: 154)

[0067] LCVR Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Trp Ala Ser Gln Gly Ile Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 His Thr Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asn Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Phe 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105 (SEQ ID NO: 162)

[0068] H4H12168P HCVR Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Gly His 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Ala Val Ile Ser Ser Asp Gly Ser Asn Lys Gln Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Val Gly Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Lys Glu Val Ala Pro Arg Tyr Tyr Tyr Tyr Gly Leu Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 (SEQ ID NO: 170)

[0069] LCVR Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Phe 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile 35 40 45 Tyr Thr Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Val Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr Ala Gly Ala Leu Thr 85 90 95 Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105 (SEQ ID NO: 178)

[0070] H4H12169P HCVR Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ala Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val 35 40 45 Ser Gly Ile Gly Gly Asn Gly Val Thr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Gln Gly Gly Leu Gly Gly Tyr Phe Thr Gly Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 (SEQ ID NO: 186)

[0071] LCVR Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Thr Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Asn Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Phe Asp Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Gly Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Ala Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 (SEQ ID NO: 194)

[0072] H4H12170P HCVR Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Leu Ile Trp Leu Asp Gly Ser Asn Asp Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Arg Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Pro Val Ala Ala Ile Pro Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 (SEQ ID NO: 202)

[0073] LCVR Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Arg Trp 20 25 30 Leu Ala Trp Tyr Gln Leu Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Thr Tyr Ser Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 (SEQ ID NO: 210)

[0074] H4H12171P HCVR Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Glu Tyr 20 25 30 Gly Met Thr Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Thr Trp Asn Gly Gly Phe Thr Asp Tyr Thr Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ser Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Tyr Ser Ser Ser Trp Gly Ala Tyr Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser 115 120 (SEQ ID NO: 218)

[0075] LCVR Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Thr Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Leu Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Ser Tyr Phe Cys Gln Gln Ser Tyr Ser Thr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 (SEQ ID NO: 226)

[0076] H4H12175P HCVR Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Leu Ile Ser Gly Asp Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Leu Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Lys Gly Trp Asn Phe Gly Tyr Phe Asp Leu Trp Gly Arg 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 (SEQ ID NO: 234)

[0077] LCVR Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Ile Asp Thr Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Asp Asn Ile Leu His 85 90 95 Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 (SEQ ID NO: 242)

[0078] H4H12176P2 HCVR Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe His Ser Asn Arg Tyr 20 25 30 Trp Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn Ile Lys Gln Asp Gly Ser Glu Glu Asn Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Ser Thr Ser Trp Val Pro Tyr Trp Phe Phe Asp Leu 100 105 110 Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 (SEQ ID NO: 250)

[0079] LCVR Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 (SEQ ID NO: 258)

[0080] H4H12177P2 HCVR Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Arg Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Ala Ser Asp Phe Ile Phe Lys Asp Tyr 20 25 30 Ala Met Tyr Trp Val Arg Gln Ile Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Ser Leu Ile Ser Gly Asp Gly Asp Thr Thr Trp Tyr Gly Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Asn Glu Asn Ser Leu Phe 65 70 75 80 Leu Gln Met Asn Asp Leu Arg Thr Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Asp Met Gly Trp Asn Phe Phe Gln Leu Gln Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 (SEQ ID NO: 266)

[0081] LCVR Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 (SEQ ID NO: 258)

[0082] H4H12183P2 HCVR Gln Val Gln Leu Gln Glu Ser Gly Pro Ala Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ile Arg Gly 20 25 30 Ser Thr Tyr Trp Ser Trp Val Arg Gln Phe Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ser Tyr Tyr Ser Gly Thr Ala Tyr Tyr Asn Pro Ser 50 55 60 Leu Glu Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Asn Leu Lys Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Thr Arg Glu Ile Gly Val Ala Gly Leu Phe Asp Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 (SEQ ID NO: 274)

[0083] LCVR Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 (SEQ ID NO: 282)

[0084] H2M11682N HCVR Gln Glu Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Leu Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Lys Arg Leu Lys Ser Asp Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ala Pro Pro His Asp Val Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 (SEQ ID NO: 290)

[0085] LCVR Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ile Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 (SEQ ID NO: 298)

[0086] H2M11684N HCVR Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Ala Tyr His Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Asn Gly Asp Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Phe Leu Lys Val Thr Ser Val Thr Ala Ala Asp Thr Ala Met Tyr Tyr 85 90 95 Cys Ala Gly Glu Lys Gln Leu Thr Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 (SEQ ID NO: 306)

[0087] LCVR Val Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Asn Asn Phe 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Leu Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Ser Asp Ala Ser Asn Leu Gln Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Ala Tyr Tyr Cys Gln Gln Tyr Asp His Phe Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Arg Leu Glu Asn Asn 100 105 (SEQ ID NO: 314)

[0088] H2M11694N HCVR Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Gly Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Asn Trp Asn Gly Asp Ser Thr Glu Tyr Ser Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Phe Tyr His Cys 85 90 95 Ala Arg Glu Asn Asn Trp Asn Phe Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 (SEQ ID NO: 322)

[0089] LCVR Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Arg Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Leu Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 (SEQ ID NO: 330)

[0090] H2M11695N HCVR Gln Val His Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Val Ser Gly Asn Thr Leu Thr Glu Leu 20 25 30 Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Gly Phe Asp Pro Glu Asp Gly Asp Thr Ile Tyr Ser Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Leu Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Thr Val Gly Gly Pro Thr Ser Asp Cys Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 (SEQ ID NO: 338)

[0091] LCVR Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 35 40 45 Phe Asp Ala Ser Asn Leu Glu Pro Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ile Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Arg Leu Asp Ile Lys 100 105 (Sequence ID 346)

[0092] In one embodiment of the present invention, any antigen-binding protein (anti-C5) that specifically binds to C5 as discussed herein is an antagonist. Such an antagonist (e.g., an antagonist antigen-binding protein that specifically binds to C5) binds to C5 and inhibits at least one of the biological activities of C5; for example, preventing or blocking complement-mediated hemolysis by the classical or alternative pathway, and / or inhibiting the cleavage of C5 into C5a and C5b, and / or inhibiting complement-mediated lysis of erythrocytes, and / or inhibiting the formation of membrane invasion complexes (MACs), and / or inhibiting the formation of the C5b-6 complex.

[0093] In one embodiment of the present invention, the antagonist antigen-binding protein that specifically binds to C5 is eculizumab (marketed as Soliris), ravulizumab (ALXN1210; marketed as Ultomiris), tesidorumab (see US8241628; WO2010 / 015608; or WO2017 / 212375), or mubodina (see US7999081); or its antigen-binding fragment. In one embodiment of the present invention, the antagonist antigen-binding protein that specifically binds to C5 is pozerimab (REGN3918; H4H12166P) antibody; or its antigen-binding fragment. The pozerimab (REGN3918; H4H12166P) antibody has the following amino acid sequence: QVQLQESGPG LVKPSETLSL TCTVSGDSVS SSYWTWIRQP PGKGLEWIGY IYYSGSSNYN 60 PSLKSRATIS VDTSKNQFSL KLSSVTAADT AVYYCAREGN VDTTMIFDYW GQGTLVTVSS 120 ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 180 GLYSLSSVVT VPSSSLGTKT YTCNVDHKPS NTKVDKRVES KYGPPCPPCP APEFLGGPSV 240 FLFPPKPKDT LMISRTPEVT CVVVDVSQED PEVQFNWYVD GVEVHNAKTK PREEQFNSTY 300 RVVSVLTVLH QDWLNGKEYK CKVSNKGLPS SIEKTISKAK GQPREPQVYT LPPSQEEMTK 360 NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSRL TVDKSRWQEG 420 NVFSCSVMHE ALHNHYTQKS LSLSLGK 447 (Sequence number 368); Heavy chain immunoglobulins containing and amino acid sequence: AIQMTQSPSS LSASVGDRVT ITCRASQGIR NDLGWYQQKP GKAPKLLIYA ASSLQSGVPS 60 RFAGRGSGTD FTLTISSLQP EDFATYYCLQ DFNYPWTFGQ GTKVEIKRTV AAPSVFIFPP 120 SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT 180 LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC 214 (Sequence ID 369) Contains light chain immunoglobulins.

[0094] The present invention relates to the variable region (V) of pozelimubb, which is specifically discussed herein. H and V L ) and / or CDR (including LCDR1, LCDR2 and LCDR3) L ; and V including HCDR1, HCDR2 and HCDR3 H The method includes using an antagonist antigen-binding protein that specifically binds to C5, such as an antibody and its antigen-binding fragment, which includes a variable region and CDR that are variants of those discussed herein.

[0095] Immunoglobulin chains (e.g., H2M11683N;H2M11686N;H4H12159P;H4H12161P;H4H12163P;H4H12164P;H4H12166P;H4H12166P2;H4H12166P3;H4H12166P4;H4H12166P5;H4H12166P 6;H4H12166P7;H4H12166P8;H4H12166P9;H4H12166P10;H4H12167P;H4H12168P;H4H12169P;H4H12170P;H4H12171P;H4H12175P;H4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N;H2M11695N;Labrizumab, eculizumab, tesidorumab or mubodina V H , V LA "mutant" of a polypeptide such as HC or LC or its CDR is defined as a reference amino acid sequence as described herein (e.g., SEQ ID NOs: 2;4;6;8;10;12;14;16;18;20;22;24;26;28;30;32;34;36;38;40;42;44;46;48;50;52;54;56;58;60;62;64;66;68;70;72;74;76;78;80;82;84;86;88;90;92;94;96;98;1 00;102;104;106;108;110;112;114;116;118;120;122;124;126;128;130;132;134;136;138;140;142;144;146;148;150;152;154;156;158;160;162;164;166;168;170;172;174;176;178;180;182;184;186;188;190;192;194;196;198;200;202;204 ;206;208;210;212;214;216;218;220;222;224;226;228;230;232;234;236;238;240;242;244;246;248;250;252;254;256;258;260;262;264;266;268;270;272;274;276;278;280;282;284;286;288;290;292;294;296;298;300;302;304;306;308;3 10;312;314;316;318;320;322;324;326;328;330;332;334;336;338;340;342;344;346;348;350 and / or 352) and at least approximately 70-99.9% (e.g., at least 70, 72, 74, 75, 76, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5 or 99).Refers to a polypeptide comprising an amino acid sequence that is identical or similar to 9%); for example, see Table A; the comparison is performed by the BLAST algorithm, and the parameters of the algorithm are selected to give the maximum match between the respective sequences over the entire length of the respective reference sequences (for example, expectation threshold: 10; word size: 3; maximum match in query range: 0; BLOSUM 62 matrix; gap cost: existence 11, extension 1; conditional composition score matrix adjustment).

[0096] Furthermore, variants of the polypeptide include immunogloblin chains specifically described herein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, eculizumab, tesidolumab or mubodina V H , V L , HC or LC or its CDR), etc.; provided that it may include a polypeptide having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) mutations, such as one or more missense mutations (e.g., conservative substitutions), nonsense mutations, deletions, or insertions. For example, the present invention includes an immunoglobulin light chain (or V L ) variant comprising the amino acid sequence set forth in SEQ ID NO: 106 and having one or more such mutations, and / or an immunoglobulin heavy chain (or V H ) variant comprising the amino acid sequence set forth in SEQ ID NO: 98 and having one or more such mutations, specifically for C5 The present invention includes a method using a binding antagonist antigen-binding protein, such as an antibody and its antigen-binding fragment. In one embodiment of the present invention, the antagonist antigen-binding protein that specifically binds to C5 includes CDR-L1, CDR-L2, and CDR-L3, wherein one or more such CDRs (e.g., one, two, or three) are immunoglobulin light chain variants having one or more such mutations (e.g., conservative substitutions), and / or includes CDR-H1, CDR-H2, and CDR-H3, wherein one or more such CDRs (e.g., one, two, or three) are immunoglobulin heavy chain variants having one or more such mutations (e.g., conservative substitutions).

[0097] The following references concern the BLAST algorithm, which is often used in sequence analysis: BLAST ALGORITHMS: Altschul et al. (2005) FEBS J. 272(20): pp. 5101-5109; Altschul, SF et al., (1990) J. Mol. Biol. 215: pp. 403-410; Gish, W. et al., (1993) Nature Genet. 3: pp. 266-272; Madden, TL et al., (1996) Meth. Enzymol. 266: pp. 131-141; Altschul, SF et al., (1997) Nucleic Acids Res. 25: pp. 3389-3402; Zhang, J. et al., (1997) Genome Res. 7: pp. 649-656; Wootton, JC et al., (1993) Comput. Chem. 17: pp. 149-163; Hancock, JM et al., (1994) Comput. Appl. Biosci. 10: pp. 67-70; ALIGNMENT SCORING SYSTEMS: Atlas of Protein Sequence and Structure, (1978) Vol. 5, Supplement No. 3. MO Dayhoff (ed.), pp. 345-352, Dayhoff, MO et al., in Natl. Biomed. Res. Found., Washington, DC, "A model of evolutionary change in proteins."; Atlas of Protein Sequence and Structure, (1978) Vol. 5, Supplement No. 3. MO Dayhoff (ed.), pp. 353-358, Schwartz, RM et al., in Natl. Biomed. Res. Found., Washington, DC, "Matrices for detecting distant relationships."; Altschul, SF, (1991) J. Mol. Biol. 219: pp. 555-565; States, DJ et al., (1991) Methods 3: pp. 66-70; Henikoff, S. et al., (1992) Proc. Natl. Acad. Sci. USA 89: pp. 10915-10919; Altschul, S. et al., (1993) J.Mol. Evol. 36: pp. 290-300; ALIGNMENT STATISTICS: Karlin, S. et al., (1990) Proc. Natl. Acad. Sci. USA 87: pp. 2264-2268; Karlin, S. et al., (1993) Proc. Natl. Acad. Sci. USA 90: pp. 5873-5877; Dembo, A. et al., (1994) Ann. Prob. 22: pp. 2022-2039; and Theoretical and Computational Methods in Genome Research (edited by S. Suhai), (1997) pp. 1-14, Altschul, SF, "Evaluating the statistical significance of multiple distinct local alignments." in Plenum, NY.

[0098] Unless otherwise specified, the following are the names: "H2M11683N"; "H2M11686N"; "H4H12159P"; "H4H12161P"; "H4H12163P"; "H4H12164P"; "H4H12166P"; "H4H12166P2"; "H4H12166P3"; "H4H12166P4"; "H4H12166P5"; "H4H12166P6"; "H4H12166P7"; "H4H12166P8"; "H4H12166P9"; "H4H12166P10"; "H4H12167P"; "H4H121 68P";"H4H12169P";"H4H12170P";"H4H12171P";"H4H12175P";"H4H12176P2";"H4H12 "177P2"; "H4H12183P2"; "H2M11682N"; "H2M11684N"; "H2M11694N" or "H2M11695N" are, respectively, H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H121 66P;H4H12166P2;H4H12166P3;H4H12166P4;H4H12166P5;H4H12166P6;H4H12166P7;H4 H12166P8;H4H12166P9;H4H12166P10;H4H12167P;H4H12168P;H4H12169P;H4H12170P; Immunoglobulin heavy chains or their variable regions (V) containing amino acid sequences specifically described herein, corresponding to H4H12171P;H4H12175P;H4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N; or H2M11695N H)(for example, SEQ ID NOs: 2;18;34;50;66;82;98;138;146;122;146;154;170;186;202;218;234;250;266;274;290;306;322 or 338) (or their variants), as well as / or H2M11683N;H2M11686N;H4H12159P;H4H12161P;H4H12163P;H4H12164P;H4H12166P;H4H12166P2;H4H12166P3;H4H12166P4;H4H12166P5;H4 Immunoglobulin light chains or their variable regions (V) containing amino acid sequences specifically described herein, corresponding to H12166P6;H4H12166P7;H4H12166P8;H4H12166P9;H4H12166P10;H4H12167P;H4H12168P;H4H12169P;H4H12170P;H4H12171P;H4H12175P;H4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N or H2M11695N L ) (for example, SEQ ID NOs: 10;26;42;58;74;90;106;114;130;162;178;194;210;226;242;258;282;298;314;330 or 346) (or its variants) and / or its CDR (CDR-H1 (or its variants), CDR-H2 (or its variants) and CDR-H3 (or its variants)) heavy chain or V H , and / or light chains or V containing the CDR (CDR-L1 (or its variants), CDR-L2 (or its variants), and CDR-L3 (or its variants)) L This refers to an antagonist antigen-binding protein that specifically binds to C5, for example, an antibody that specifically binds to C5 (e.g., human C5) and its antigen-binding fragment (including a multispecific antigen-binding protein) -- or see International Patent Application Publication WO2017 / 218515. In one embodiment of the present invention, V HIt is linked to a constant heavy chain domain such as the human constant heavy chain domain (e.g., IgG, IgG1 or IgG4 (e.g., IgG4 (S228P mutant, Eu-nuvaring))) and / or V L This is linked to a constant light chain domain (e.g., lambda or kappa), such as a human constant light chain domain. In one embodiment of the present invention, the heavy chain constant domain is IgG4 having the S108P mutation.

[0099] In one embodiment of the present invention, the antagonist antigen-binding protein H2M11683N, which specifically binds to C5, includes an HCVR containing the amino acid sequence described in SEQ ID NO: 2 and an LCVR containing the amino acid sequence described in SEQ ID NO: 10 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0100] In one embodiment of the present invention, the antagonist antigen-binding protein H2M11686N, which specifically binds to C5, includes HCVR containing the amino acid sequence described in SEQ ID NO: 18, and LCVR containing the amino acid sequence described in SEQ ID NO: 26 (for example, antigen-binding tan A protein is an antibody or its antigen-binding fragment.

[0101] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12159P, which specifically binds to C5, includes an HCVR containing the amino acid sequence described in SEQ ID NO: 34 and an LCVR containing the amino acid sequence described in SEQ ID NO: 42 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0102] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12161P, which specifically binds to C5, includes an HCVR containing the amino acid sequence described in SEQ ID NO: 50 and an LCVR containing the amino acid sequence described in SEQ ID NO: 58 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0103] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12163P, which specifically binds to C5, includes an HCVR containing the amino acid sequence described in SEQ ID NO: 66 and an LCVR containing the amino acid sequence described in SEQ ID NO: 74 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0104] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12164P, which specifically binds to C5, includes an HCVR containing the amino acid sequence described in SEQ ID NO: 82 and an LCVR containing the amino acid sequence described in SEQ ID NO: 90 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0105] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12166P, which specifically binds to C5, includes an HCVR containing the amino acid sequence described in SEQ ID NO: 98 and an LCVR containing the amino acid sequence described in SEQ ID NO: 106 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0106] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12166P2, which specifically binds to C5, includes an HCVR containing the amino acid sequence described in SEQ ID NO: 98 and an LCVR containing the amino acid sequence described in SEQ ID NO: 114 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0107] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12166P3, which specifically binds to C5, includes an HCVR containing the amino acid sequence described in SEQ ID NO: 122 and an LCVR containing the amino acid sequence described in SEQ ID NO: 106 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0108] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12166P4, which specifically binds to C5, includes an HCVR containing the amino acid sequence described in SEQ ID NO: 98 and an LCVR containing the amino acid sequence described in SEQ ID NO: 130 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0109] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12166P5, which specifically binds to C5, includes an HCVR containing the amino acid sequence described in SEQ ID NO: 138 and an LCVR containing the amino acid sequence described in SEQ ID NO: 106 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0110] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12166P6, which specifically binds to C5, includes HCVR containing the amino acid sequence described in SEQ ID NO: 146, and LCVR containing the amino acid sequence described in SEQ ID NO: 106 (for example, antigen binding A synthetic protein is an antibody or its antigen-binding fragment.

[0111] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12166P7, which specifically binds to C5, includes an HCVR containing the amino acid sequence described in SEQ ID NO: 122 and an LCVR containing the amino acid sequence described in SEQ ID NO: 130 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0112] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12166P8, which specifically binds to C5, includes an HCVR containing the amino acid sequence described in SEQ ID NO: 146 and an LCVR containing the amino acid sequence described in SEQ ID NO: 114 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0113] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12166P9, which specifically binds to C5, includes an HCVR containing the amino acid sequence described in SEQ ID NO: 146, and an LCVR containing the amino acid sequence described in SEQ ID NO: 130 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0114] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12166P10, which specifically binds to C5, includes an HCVR containing the amino acid sequence described in SEQ ID NO: 138 and an LCVR containing the amino acid sequence described in SEQ ID NO: 130 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0115] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12167P, which specifically binds to C5, includes an HCVR containing the amino acid sequence described in SEQ ID NO: 154 and an LCVR containing the amino acid sequence described in SEQ ID NO: 162 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0116] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12168P, which specifically binds to C5, includes an HCVR containing the amino acid sequence described in SEQ ID NO: 170 and an LCVR containing the amino acid sequence described in SEQ ID NO: 178 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0117] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12169P, which specifically binds to C5, includes an HCVR containing the amino acid sequence described in SEQ ID NO: 186 and an LCVR containing the amino acid sequence described in SEQ ID NO: 194 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0118] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12170P, which specifically binds to C5, includes an HCVR containing the amino acid sequence described in SEQ ID NO: 202 and an LCVR containing the amino acid sequence described in SEQ ID NO: 210 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0119] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12171P, which specifically binds to C5, includes an HCVR containing the amino acid sequence described in SEQ ID NO: 218, and an LCVR containing the amino acid sequence described in SEQ ID NO: 226 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0120] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12175P, which specifically binds to C5, includes HCVR containing the amino acid sequence described in SEQ ID NO: 234, and LCVR containing the amino acid sequence described in SEQ ID NO: 242 (for example, antigen binding Proteins are antibodies or their antigen-binding fragments.

[0121] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12176P2, which specifically binds to C5, includes an HCVR containing the amino acid sequence described in SEQ ID NO: 250, and an LCVR containing the amino acid sequence described in SEQ ID NO: 258 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0122] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12177P2, which specifically binds to C5, includes an HCVR containing the amino acid sequence described in SEQ ID NO: 266, and an LCVR containing the amino acid sequence described in SEQ ID NO: 258 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0123] In one embodiment of the present invention, the antagonist antigen-binding protein H4H12183P2, which specifically binds to C5, includes an HCVR containing the amino acid sequence described in SEQ ID NO: 274 and an LCVR containing the amino acid sequence described in SEQ ID NO: 282 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0124] In one embodiment of the present invention, the antagonist antigen-binding protein H2M11682N, which specifically binds to C5, includes HCVR containing the amino acid sequence described in SEQ ID NO: 290 and LCVR containing the amino acid sequence described in SEQ ID NO: 298 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0125] In one embodiment of the present invention, the antagonist antigen-binding protein H2M11684N, which specifically binds to C5, includes HCVR containing the amino acid sequence described in SEQ ID NO: 306 and LCVR containing the amino acid sequence described in SEQ ID NO: 314 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0126] In one embodiment of the present invention, the antagonist antigen-binding protein H2M11694N, which specifically binds to C5, includes HCVR containing the amino acid sequence described in SEQ ID NO: 322 and LCVR containing the amino acid sequence described in SEQ ID NO: 330 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0127] In one embodiment of the present invention, the antagonist antigen-binding protein H2M11695N, which specifically binds to C5, includes HCVR containing the amino acid sequence described in SEQ ID NO: 338 and LCVR containing the amino acid sequence described in SEQ ID NO: 346 (for example, the antigen-binding protein is an antibody or its antigen-binding fragment).

[0128] Therefore, the present invention relates to heavy chain and / or light chain constant domains, for example, the V described herein which are linked to the heavy chain and / or light chain constant domains as described above.H and V L Variable domains (e.g., V linked to the constant region of human IgG quadruplex) H , and V linked to the constant region of the human kappa light chain L Antigen-binding proteins containing ) (e.g., H2M11683N;H2M11686N;H4H12159P;H4H12161P;H4H12163P;H4H12164P;H4H12166P;H4H12166P2;H4H12166P3;H4H12166P4;H4H12166P5;H4H12166P6;H4H12166P7;H4H12166P8;H4H12166P9;H4 H12166P10;H4H12167P;H4H12168P;H4H12169P;H4H12170P;H4H12171P;H4H12175P;H4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N;H2M11695N;Includes ravulizumab, eculizumab, tesidolumab, or mubodina).

[0129] When used herein, the term "antibody" refers to an immunoglobulin molecule comprising four polypeptide chains interconnected by disulfide bonds (e.g., IgG4), two heavy chains (HC) containing three H-CDRs, and two light chains (LC) containing three L-CDRs—e.g., H2M11683N;H2M11686N;H4H12159P;H4H12161P;H4H12163P;H4H12164P;H4H12166P;H4H12166P2;H4H12166P3;H4H12166P4;H4H12166P5;H4H12166P6;H4H12166P7;H4H12166P8;H4H1216 This refers to 6P9;H4H12166P10;H4H12167P;H4H12168P;H4H12169P;H4H12170P;H4H12171P;H4H12175P;H4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N;or H2M11695N. In one embodiment of the present invention, the assignment of amino acids to each CDR domain within the immunoglobulin chain follows the definitions in Sequences of Proteins of Immunological Interest, Kabat et al.; National Institutes of Health, Bethesda, Md.; 5th edition; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32: pp. 1-75; Kabat et al., (1977) J. Biol. Chem. 252: pp. 6609-6616; Chothia et al., (1987) J Mol. Biol. 196: pp. 901-917 or Chothia et al., (1989) Nature 342: pp. 878-883. Therefore, the present invention follows the definitions in V H and V L V comprises an amino acid sequence (or variant thereof) described herein, and CDR is defined by Kabat and / or Chothia. H CDR and V L It contains antibodies and antigen-binding fragments that include CDRs.

[0130] The terms “antigen-binding portion” or “antigen-binding fragment” of an antibody or antigen-binding protein, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically modified polypeptide or glycoprotein that specifically binds an antigen (e.g., C5), but does not include the entire sequence of an antibody. Non-limiting examples of antigen-binding fragments include: (i) F(ab) and F(ab') fragments; (ii) F(ab')2 fragment; (iii) Fd fragment (heavy chain portion of Fab fragment cleaved with papain); (iv) Fv fragment (V H or V L (v) single-chain Fv(scFv) molecules; examples include FR3-CDR3-FR4 peptides having amino acid residues that mimic the hypervariable region of an antibody (e.g., isolated complementarity-determining regions (CDRs) such as the CDR3 peptide). Other modified molecules such as single-domain antibodies, domain deletion antibodies, mini-bodies, and small modular immunotherapy drugs (SMIPs) are also included within the expression “antigen-binding fragment” as used herein. In one embodiment, the antigen-binding fragments are H2M11683N;H2M11686N;H4H12159P;H4H12161P;H4H12163P;H4H12164P;H4H12166P;H4H12166P2;H4H12166P3;H4H12166P4;H4H12166P5;H4H12166P6;H4H12166P7;H4H12166P8;H4H12166P9;H4H12166P10;H4H12167 Includes three or more CDRs of the following types: P;H4H12168P;H4H12169P;H4H12170P;H4H12171P;H4H12175P;H4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N; or H2M11695N (e.g., CDR-H1, CDR-H2 and CDR-H3; and / or CDR-L1, CDR-L2 and CDR-L3).

[0131] The term “recombinant” antigen-binding protein, such as an antibody or its antigen-binding fragment, refers to a protein created, expressed, isolated, or obtained by techniques or methods known in the art, such as recombinant DNA technologies including DNA splicing and transgenic expression. This refers to molecules such as [specific molecules]. The term includes antibodies expressed in non-human mammals (including transgenic non-human mammals, e.g., transgenic mice), or in host cells (e.g., Chinese hamster ovary (CHO) cells) or cell expression systems, or antibodies isolated from recombinant combinatorial human antibody libraries. The present invention refers to recombinant antigen-binding proteins described herein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H121 This includes methods using 66P8;H4H12166P9;H4H12166P10;H4H12167P;H4H12168P;H4H12169P;H4H12170P;H4H12171P;H4H12175P;H4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N;or H2M11695N).

[0132] The present invention includes methods using monoclonal antagonist antigen-binding proteins (e.g., antibodies and their antigen-binding fragments) that specifically bind to C5. The terms “monoclonal antibody” or “mAb,” as used herein, refer to antibodies derived from a substantially homogeneous population of antibodies; that is, antibody molecules comprising such population have identical amino acid sequences except for naturally occurring mutations that may be present in small amounts. The modifying phrase “monoclonal” should not be construed as requiring the production of antibodies by any particular method. Monoclonal antibodies can be produced by the hybridoma method described in Kohler et al. (1975) Nature 256:495, or by the recombinant DNA method (see, for example, U.S. Patent No. 4,816,567).

[0133] "Isolated" antagonist antigen-binding proteins (e.g., antibodies or their antigen-binding fragments), polypeptides, polynucleotides, and vectors that specifically bind to C5 are at least partially freed from other biomolecules derived from the system, cells, or cell culture in which they are produced. Such biomolecules include nucleic acids, proteins, other antibodies or antigen-binding fragments, lipids, carbohydrates, or other substances such as cell debris and growth media. Isolated antigen-binding proteins may also be at least partially freed from the growth medium in which the host cells expressing the antigen-binding protein grow. In general, the term "isolated" is not limited to the complete absence of such biomolecules (e.g., small or trace amounts of impurities may remain), nor is it limited to the absence of water, buffers, or salts, or components of a pharmaceutical formulation containing antigen-binding proteins (e.g., antibodies or antigen-binding fragments).

[0134] The "anti-C5" antigen-binding protein specifically binds to C5 (e.g., human C5 or cynomolgus monkey C5). The term "specifically binds" means that, as measured by real-time, label-free biolayer interference assays, e.g., Octet® HTX biosensor, or surface plasmon resonance, e.g., BIACORE®, or solution affinity ELISA, it binds at least approximately 10 times. -9 M or less (lower numbers) (for example, about 10 -10 M, about 10 -11 M or about 10 -12 M)'s K D This refers to antigen-binding proteins (e.g., mAbs) that have binding affinity to the antigen at 25°C, expressed as follows. In one embodiment of the present invention, K is used to express the binding affinity to human C5 at 25°C and pH 7.4 by surface plasmon resonance assay. D The ratio is approximately 189 pM; K for binding to human C5 (R885C or R885H) D The concentration is approximately 400-500 pM; K is the concentration of the binding to C5 in cynomolgus monkeys. D The molecular weight is approximately 2-3 nM. In one embodiment of the present invention, human C5 (including the signal sequence) comprises the amino acid sequence described in SEQ ID NO: 362; mature human C5 containing mutant R885H comprises the amino acid sequence described in SEQ ID NO: 363.

[0135] dosage The present invention includes a method for treating or preventing C5-related disease in a subject and / or improving at least one sign or symptom associated with such C5-related disease by administering an antagonist antigen-binding protein (e.g., REGN3918) that specifically binds to C5 to the subject as follows: (i) administer approximately 30 mg / kg (body weight (BW)) intravenously (IV) once or multiple times (e.g., once); then (ii) administer approximately 800 mg of antigen-binding protein once or multiple times (e.g., two or more times) subcutaneously (e.g., subcutaneously (SC)) (this is referred to herein as the 30+800 dose regimen), or administer one or multiple times via SC according to body weight as follows: for body weight (BW) < 10 kg: approximately 125 mg; for BW ≥ 10 kg and < 20 kg: approximately 200 mg; for BW ≥ 20 kg and < 40 kg: approximately 350 mg; for BW ≥ 40 kg and < 60 kg: approximately 500 mg; and for BW ≥ 60 kg: approximately 800 mg. Such SC doses(s) are given on a weekly basis after the initial IV dose(s). Weekly administration can be continued indefinitely, for example, as long as a therapeutic effect or prevention of undesirable outcomes (e.g., loss of serum albumin or increased serum LDH levels) is desired. In some cases, the patient may receive one or more doses of an oligonucleotide (e.g., semdisilane) in combination with an antigen-binding protein.

[0136] In one embodiment of the present invention, an antagonist antigen-binding protein that specifically binds to C5 (e.g., pozelimube) is administered to a patient in the manner described herein (for example, to treat or prevent PNH or CHAPLE), provided that no other agents that reduce complement activity (e.g., reduce C5 activity), such as oligonucleotides like semudisilane (e.g., that reduce C5 expression), or antibodies or antigen-binding fragments thereof that specifically bind to C5 are administered to the patient.

[0137] The present invention also includes a method for treating or preventing C5-related diseases (e.g., PNH or CHAPLE) by administering approximately 30 mg / kg (body weight (BW)) of an antagonist antigen-binding protein (e.g., REGN3918) or a pharmaceutical formulation thereof intravenously (IV) once or more times (e.g., once or more times). Intravenous administration of 30 mg / kg has been demonstrated to rapidly achieve the steady-state trough concentration of the antigen-binding protein (e.g., antibody) required for sustained maximum CH50 inhibition, and therefore helps to produce a therapeutic effect in the subject. Further subcutaneous administration of an optional antigen-binding protein may be given to the subject, for example, weekly, or after the IV administration(s).

[0138] In one embodiment of the present invention, a subject (e.g., suffering from PNH) is administered: (i) approximately 30 mg / kg of an antagonist antigen-binding protein that specifically binds to C5 intravenously (IV) first (on day 1); then (ii) approximately 800 mg of the antigen-binding protein once a week (e.g., on days +1, +2, or +3), for example, on about day 8 (e.g., on day +1, +2, or +3), on day 15 (e.g., on day +1, +2, or +3), on day 22 (e.g., on day +1, +2, or +3), and thereafter weekly (e.g., on days +1, +2, or +3) (e.g., subcutaneously (SC)).

[0139] The present invention applies to H2M11683N;H2M11686N;H4H12159P;H4H12161P;H4H12163P;H4H12164P;H4H12166P;H4H12166P2;H4H12166P3;H4H12166P4;H4H12166P5;H4H12166P6;H4H12166P7;H4H12166P8;H4H Selected from 12166P9;H4H12166P10;H4H12167P;H4H12168P;H4H12169P;H4H12170P;H4H12171P;H4H12175P;H4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N;and H2M11695N A method for treating or preventing CHAPLE disease in a subject includes the step of administering an antagonist antigen-binding protein that specifically binds to C5, or a therapeutically effective dose (e.g., 30 mg / kg intravenously) of the pharmaceutical formulation thereof. In one embodiment of the present invention, the subject (e.g., suffering from CHAPLE) is: (i) Approximately 30 mg / kg of antigen-binding protein is administered intravenously (IV) on day 1; then (ii) Starting around day 8 (for example, day 8, day 8+1, day 8+2, or day 8+3), administered subcutaneously (SC) once or multiple times, and then continued on a weekly basis with a dose according to body weight (BW) as follows: • For body weight (BW) < 10kg: approximately 125mg; For body weight ≥ 10 kg and < 20 kg: approximately 200 mg; • For body weight ≥ 20 kg and < 40 kg: approximately 350 mg; • For BW ≥ 40 kg and < 60 kg: approximately 500 mg; and For BW ≥ 60kg: Approximately 800mg.

[0140] Once-weekly administration, or weekly administration, or QW administration refers to administration one or more times (each dose occurring approximately 7 days (e.g., +1, +2, or +3) days after the previous dose).

[0141] In one embodiment of the present invention, the IV and the first SC dose are administered on the same day.

[0142] In one embodiment of the present invention, the antagonist antigen-binding protein that specifically binds to C5 is delivered subcutaneously (SC) in volumes of less than 7 ml, approximately 0.625 ml, approximately 1 ml, approximately 1.75 ml, approximately 2.5 ml, approximately 4 ml, approximately 0.5 to 4.0 ml, or approximately 0.625 to 4.0 ml. In one embodiment of the present invention, each SC administration is delivered by a single injection. In one embodiment of the present invention, the SC injection is delivered in approximately 60 seconds or less.

[0143] In one embodiment of the present invention, a subject (for example, suffering from a C5-related disease) is administered an antagonist antigen-binding protein that specifically binds to C5 in one or more doses as follows: 1 mg / kg IV; 3 mg / kg IV; 300 mg SC; 800 mg SC; 10 mg / kg IV; 600 mg SC; or 30 mg / kg IV; or a loading dose of 15 mg / kg IV followed by one or more doses of SC administered once a week.

[0144] Serum concentrations of approximately 100 mg / liter of an antagonist antigen-binding protein (e.g., REGN3918) that specifically binds to C5 in human subjects maximally suppress C5 activity (e.g., surrogate, classical, and lectin pathways) (e.g., when measured by AH50 and / or CH50 assays). Therefore, the present invention relates to a method for inhibiting complement activity or C5 activity (e.g., alternative pathway (AP)) in a subject (e.g., inhibiting C5 activity to approximately its maximum level (e.g., at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%); for example, as measured as AH50 and / or CH50 activity), the method comprising the step of administering an antigen-binding protein in sufficient levels once or more to maintain a serum concentration of anti-C5 antigen-binding protein at about 100 mg / liter or higher (e.g., 150, 400, 600, or 700 mg / liter). In one embodiment of the present invention, the administration regimen comprises the steps of (i) administering approximately 30 mg / kg (body weight (BW)) of antigen-binding protein intravenously (IV) once or multiple times (e.g., once); and then, optionally, (ii) A procedure in which approximately 800 mg of antigen-binding protein is administered once or multiple times per week (e.g., twice or more times) (e.g., subcutaneously (SC)); or The medication is administered subcutaneously (SC) one or more times per week, depending on body weight (BW), as follows: approximately 125 mg for BW < 10 kg; approximately 200 mg for BW ≥ 10 kg and < 20 kg; approximately 350 mg for BW ≥ 20 kg and < 40 kg; approximately 500 mg for BW ≥ 40 kg and < 60 kg; or approximately 800 mg for BW ≥ 60 kg. Weekly administration can be continued indefinitely, for example, as long as maintenance of serum levels of anti-C5 antigen-binding protein and / or suppression of C5 activity is desired.

[0145] The present invention relates to a method for achieving, or achieving and maintaining, a serum concentration (e.g., steady-state serum trough concentration over time) of an antagonist antigen-binding protein of approximately 100 mg / liter or more that specifically binds to C5 in a subject, comprising: (i) administering approximately 30 mg / kg (body weight (BW)) of antigen-binding protein intravenously (IV) once or multiple times (e.g., once); and then, optionally, (ii) A step of administering approximately 800 mg of antigen-binding protein once or more times per week (e.g., two or more times) (e.g., subcutaneously (SC)); or the method comprising one or more weekly administrations administered subcutaneously (SC) according to body weight (BW), as follows: for body weight (BW) < 10 kg: approximately 125 mg; for BW ≥ 10 kg and < 20 kg: approximately 200 mg; for BW ≥ 20 kg and < 40 kg: approximately 350 mg; for BW ≥ 40 kg and < 60 kg: approximately 500 mg; or for BW ≥ 60 kg: approximately 800 mg. Weekly administration can be continued indefinitely, for example, as long as maintenance of anti-C5 antigen-binding protein serum concentration is desired.

[0146] The present invention further includes treatment regimens comprising administration of eculizumab or ravulizumab: H2M11683N;H2M11686N;H4H12159P;H4H12161P;H4H12163P;H4H12164P;H4H12166P;H4H12166P2;H4H12166P3;H4H12166P4;H4H12166P5;H4H12166P6;H4H12166P7;H4H12166P8;H4H12166P9;H4H12166P10;H4H12167P;H4H12168P;H4H12169P;H4H12170P;H4H12 A method for switching a subject to a therapeutic regimen comprising the administration of an antagonist antigen-binding protein that specifically binds to C5, selected from 171P;H4H12175P;H4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N; and H2M11695N; the method comprising the step of administering the antigen-binding protein as an initial dose to the subject and discontinuing further administration of eculizumab or ravulizumab when the next dose is scheduled to be an eculizumab or ravulizumab therapeutic regimen. In one embodiment of the present invention, the initial dose of the antigen-binding protein is approximately 30 mg / kg (body weight (BW)) intravenously (IV), and optionally one or more further IV doses are administered thereafter. In one embodiment of the present invention, after IV administration (or multiple administrations), the subject receives approximately 800 mg of antigen-binding protein subcutaneously once or multiple times weekly (e.g., two or more times); or subcutaneously once or multiple times weekly depending on body weight (BW), as follows: for BW < 10 kg: approximately 125 mg; for BW ≥ 10 kg and < 20 kg: approximately 200 mg; for BW ≥ 20 kg and < 40 kg: approximately 350 mg; for BW ≥ 40 kg and < 60 kg: approximately 500 mg; or for BW ≥ 60 kg: approximately 800 mg. In one embodiment of the present invention, such a switching method eliminates overlap between the eculizumab or ravulizumab administration regimen and the administration regimen of an antagonist antigen-binding protein that specifically binds to C5.

[0147] In one embodiment of the present invention, intravenous infusion of an antagonist antigen-binding protein that specifically binds to C5 is performed when the subject experiences symptoms such as: cough, chills, rash, itching, urticaria (hives, welts, wheals), diaphoresis (sweating), hypotension, dyspnea (shortness of breath), and vomiting. If one or more adverse events, such as flushing, occur, the treatment will be interrupted and resumed at 50% of the initial infusion rate.

[0148] The term "C5-related disease" refers to a disease, disorder, condition or syndrome, or a disease, disorder, condition or syndrome, whose signs and / or symptoms are caused, maintained or exacerbated, directly or indirectly by complement system activity, which can be reduced, stabilized or eliminated by inhibition of C5 activity. Such C5 activity can be inhibited, for example, by preventing the cleavage of C5 precursors into C5a and C5b chains, the formation of membrane invasion complexes (MACs), and / or the binding of MACs to the surface of target cells (e.g., erythrocytes). In one embodiment of the present invention, C5 activity inhibition is inhibition measured by a CH50 assay.

[0149] CH50 (50% Hemolytic Complement) is an assay for determining the level of the classical complement pathway, and is sensitive to reductions, deficiencies, and / or inactivation of any component of the pathway known in the art. CH50 tests the functional ability of serum complement components of the classical pathway to lyse, for example, sheep erythrocytes (SRBCs) pre-coated with rabbit anti-sheep erythrocyte antibody (hemolysin). For example, when antibody-coated SRBCs are incubated with the test serum, the classical complement pathway is activated, and hemolysis occurs. If the complement component is deficient, the CH50 level will be zero; if one or more components of the classical pathway are reduced, CH50 will decrease. A fixed volume of optimally sensitized SRBCs is added to each serum dilution. For example, after incubation, the mixture is centrifuged and the degree of hemolysis is quantified by measuring the absorbance of hemoglobin released into the supernatant at 540 nm. The amount of complement activity is determined by examining the ability of various dilutions of the test serum to dissolve antibody-coated SRBCs. See Costabile, Measuring the 50% hemolytic complement (CH50) activity of serum, J Vis Exp. 2010(37):1923; and E.A. 2 Kabat and M.M. Mayer (eds.), Experimental immunochemistry. Thomas, Springfield, III. Mayer, Complement and complement fixation, pp. 133-240. AH50 is a similar test that measures alternative pathway function. See, for example, E. Kabat and M.M. Mayer (eds.), Experimental immunochemistry. C.C. Thomas, Springfield, III. Mayer, Complement and complement fixation, pp. 133-240; and Rapp and Borsos. Molecular basis of complement action. Appton Century Crofts, New See York, NY 1970. The test to evaluate the functional activity of the alternative pathway (AH50) uses guinea pig, rabbit, or chicken erythrocytes as target cells. AP has weak hemolytic activity against sheep erythrocytes. Here, activation of the classical pathway is achieved by chelating EGTA 2. + It must be blocked by adding Mg2 + An optimal concentration is required. Detection of low or absent hemolytic activity in CH50 and / or AH50 indicates further complement analysis. See, for example, Joiner et al., 1983. See "A study of optimal reaction conditions for an assay of the human alternative complement pathway." Am. J. Clin. Pathol. 79: pp. 65-72.

[0150] A therapeutically effective amount of an antagonist antigen-binding protein that specifically binds to C5 may, for example, lead to a decrease or maintenance of complement activity in relation to C5-related diseases, thereby causing regression or stabilization of one or more signs or symptoms of such diseases or disorders. This is the amount that causes elimination, reversing, stabilizing, or eliminating an undesirable disease or disorder (e.g., C5-related disease) to any clinically measurable extent. The drug regimens described herein are examples of therapeutically effective doses of antagonist antigen-binding proteins.

[0151] The terms “to treat” or “to cure” refer to therapeutic means that, for example with respect to C5-related disorders, reverse, stabilize or eliminate an undesirable disorder or disorder (e.g., C5-related disorders such as PNH, MG, aHUS, or CHAPLE) to any clinically measurable degree by causing, for example, a decrease or maintenance of complement activity, thereby resulting in regression, stabilization, or elimination of one or more signs or symptoms of such disorder or disorder.

[0152] Symptoms are subjective evidence of a disease, disorder, condition, or syndrome. Signs are objective evidence of a disease, disorder, condition, or syndrome. For example, blood flowing from the nostrils is a sign insofar as it is obvious to the patient, the doctor, and others. Anxiety, back pain, and fatigue are symptoms insofar as only the patient can perceive them.

[0153] The term "subject" refers to mammals such as humans, mice, goats, rabbits, rats, dogs, non-human primates, or monkeys. In one embodiment of the present invention, the amino acid arginine 885 is mutated in the subject's C5 (e.g., human C5) to another amino acid, e.g., R885H or R885C. In one embodiment of the present invention, the subject has previously taken an antagonist antigen-binding protein that specifically binds to C5, in addition to the one currently being administered. For example, the subject has previously taken ravulizumab or eculizumab.

[0154] C5-related diseases include, for example: ·Adult respiratory distress syndrome • Age-related macular degeneration (AMD) ·allergy Alport syndrome Alzheimer's disease Amyotrophic lateral sclerosis (ALS) • Antiphospholipid syndrome (APS) ·asthma • Atherosclerosis ·Atypical hemolytic uremic syndrome (aHUS) ·Autoimmune diseases ·Autoimmune hemolytic anemia (AIHA) • Balloon angiogenesis • Bronchoconstriction Bullous pemphigoid ·burn C3 glomerulosis ·Capillary leak syndrome • Cardiovascular disorders • Fulminant antiphospholipid syndrome (CAPS) • Cerebrovascular disorders • CHAPLE's disease (CD55 deficiency with complement hyperactivation, vascular thrombosis, and protein-losing enteropathy) ·Chemical damage ·Chronic obstructive pulmonary disease (COPD) ·Cold agglutinin disease (CAD) • Corneal and / or retinal tissue Crohn's disease Degos disease Dense deposit disease (DDD) ·Dermatomyositis ·Diabetes ·Diabetic vasculopathy ·Diabetic macular edema (DME) ·Diabetic nephropathy ·Diabetic retinopathy • Dilated cardiomyopathy • Impairment of inappropriate or undesirable complement activation ·Difficulty breathing • Eclampsia • Emphysema ·Epidermolysis bullosa • Epilepsy Fibroplastic pneumoconiosis ·frostbite • Geographic atrophy (GA) • Glomerulonephritis Glomerulosis Goodpasture syndrome Graves' disease Guillain-Barré syndrome Hashimoto's thyroiditis ·Hemodialysis complications • Hemolysis, elevated liver enzymes, thrombocytopenia (HELLP) syndrome ·Hemolytic anemia • Hemoptysis • Henoch-Schönlein purpura nephritis Hereditary angioedema • Hyperacute allograft rejection ·Hypersensitivity pneumonitis • Idiopathic thrombocytopenic purpura (ITP) IgA nephropathy • Immune complex disorder ·Immune complex vasculitis • Immune complex-associated inflammation ·Infectious disease • Inflammation caused by autoimmune disease • Inflammatory disorders • Hereditary CD59 deficiency • Damage caused by inert dust and / or inorganic materials Interleukin-2 induction toxicity during IL-2 therapy • Ischemia-reperfusion injury Kawasaki disease • Lung disease or disorder • Lupus nephritis • Membranoproliferative glomerulonephritis • Membranoproliferative glomerulonephritis • Mesenteric artery reperfusion after aortic reconstruction • Mesenteric / intestinal circulatory disorders • Multifocal motor neuropathy (MMN) Multiple sclerosis ·Myasthenia gravis Myocardial infarction Myocarditis • Neurological disorders • Neuromyelitis optica ·obesity ·Intraocular neovascularization • Intraocular neovascularization affecting the choroid • Organic pneumoconiosis Parasitic diseases Parkinson's disease • Paroxysmal nocturnal hemoglobinuria (PNH), for example, active PNH ·Microimmune vasculitis ·Pemphigus • Percutaneous transcatheter coronary angioplasty (PTCA) • Peripheral (e.g., musculoskeletal) vascular disorders ·pneumonia • Post-ischemia reperfusion state • Post-pump syndrome in cardiopulmonary bypass surgery • Post-pump syndrome in renal bypass surgery • Preeclampsia ·Progressive renal failure • Proliferative glomerulonephritis • Proteinuria (kidney disease) ·psoriasis • Pulmonary embolism • Pulmonary fibrosis ·Pulmonary infarction ·Pulmonary vasculitis • Recurrent miscarriage • Renal impairment ·renal ischemia • Renal ischemia-reperfusion injury • Renal vascular disorders • Restenosis after stent placement • Rheumatoid arthritis (RA) Rotational atherosclerosis Schizophrenia ·Sepsis • Septic shock ·SLE nephritis • Smoke damage • Spinal cord injury • Spontaneous miscarriage ·stroke • Systemic inflammatory response to sepsis • Systemic lupus erythematosus (SLE) • Systemic lupus erythematosus-associated vasculitis ·Takayasu disease • Burns Thrombotic thrombocytopenic purpura (TTP) Traumatic brain injury ·Type I diabetes ·Typical hemolytic uremic syndrome (tHUS) Uveitis ·Vasculitis • Vasculitis associated with rheumatoid arthritis • Venous gas embolism (VGE); or • Rejection of xenobiotic grafts

[0155] Therefore, the present invention relates to a method for treating or preventing C5-related disease (e.g., PNH or aHUS) in a subject that requires it (e.g., a human), for example, a subject suffering from C5-related disease, wherein the antagonist antigen-binding protein specifically binds to C5 (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P The method includes the step of administering 7;H4H12166P8;H4H12166P9;H4H12166P10;H4H12167P;H4H12168P;H4H12169P;H4H12170P;H4H12171P;H4H12175P;H4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N;H2M11695N;ravulizumab or eculizumab) to a subject in combination with an additional therapeutic agent (e.g., cemdisiran) as appropriate, according to the dosing regimen described herein. Furthermore, the present invention provides a method for reducing the need for therapeutic interventions required to address the various signs and symptoms of C5-related disorders such as PNH or CHAPLE.

[0156] Paroxysmal nocturnal hemoglobinuria (PNH) is caused by pluripotent hematopoietic stem cells (HSCs) that acquire mutations in the phosphatidylinositol glycan anchor biosynthesis class A (PIGA) gene. The PIGA gene product is required for the biosynthesis of glycophosphatidylinositol (GPI) anchors, which are glycolipid portions that attach dozens of proteins to the cell membrane. As a result, all PNH stem cells and their offspring have reduced or absent GPI-anchored proteins. Mature blood cells derived from hematopoietic clones may have complete (type III) or partial (type II) GPI-binding proteins (Hillmen et al., Effect of eculizumab on hemolysis and Transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med 2004;350(6):552-559). Two proteins affected by the absence of GPI anchors are the complement regulatory proteins CD55 and CD59. CD55 regulates complement activation by inhibiting complement component 3 (C3) convertase, while CD59 inhibits the assembly of membrane invasion complex (MAC) C5b-C9 by interacting with C8 and C9 (Brodsky, How I Treat paroxysmal nocturnal hemoglobinuria. Blood 2009;113(26):6522~7). Due to their deficiency, PNH red blood cells are more susceptible to complement-mediated intravascular hemolysis. This intravascular hemolysis in PNH patients causes anemia (often requiring blood transfusions) and hemoglobinuria. Complications of PNH include thrombosis, abdominal pain, dysphagia, erectile dysfunction, and pulmonary hypertension (Hillmen et al., The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2006;355(12):1233~43). Thromboembolism is a common cause of mortality in PNH patients. Potential mechanisms of thromboembolism include platelet activation, free hemoglobin toxicity, nitric oxide depletion, deficiency of other GPI-binding proteins, and endothelial cell dysfunction (Hill et al., Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 2013;121(25):4985~96). PNH is often complicated by autoimmune aplastic anemia (Luzzatto and Risitano, Advances in understanding the pathogenesis of acquired aplastic anaemia. Br J Haematol 2018;182(6):758-76). The present invention includes a method for reducing the need for blood transfusions to address anemia secondary to hemolysis caused by PNH, reducing the need for erythropoietin, iron supplements and / or folic acid, reducing the incidence of anemia, reducing the incidence of hemoglobinuria, or reducing the incidence of hemolysis in subjects with PNH, by targeting an antagonist antigen-binding protein that specifically binds to C5, such as REGN3918, using the administration regimen described herein.

[0157] The diagnosis of PNH can be established using the internationally accepted definition of the presence of PNH granulocyte clone size >10% as measured in peripheral blood by flow cytometry. The accepted definition of “active disease” (active PNH) is the presence within three months of one or more of the following PNH-related signs or symptoms: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia (hemoglobin <10 g / dL), a history of major adverse vascular events (MAVE; including thrombosis), dysphagia, or erectile dysfunction. Alternatively, activity can be established by a history of RBC transfusion within three months due to PNH. Methods for treating active PNH are also included within the scope of this invention.

[0158] CHAPLE disease (CD55 deficiency with complement hyperactivation, vasotoxic thrombosis, and protein-losing enteropathy) is an autosomal recessive disorder caused by loss-of-function mutations in the CD55 gene (also known as pro-disintegration factor, DAF). Signs and symptoms of CHAPLE include hypoproteinemia (low serum levels of albumin and immunoglobulins; hypoproteinemia leads to facial and limb edema as well as recurrent infections), malabsorption syndrome (chronic diarrhea, stunted growth, anemia, and micronutrient deficiencies), complement hyperactivation, intestinal lymphangiectasia (IL), and intestinal inflammation; and / or increased susceptibility to visceral thrombosis. CHAPLE disease is caused by biallelic loss-of-function mutations in the CD55 gene. Clinically, CHAPLE disease presents as a familial form of protein-losing enteropathy (PLE) caused by primary intestinal lymphangiectasia (PIL) or Waldmann's disease, often severe and potentially fatal systemic symptoms. CD55 is a glycophosphatidylinositol (GPI)-anchored membrane protein that inhibits the enzymatic activity of C3b and C4b, thus preventing the formation of C3 and C5 convertases, which ultimately lead to the assembly of the membrane invasion complex (C5b-C9). Therefore, a lack of CD55 leads to overactivation of the complement system, resulting in the production of various complement products, including anaphylatoxins and the membrane invasion complex. When CD55 is absent due to somatic mutations in the PIGA gene (required for GPI anchor biosynthesis) in hematopoietic stem cells, CD55 loss and CD59 loss become specific to hematopoietic cells (CD59 is another GPI-binding complement regulatory protein). Typically, the resulting complement-mediated lysis of red blood cells and platelets leads to intravascular hemolysis and thrombosis in PNH. In CHAPLE, a single germline deletion of CD55 expression in any tissue causes PLE as primary intestinal lymphangiectasia. It appears in the tube. Generally, unlike PNH, hemolysis is not observed in CHAPLE patients. The present invention includes methods for reducing the need for administration of corticosteroids, immunoglobulins, albumin, biological agents (e.g., antibodies or antigen-binding fragments such as anti-TNF alfa or vedolizumab), immunomodulators (e.g., azathioprine or mesalazine), micronutrients, enteral or parenteral supplementation, anticoagulants (e.g., low molecular weight heparin), antibiotics and / or antiplatelet agents (e.g., aspirin such as low-dose aspirin) in subjects suffering from CHAPLE by targeting an antagonist antigen-binding protein that specifically binds to C5, such as REGN3918, by the administration regimens described herein. See Kurolap et al., Loss of CD55 in Eculizumab-Responsive Protein-Losing Enteropathy. N Engl J Med 2017;377(1):pp. 87-89; and Ozen et al., CD55 Deficiency and Protein-Losing Enteropathy. N Engl J Med 2017b;377(15):pp. 1499-500.

[0159] CD55 mutations associated with CHAPLE disease include, for example, 149-150delAA; 149-150 in CCTT; 109delC; 800G>C; 287-1G>C; 149-150delAAinsCCTT; (As stated in WO2018 / 053039) Alternatively, CD55 mutations resulting in the same mutant amino acid sequence may be cited. Therefore, the present invention includes a method for treating CHAPLE disease characterized by one or more such mutations. In one embodiment of the present invention, human CD55 comprises the amino acid sequence described in SEQ ID NO: 364; mutation Glu50Alafs *Human CD55 containing 12 contains the amino acid sequence (residues 101-200) described in SEQ ID NO: 365; mutant Gly37Alafs * Human CD55 containing 24 contains the amino acid sequence (residues 1-100) described in SEQ ID NO: 366; human CD55 containing mutant Cys267Ser contains the amino acid sequence (residues 201-300) described in SEQ ID NO: 367 (see International Patent Application Publication WO2018 / 053039).

[0160] The diagnosis of CHAPLE can be made by genetic analysis to identify CD55 loss-of-function mutations. The diagnosis can be confirmed by flow cytometry or Western blotting of peripheral blood cells to identify a reduced presence of CD55. Active CHAPLE disease, in one embodiment of the present invention, is characterized by hypoalbuminemia of ≤3.2 g / dL and one or more of the following signs or symptoms that may be attributable to CHAPLE: diarrhea, vomiting, abdominal pain, peripheral or facial edema, or an episode of infection complicated with hypogammaglobulinemia, or a new thromboembolic event. The normal range for serum albumin is typically about 3.5–5.5 g / dL.

[0161] Atypical hemolytic uremic syndrome (aHUS) is a rare disorder characterized by low levels of circulating red blood cells due to destruction (hemolytic anemia), low platelet count due to platelet consumption (thrombocytopenia), and a condition known as uremia, in which the kidneys are unable to process waste products from the blood and excrete them in the urine (acute renal failure). Most aHUS is caused by complement system abnormalities that impair normal regulatory mechanisms. The activation event therefore leads to unsuppressed, progressive complement activity and widespread endothelial damage. Signs and symptoms of aHUS include, for example, malaise, fatigue, irritability, and somnolence, as well as anemia, thrombocytopenia, acute renal failure, hypertension, and organ dysfunction.

[0162] Antiphospholipid syndrome (APS) is an autoimmune disease characterized by arterial and venous thrombosis caused by antiphospholipid antibodies. When the disorder occurs in the absence of another autoimmune disease, it is called primary APS. Secondary APS occurs in association with other autoimmune disorders such as systemic lupus erythematosus. Fulminant APS (CAPS) is a rare, lethal form of APS in which widespread intravascular thrombosis leads to multi-organ ischemia and failure.

[0163] Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease that causes a decrease in skeletal muscles involved in breathing and movement, including the limbs.

[0164] Typical hemolytic uremic syndrome (tHUS) can occur secondary to gastrointestinal infections caused by Shiga toxin-producing Escherichia coli (STEC). Typical HUS (STEC-HUS; Shiga toxin-producing Escherichia coli (STEC)-hemolytic uremic syndrome (HUS)) is induced when the known potent cytotoxin, Shiga toxin (or Shiga-like toxin), binds to the cell membrane glycolipid Gb3 (via domain B). Domain A is internalized, subsequently halting protein synthesis and inducing apoptosis in affected cells. Shiga toxin has several further effects on endothelial cells, one of which is increased expression of functional tissue factor, which can contribute to microvascular thrombosis. The toxin causes damage or activation of endothelium, erythrocytes, and platelets.

[0165] The present invention relates to a method for administering an antagonist antigen-binding protein (e.g., REGN3918) that specifically binds to C5, comprising: (i) administering approximately 30 mg / kg (body weight (BW)) of the antigen-binding protein (e.g., REGN3918) intravenously (IV) once or more times (e.g., once); and optionally, (ii) administering approximately 800 mg of the antigen-binding protein once or more times (e.g., two or more times) subcutaneously (SC). Such SC administrations are given on a weekly basis after the initial IV administration. The present invention also provides a method for administering an antigen-binding protein (e.g., REGN3918) to a subject, comprising the steps of (i) administering approximately 30 mg / kg (body weight (BW)) of the antigen-binding protein intravenously (IV) once or more times (e.g., once); and optionally (ii) administering one or more SC doses according to body weight as follows: for body weight (BW) < 10 kg: approximately 125 mg; for BW ≥ 10 kg and < 20 kg: approximately 200 mg; for BW ≥ 20 kg and < 40 kg: approximately 350 mg; for BW ≥ 40 kg and < 60 kg: approximately 500 mg; and for BW ≥ 60 kg: approximately 800 mg. Such SC doses(optional) are given on a weekly basis after the initial IV dose(optional). Optionally, the subject is administered one or more times an oligonucleotide (e.g., semdisilane) in conjunction with the antigen-binding protein. In one embodiment of the present invention, the subject suffers from a C5-related disease such as chaple, pneumoconiosis, aHUS, or myelopathy.

[0166] Diagnostic methods The present invention includes methods for treating or preventing C5-related disorders such as PNH. PNH is, for example: (i) Flow cytometry analysis of peripheral blood; (ii) Serum lactate dehydrogenase (LDH) level ≥ 2 × upper limit of normal (ULN); and / or (iii) PNH granulocytes (represented as polymorphic nuclei [PMN]) > 10% Diagnosis is made in the subject based on the following criteria.

[0167] Flow cytometry analysis of peripheral blood is a means for laboratory detection of PNH. Flow cytometry immunophenotyping uses fluorescently labeled monoclonal antibodies or FLAER (fluorescein-labeled proaerolysin) to analyze granulocytes, monocytes, and erythrocytes. This is done to detect the presence or absence of GPI-binding proteins. FLAER is a fluorescently labeled variant of an aerolidine that directly binds to the GPI anchor and can be used to assess GPI binding expression. Individuals with PNH have reduced or absent expression of CD14 in monocytes, CD16 in neutrophils and NK cells, CD24 in neutrophils, CD59 in erythrocytes, and FLAER in neutrophils and monocytes.

[0168] Proaerolysin is a 52 kDa protein secreted by Aeromonas hydrophylla. After proteolytic nicking at the C-terminus, an active aerolysin is produced that binds to cell surface structures, multimerizes, and forms channels that lead to cell lysis (Howard and Buckley, Activation of the hole-forming toxin aerolysin by extracellular processing. J. Bacteriol. 1985;163:336-340). Aerolysin did not lyse PNH cells, and it was shown that the toxin binds to the GPI portion of the GPI-binding structure (Diep et al., Glycosyl-phosphatidylinositol anchors of membrane glycoproteins are binding determinants for the channel-forming toxin aerolysin. J. Biol. Chem. 1998;273:2355~2360, p. 25; Brodsky et al., Resistance of paroxysmal nocturnal hemoglobinuria cells to the glycosylphosphatidylinositol-binding toxin aerolysin. Blood 1999;93:1749~1756). Initially, this reagent was used to enrich rare GPI-negative PNH clones. Subsequently, a non-lysogenic mutant proaerolysin with a fluorescent dye conjugation (Alexa 488) (FLAER) was generated, retaining specificity for the GPI-binding structure without causing cell lysis.

[0169] PNH is characterized by chronic, uncontrolled terminal complement activation and hemolysis. Uncontrolled complement activation leads to erythrocyte (RBC) hemolysis, platelet activation, and subsequent thromboembolism (TE), renal and other organ dysfunction, pain, severe fatigue, poor quality of life, and premature death. An indicator of cytolysis is the presence of abnormally high levels of lactate dehydrogenase (LDH) in the serum. Serum LDH levels ≥1.5 or 2.0 × upper limit of normal (LDH ≥ 1.5 ×; LDH ≥ 2.0 ×) are markers of uncontrolled complement activation used in multinational PNH clinical trials. Normal serum levels of LDH can vary depending on the institution and the method used for measurement; however, normal levels in children are approximately 60–170 U / L, and in adults approximately 100–190 U / L. Other reports indicate a normal adult LDH range of 140–280 U / L. In one embodiment of the present invention, a normal female LDH ULN is 330 U / L, and a male LDH ULN is 281 U / L. Receiving one or more red blood cell transfusions, for example, within the last three months, is also an indicator of PNH.

[0170] Large populations of GPI-AP (glycosylphosphatidylinositol-anchored protein)-deficient PMNs (polymorphonuclear cells) are also an indicator of PNH. Flow cytometry is a means of determining the presence of such PMNs.

[0171] Signs and symptoms of PNH include fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia (hemoglobin <10 g / dL), a history of major adverse vascular events (MAVE; including thrombosis), dysphagia, or erectile dysfunction.

[0172] CHAPLE disease can be diagnosed based on a genotype characterized, for example, by biallelelic CD55 loss-of-function mutations and persistent protein-losing enteropathy (PLE). In one embodiment of the present invention, active CHAPLE disease is characterized by: hypoalbuminemia of ≤3.2 g / dL; Furthermore, it is identified in patients who, within the past six months and who exhibit at least one of the following symptoms or signs for at least seven days (not necessarily consecutively) that may be attributable to CD55-deficient PLE: diarrhea, vomiting, abdominal pain, peripheral or facial edema, or an episode of infection complicated with hypogammaglobulinemia, or a new thromboembolic event. Other features that may underpin the diagnosis of CHAPLE disease include, for example, primary enteric lymphangiectasia or Bartmann's disease, growth retardation, anemia, vitamin or micronutrient deficiencies, GI mucosal ulcers, lymphocyte infiltration into GI mucosa, recurrent lung infections, hypothyroidism, arthritis, arthralgia, or clubbing of the fingers. See, for example, Ozen et al., CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis, New England J. of Med. 377(1):52-61 (2017).

[0173] The present invention relates to a method for treating or preventing C5-related diseases (e.g., PNH) in a subject, (i) Evaluating the subject for the presence of signs and / or symptoms of the disease, and if one or more such signs and / or symptoms are identified (e.g., as discussed herein), diagnosing the subject with the disease; Furthermore (ii) The step of administering an antagonist antigen-binding protein that specifically binds to C5 (e.g., an antibody or its antigen-binding fragment; e.g., REGN3918) to a subject according to the administration regimen of the present invention—for example, the method comprising (i) administering about 30 mg / kg (body weight (BW)) of antigen-binding protein intravenously (IV) once or more times (e.g., once); and optionally (ii) administering about 800 mg of antigen-binding protein subcutaneously (SC) once or more times (e.g., two or more times). In one embodiment of the present invention, SC administration is given on a weekly basis. In one embodiment of the present invention, the signs and symptoms include LDH levels ≥ 1.5 or 2 × ULN; type III PNH granulocytes > 10%; and / or signs and symptoms of active PNH disease.

[0174] The present invention relates to a method for treating or preventing C5-related diseases (e.g., CHAPLE) in a subject, (i) Evaluating the subject for the presence of the signs and / or symptoms of the disease, e.g., CHAPLE, and diagnosing the subject with the disease if one or more such signs and / or symptoms are identified (e.g., as discussed herein); Furthermore (ii) The method comprises the steps of (ii) administering approximately 30 mg / kg (body weight (BW)) of an antagonist antigen-binding protein that specifically binds to C5 intravenously (IV) in one or more doses (e.g., one dose); and then (ii) administering SC in one or more doses according to body weight, such as: for body weight (BW) < 10 kg: approximately 125 mg; for BW ≥ 10 kg and < 20 kg: approximately 200 mg; for BW ≥ 20 kg and < 40 kg: approximately 350 mg; for BW ≥ 40 kg and < 60 kg: approximately 500 mg; and for BW ≥ 60 kg: approximately 800 mg. In one embodiment of the present invention, the SC administration is given on a weekly basis. In one embodiment of the present invention, such signs and symptoms include loss-of-function mutations in the CD55 gene, flow cytometry or Western blotting of peripheral blood cells to identify a decrease in the presence of CD55, hypoalbuminemia of ≤3.2 g / dL, and / or: one or more of the following: diarrhea, vomiting, abdominal pain, peripheral edema or facial edema, or an episode of infection complicated with hypogammaglobulinemia, or a new thromboembolic event.

[0175] Pharmaceutical preparations and compositions The present invention relates to an antagonist antigen-binding protein that specifically binds to C5 (e.g., H2M11683N; H2M11686N; H4H1215) according to the administration regimen of the present invention. 9P;H4H12161P;H4H12163P;H4H12164P;H4H12166P;H4H12166P2;H4H12166P3;H4H12166P4;H4H12166P5;H4H12166P6;H4H12166 P7;H4H12166P8;H4H12166P9;H4H12166P10;H4H12167P;H4H12168P;H4H12169P;H4H12170P;H4H12171P;H4H12175P;H4H12176P A method for treating or preventing C5-related disease is provided, comprising the step of administering 2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N;H2M11695N;ravulizumab, eculizumab, tesidorumab or mubodina) (for example, (i) administering approximately 30 mg / kg (body weight (BW)) of antigen-binding protein once or more intravenously (IV); then, optionally, (ii) approximately 800 mg Administer mg of SC weekly in one or more doses; or administer SC weekly in one or more doses according to body weight as follows: for body weight (BW) < 10 kg: approximately 125 mg; for BW ≥ 10 kg and < 20 kg: approximately 200 mg; for BW ≥ 20 kg and < 40 kg: approximately 350 mg; for BW ≥ 40 kg and < 60 kg: approximately 500 mg; and for BW ≥ 60 kg: approximately 800 mg; optionally in combination with one or more additional therapeutic agents (e.g., oligonucleotides such as semdisilane). In one embodiment of the present invention, the antagonist antigen-binding protein that specifically binds to C5 to be administered to the subject is contained in a pharmaceutical formulation comprising a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier comprises one or more excipients. In one embodiment of the present invention, the pharmaceutical formulation is aqueous, i.e., contains water. In one embodiment of the present invention, the pharmaceutical formulation contains approximately 200 mg / ml of antagonist antigen-binding protein that specifically binds to C5.

[0176] Pharmaceutical formulations containing an antagonist antigen-binding protein that specifically binds to C5 (e.g., REGN3918) are prepared by mixing the antigen-binding protein with one or more excipients (e.g., Hardman et al. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel See Dekker, NY; Lieberman et al. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, NY.

[0177] In one embodiment of the present invention, a further therapeutic agent is, for example, an oligonucleotide (e.g., double-stranded DNA or RNA or both) that binds to DNA or mRNA encoding C5 and inhibits C5 expression. In one embodiment of the present invention, the oligonucleotide is up to about 23, about 19-22, about 19-23 or about 19, about 20, about 21, about 22 or about 23 nucleotides long (e.g., a 19-23 nucleotide RNA molecule). In one embodiment of the present invention, the oligonucleotide is single-stranded (e.g., antisense-oriented) or double-stranded. A double-stranded oligonucleotide includes a sense-oriented strand and an antisense-oriented strand. In one embodiment of the present invention, a double-stranded oligonucleotide (e.g., RNA) has, for example, 3' overhangs and / or 5' overhangs of at least two nucleotides. In one embodiment of the present invention, the oligonucleotide is naked, and in another embodiment So, the oligonucleotides are chemically modified.

[0178] In one embodiment of the present invention, a further therapeutic agent is an oligonucleotide that is an RNAi agent that binds to the RNA or a portion thereof encoding C5. An RNAi agent refers to a drug that contains RNA and mediates targeted cleavage of RNA transcripts via the RNA-induced silencing complex (RISC) pathway. RNAi directs sequence-specific degradation of mRNA through a process known as RNA interference. RNAi modulates, for example, inhibits, the expression of C5 in cells, such as cells within a target, such as a mammalian target.

[0179] In one embodiment of the present invention, the RNAi agent comprises a single-stranded RNA that interacts with a target RNA sequence, such as a C5 target mRNA sequence, to direct the cleavage of the target RNA. While we do not wish to be bound by theory, it is thought that long double-stranded RNA introduced into cells is degraded into short interfering RNA (siRNA) by a type III endonuclease known as Dicer (Sharp et al. (2001) Genes Dev. 15:485). Dicer, a ribonuclease III-like enzyme, processes dsRNA into 19-23 base pair short interfering RNA (siRNA) with a characteristic 2-base 3' overhang (Bernstein et al., (2001) Nature 409:363). The siRNA is then incorporated into an RNA-induced silencing complex (RISC), where one or more helicases unwind the siRNA double-strand, allowing a complementary antisense strand to induce target recognition (Nykanen et al., (2001) Cell 107:309). Upon binding to a suitable target mRNA, one or more endonucleases within the RISC complex cleave the target, inducing silencing (Elbashir et al., (2001) Genes Dev. 15:188). Therefore, in one aspect, the present invention relates to single-stranded RNA (siRNA) generated in cells that promotes the formation of the RISC complex, resulting in the silencing of a target gene, namely the C5 gene. Accordingly, the term “siRNA” is also used herein to refer to the RNAi described herein.

[0180] In another embodiment, the RNAi agent may be a single-stranded siRNA that is introduced into a cell or organism to inhibit a target mRNA. In one embodiment of the present invention, the single-stranded RNAi agent binds to the RISC endonuclease, Argonaut 2, which then cleaves the target mRNA. The single-stranded siRNA in one embodiment of the present invention is 15 to 30 nucleotides and is chemically modified. Design and testing of single-stranded siRNA are described in U.S. Patent No. 8,101,348 and Lima et al., (2012) Cell 150:883-894, the entire contents of which are thereby incorporated herein by reference. Any of the antisense nucleotide sequences described herein may be used as single-stranded siRNA as described herein, or in a form chemically modified by the method described in Lima et al., (2012) Cell 150:883-894.

[0181] In one embodiment of the present invention, oligonucleotides (e.g., RNAi) are replaced by other molecules, such as sugars, such as N-acetylgalactosamine (GalNAc) derivatives, for example. [ka] It is conjugated to.

[0182] In one embodiment of the present invention, an oligonucleotide (e.g., RNAi) is conjugated to another molecule shown in the schematic diagram below: [ka] (In the equation, X is either O or S).

[0183] In one embodiment of the present invention, the further therapeutic agent is cemdisilane. In one embodiment of the present invention, the further therapeutic agent is an antisense chain nucleotide sequence: It is a double-stranded RNA containing 5'-UAUUAUAAAAAUAUCUUGCUUUU-3' (SEQ ID NO: 370); and / or sense strand is a nucleotide sequence: Includes 5'-AAGCAAGAUAUUUUUAUAAUA-3' (SEQ ID NO: 371).

[0184] In one embodiment of the present invention, a further therapeutic agent is a double-stranded ribonucleic acid (dsRNA) agent that inhibits the expression of complement component C5, wherein the dsRNA agent comprises a sense strand and an antisense strand, and the sense strand is: Includes 5'-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3' (SEQ ID NO: 372) The antisense chain is: Includes 5'-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3' (SEQ ID NO: 373), a, g, c, and u are 2'-O-methyl(2'-OMe)A, G, C, and U, respectively; Af, Gf, Cf, and Uf are 2'-fluoroA, G, C, and U, respectively; dT is a deoxythymine nucleotide; and s is a phosphorothioate bond; and the sense strand has a ligand at its 3' end: [ka] It is conjugated to. See U.S. Patent No. 9,249,415.

[0185] In one embodiment of the present invention, RNAi is present in a pharmaceutical formulation containing lipid nanoparticles (LNPs). LNPs are vesicles containing a lipid layer that encapsulates pharmaceutically active molecules such as RNAi. LNPs are described, for example, in U.S. Patents 6,858,225, 6,815,432, 8,158,601, and 8,058,069, the entire contents of which are thereby incorporated herein by reference.

[0186] In one embodiment of the present invention, further therapeutic agents include acetaminophen, albumin (e.g., in infusion form), Anklod, angiotensin-converting enzyme inhibitors, antibiotics (e.g., oral antibiotics), further antibodies, anti-CD20 agents, rituximab, anticoagulants, antifungal agents, antihypertensive agents, anti-inflammatory agents, anti-plasmin-α1, anticonvulsants, antithrombotic agents, anti-TNF-α agents, antiviral agents, argatroban, aspirin, biological therapeutic agents, bivalirudin, C3 inhibitors, corticosteroids, cyclosporine A, dabigatran, defibrotide, E-aminocaproic acid, enteral nutrition, erythromycin, erythropoietin, fibrinolytic agents, folic acid, fondaparinux, heparin, hormone replacement therapy, ibuprofen, hydraparinax, immunosuppressants, infliximab, hydroxymethylglutaryl-CoA reductase inhibitors, iron supplements, repirudin, lipid-lowering agents, magnesium sulfate, meningococcal vaccine (e.g., These include serotypes A, C, Y, W, and B), methotrexate, nonsteroidal anti-inflammatory drugs (NSAIDs), oligonucleotides, paracetamol, parenteral nutrition, penicillin, phenindione, contraceptives, prostacyclin, rituximab, thrombin inhibitors, vaccines, vincristine, vitamins, and / or warfarin.

[0187] The term "in association with" indicates, for example, that a component of a composition containing (1) an antagonist antigen-binding protein that specifically binds to C5 and a pharmaceutically acceptable carrier component, and (2) one or more further therapeutic agents, e.g., semdisilane, is formulated, for example, into a single composition for co-delivery, or into two or more compositions separately (e.g., a kit containing each component, e.g., the further therapeutic agents are in separate formulations). The component administered in association with the other is administered to the subject simultaneously or at a different time than when the other component is administered; for example, each administration is given simultaneously (e.g., together in a single composition or during the same administration session, essentially simultaneously), or non-simultaneously at one or more intervals over a period of time. Furthermore, the separate component administered in association with the other is administered to the subject by the same or a different route.

[0188] C5 oligonucleotide dosage The present invention relates to a method for treating or preventing C5-related disorders in a subject, comprising the steps of: (i) administering an antagonist antigen-binding protein (e.g., REGN3918) that specifically binds to C5, for example, (i) administering approximately 30 mg / kg (body weight (BW)) of the antigen-binding protein intravenously (IV) once or multiple times; then, optionally, (ii) administering approximately 800 mg of the antigen-binding protein weekly in one or multiple doses via SC; or, as follows, once or multiple times according to body weight The method provides the following steps: administering SC weekly: approximately 125 mg for body weight (BW) < 10 kg; approximately 200 mg for BW ≥ 10 kg and < 20 kg; approximately 350 mg for BW ≥ 20 kg and < 40 kg; approximately 500 mg for BW ≥ 40 kg and < 60 kg; and approximately 800 mg for BW ≥ 60 kg; and optionally, administering a therapeutically effective amount of an oligonucleotide that binds to a polynucleotide encoding C5 and inhibits the expression of C5 (C5 oligonucleotide).

[0189] The therapeutically effective dose of dsRNA, RNAi, or other oligonucleotides that bind to the polynucleotide encoding C5 and inhibit C5 expression would, in one embodiment of the present invention, range from about 0.001 to about 200.0 milligrams per kilogram of body weight per day, generally ranging from about 1 to 50 mg per kilogram of body weight per day. For example, dsRNA may be administered in single doses of about 0.01 mg / kg, about 0.05 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 3 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, or about 50 mg / kg.

[0190] In one embodiment of the present invention, C5 dsRNA is present in concentrations of approximately 0.1 to 20 mg / kg, approximately 0.1 to 30 mg / kg, approximately 0.1 to 40 mg / kg, approximately 0.1 to 45 mg / kg, approximately 0.1 to 50 mg / kg, approximately 0.25 to 20 mg / kg, approximately 0.25 to 30 mg / kg, approximately 0.25 to 40 mg / kg, approximately 0.25 to 45 mg / kg, approximately 0.25 to 50 mg / kg, approximately 0.5 to 20 mg / kg, approximately 0.5 to 30 mg / kg, and approximately 0.5 to 40 mg / kg. g, about 0.5 to about 45 mg / kg, about 0.5 to about 50 mg / kg, about 0.75 to about 20 mg / kg, about 0.75 to about 30 mg / kg, about 0.75 to about 40 mg / kg, about 0.75 to about 45 mg / kg, about 0.75 to about Approximately 50mg / kg, approximately 1 to approximately 20mg / mg, approximately 1 to approximately 30mg / mg, approximately 1 to approximately 40mg / mg, approximately 1 to approximately 45mg / mg, approximately 1 to approximately 50mg / mg, approximately 1.5 to approximately 20mg / kb, approximately 1.5 to approximately 30mg / kb , about 1.5 to about 40 mg / kb, about 1.5 to about 45 mg / kb, about 1.5 to about 50 mg / kb, about 10 to about 20 mg / kg, about 10 to about 30 mg / kg, about 10 to about 40 mg / kg, about 10 to about 45 mg / kg, about 10 to about 50 mg / kg, about 15 to about 20 mg / kg, about 15 to about 30 mg / kg, about 15 to about 40 mg / kg, about 15 to about 45 mg / kg, about 15 to about 50 mg / kg, about 2 to about 20 mg / kg, about 2 to about 30 mg / kg, about 2 to about 40 mg / kg, about 2 to about 45 mg / kg, about 2 to about 50 mg / kg kg, about 2.5 to about 20 mg / kg, about 2.5 to about 30 mg / kg, about 2.5 to about 40 mg / kg, about 2.5 to about 45 mg / kg, about 2.5 to about 50 mg / kg, about 20 to about 30 mg / kg, about 20 to about 40 mg / kg, about 20 to about 45 mg / kg, about 20 ~50mg / kg, 25~30mg / kg, 25~40mg / kg, 25~45mg / kg, 25~50mg / kg, 3~20mg / kg, 3~30mg / kg, 3~40mg / kg, 3~45mg / kg, 3~50 mg / kg, about 3.5 to about 20 mg / kg, about 3.5 to about 30 mg / kg, about 3.5 to about 40 mg / kg, about 3.5 to about 45 mg / kg, about 3.5 to about 50 mg / kg, about 30 to about 40 mg / kg, about 30 to about 45 mg / kg, about 30 to about 50 mg / kg, About 35 to about 40 mg / kg, about 35 to about 45 mg / kg, about 35 to about 50 mg / kg, about 4 to about 20 mg / kg, about 4 to about 30 mg / kg, about 4 to about 40 mg / kg, about 4 to about 45 mg / kg, about 4 to about 50 mg / kg, about 4.5 to about 20 mg / kg, about 4. It is administered in doses of approximately 5-30 mg / kg, approximately 4.5-40 mg / kg, approximately 4.5-45 mg / kg, approximately 4.5-50 mg / kg, approximately 40-45 mg / kg, approximately 40-50 mg / kg, approximately 45-50 mg / kg, approximately 5-20 mg / kg, approximately 5-30 mg / kg, approximately 5-40 mg / kg, approximately 5-45 mg / kg, approximately 5-50 mg / kg, approximately 7.5-20 mg / kg, approximately 7.5-30 mg / kg, approximately 7.5-40 mg / kg, approximately 7.5-45 mg / kg, and approximately 7.5-50 mg / kg. Intermediate values ​​and ranges of the listed values ​​are also intended to be part of the present invention.In one embodiment, dsRNA is administered at a dose of approximately 10 mg / kg to approximately 30 mg / kg.

[0191] For example, C5 dsRNA or RNAi or other oligonucleotides are administered subcutaneously or intravenously in amounts of approximately 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.125, 0.15, 0.175, 0.2, 0.225, 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, 0.975, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5. 1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5 It is administered in doses (or repeated doses) of 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg / kg. Multiple-dose regimens are administered daily, for example, for 2, 3, 4, 5, 6, 7 days, or so. The regimen may include the administration of therapeutic doses of C5 dsRNA or RNAi or other oligonucleotides. The repeated-dose regimen may include regular, for example, every other day, every two days, every three days, twice a week, once a week, every other week, or every month, administration of therapeutic doses of C5 dsRNA or RNAi or other oligonucleotides.

[0192] C5 dsRNA or RNAi or other oligonucleotides are administered, for example, subcutaneously or intravenously, in doses of approximately 600 mg (or repeated doses).

[0193] Pharmaceutical compositions containing oligonucleotides are administered by intravenous infusion over a set period, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, and 21, 22, 23, 24, or approximately 25 minutes. Administration is repeated, for example, regularly, once a week or every two weeks (i.e., every two weeks) for one month, two months, three months, four months, or longer. After the initial treatment regimen, treatment is performed at a reduced frequency. For example, after weekly or bi-weekly administration for three months, administration is repeated once a month for six months or one year, or longer. [Examples]

[0194] These examples are intended to illustrate the present invention and are not intended to limit it. The compositions and methods shown in the examples form part of the invention. [Examples]

[0195] An open-label, single-therapy trial evaluating the efficacy and safety of REGN3918 in patients with paroxysmal nocturnal hemoglobinuria (PNH) who are either previously untreated with complement inhibitors or have not recently received complement inhibitor therapy. This clinical trial was an open-label, single-treatment, 26-week study in patients who were either previously untreated with complement inhibitors or had received treatment with complement inhibitors within the six months prior to their screening visit, had a confirmed diagnosis of PNH, and presented with active signs and symptoms.

[0196] This clinical trial had two cohorts: a dose-finding cohort (Cohort A) and a dose-expansion cohort (Cohort B). Dose-finding consisting of 30 mg / kg of REGN3918 (IV) followed by weekly dose expansion of 800 mg was performed in an interim analysis. Inclusion and exclusion criteria and event schedules were identical for Cohort A and Cohort B. Recruitment for the trial continued during the evaluation period of data obtained from Cohort A. Patients received a single loading dose of REGN3918, 30 mg / kg intravenously (IV), on day 1, followed by weekly doses (QW; ±1 day) subcutaneously (SC) at doses of 800 mg or less until week 26.

[0197] The primary objective of this trial was to demonstrate that REGN3918 reduces intravascular hemolysis in patients with active PNH who were either previously untreated with complement inhibitor therapy or had not recently received such therapy. The secondary objectives of this trial were to evaluate the safety and tolerability of REGN3918; to evaluate the effect of REGN3918 on parameters of intravascular hemolysis; to evaluate the total serum concentration of REGN3918; to evaluate the incidence of anti-drug antibodies against REGN3918 that developed under treatment; and to evaluate the effect of REGN3918 on patient-reported outcomes (PROs) measuring fatigue and health-related quality of life.

[0198] Clinical trial period The patient's clinical trial period was approximately 27 weeks, excluding the screening period. The trial consisted of a screening period (up to 4 weeks), a 26-week treatment period, and a 1-week period from the last administration of the investigational drug. The trial consisted of a final visit one week later. After the completion of the 26-week treatment period, patients were eligible to enroll in another open-label extension trial offering non-intermittent treatment with REGN3918. Patients who discontinued treatment had a minimum follow-up period of 21 weeks.

[0199] Clinical trial population Approximately 30–42 adult men and women participated. The study population consisted of adult men and women diagnosed with PNH, exhibiting active signs and symptoms, who were either new to complement inhibitors or had previously received complement inhibitor treatment but not within the six months prior to their screening visit.

[0200] Inclusion Criteria To be eligible for enrollment in this clinical trial, patients must meet the following criteria: 1. Male or female who is 18 years of age or older or of adulthood (whichever is higher) at the time of screening; 2. Diagnosis of PNH confirmed by high-sensitivity flow cytometry; 3. At the time of screening, PNH granulocytes (represented as polymorphonuclear nuclei [PMN]) account for more than 10%; 4. An active disease defined by the presence of one or more PNH-related signs or symptoms (e.g., fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin < 10 g / dL], a history of MAVE (major adverse vascular events) [including thrombosis], dysphagia, or erectile dysfunction), or a history of RBC infusion due to PNH within three months of screening; 5. At the time of screening visit, LDH level 2 × ULN or higher (upper limit of normal); 6. Having the willingness and ability to visit the clinic and comply with clinical trial-related procedures; 7. Provide informed consent signed by the clinical trial patient; and 8. Can understand and complete clinical trial-related questionnaires completely.

[0201] Exclusion criteria Patients who met any of the following criteria were excluded from the clinical trial: 1. The patient had received prior treatment with a complement inhibitor within the six months prior to the screening visit, or, at any time, was refractory to complement inhibitor therapy in the opinion of the principal investigator (excluding eculizumab-refractory patients due to the C5 variant R885H / C); 2. Bone marrow transplant history; 3. Weighing less than 40 kilograms at the time of screening visit; 4. Modifications (initiation, discontinuation, or changes in dosage / dosage interval) to the following background concomitant medications, administered as needed during the screening and treatment periods, are planned: erythropoietin, immunosuppressants, corticosteroids, antithrombotic agents, anticoagulants, iron supplements, and folic acid; 5. Peripheral blood neutrophil absolute count (ANC) less than 500 / μL [1.0 × 10⁻¹⁰] 9 [less than / L], or peripheral blood platelet count less than 50,000 / μL; 6. Meningococcal vaccination within three years prior to screening is not documented, and the patient does not intend to receive the vaccination during the clinical trial period; 7. During the screening period, evidence of a history of systemic fungal disease or unresolved tuberculosis, or active or latent tuberculosis infection (LTBI), must be documented. Assessment for active TB and LTBI should follow local practices or guidelines, including those related to risk assessment, and the use of tuberculin skin tests or T-cell interferon-gamma-release assays; 8. Any contraindications to receiving Neisseria meningitidis vaccination or the antibiotic prophylactic therapy recommended in this clinical trial; 9. Any active, persistent infection within two weeks of screening or during the screening period; 10. Recent infection requiring continuous systemic treatment with antibiotics, antiviral drugs, or antifungal drugs within two weeks of screening or during the screening period; 11. Immunization using a live attenuated vaccine one month prior to REGN3918 administration; 12. Hereditary complement deficiency is known; 13. A documented history of active, ongoing systemic autoimmune disease; 14. Patients with a documented history of cirrhosis, or with liver disease unrelated to PNH, where ALT or AST levels exceed 3 × ULN at the time of screening; 15. At the time of screening visit, the estimated glomerular filtration rate (eGFR) was 30 mL / min / 1.73 m². 2 Patients with a value less than (according to the Chronic Renal Disease Epidemiology Collaboration Equation 2009); 16. Recent unstable medical conditions within the past three months prior to the screening visit, excluding PNH and PNH-related complications (e.g., myocardial infarction, congestive heart failure of New York Heart Association class III or higher, severe uncontrolled cardiac arrhythmia, cerebrovascular accident, active gastrointestinal bleeding); 17. The need for major surgery is anticipated during the clinical trial period; 18. Co-occurrence of chronic anemia unrelated to PNH; 19. History of cancer within the past five years, excluding appropriately treated basal cell carcinoma, squamous cell carcinoma, or in situ cervical cancer; 20. Participation in another interventional clinical trial, or use of any experimental therapy within 30 days prior to the screening visit, or within 5 half-lives of the investigational drug, whichever is longer, with the exception of complement inhibitors; 21. Known susceptibility to doxycycline or any component of REGN3918 formulations and pharmaceuticals; 22. A history of serious multiple and / or severe allergies (including latex gloves), or a history of anaphylactic reactions or serious intolerance to prescription or non-prescription drugs; 23. Any clinically significant abnormality identified at screening, such as a major systemic disease, or a patient with a short life expectancy, which, in the judgment of the principal investigator or any co-investigator, would preclude safe termination of the trial or limit endpoint evaluation; 24. The principal investigator or any investigator in charge of the clinical trial, for any reason, for example: • It is deemed that certain protocol requirements, such as scheduled visits, cannot be met. Based on the patient, principal investigator, clinical trial physician, pharmacist, clinical trial coordinator, other clinical trial staff, or other individuals directly involved in the implementation of the protocol, it is determined that the patient cannot tolerate long-term injections. • The existence of any other actual or anticipated conditions (e.g., geographical, social, etc.) that the principal investigator feels would limit or restrict patient participation during the trial; Therefore, it is considered inappropriate for this clinical trial; 25. Pregnant or breastfeeding women, or women who have a positive pregnancy test at the time of their screening visit or on day 1; 26. Patients confined to an institution by order of judicial or administrative authority; 27. Pregnant or breastfeeding women; 28. Pregnant women who are reluctant to practice highly effective contraception before the first dose / before the start of the first treatment, during the clinical trial period, and for at least 21 weeks after the last dose. * As an extremely effective means of contraception: a. Stable use of combination hormonal contraceptives (containing estrogen and progesterone) (oral, vaginal, transdermal), or progesterone-only hormonal contraceptives (oral, injectable, implantable) associated with ovulation inhibition initiated in two or more menstrual cycles prior to screening. b. Intrauterine contraceptive device (IUD); Intrauterine hormone-releasing system (IUS) c. Bilateral tubal ligation d. Vasectomy of the partner e. and / or abstinence †‡ ; * Postmenopausal women must be amenorrhea for at least 12 months to be considered fertile. Pregnancy tests and contraception are not required for women who have been documented to have undergone a hysterectomy or tubal ligation. †Abstinence is considered a highly effective method only if it is defined as refraining from heterosexual intercourse throughout the entire period of the risk associated with the clinical trial treatment. The reliability of abstinence needs to be evaluated in relation to the duration of the clinical trial and the subjects' usual preferred lifestyle. ‡ Regular abstinence (calendar method, symptomatic body temperature method, post-ovulation method), interruption (abortion intercourse), spermicides alone, and lactation-induced amenorrhea (LAM) are not acceptable methods of contraception. The use of both female and male condoms together is prohibited. or 29. Known chronic infection by hepatitis B or C, defined as a test history showing a currently positive status for hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), hepatitis B virus DNA, or hepatitis C virus RNA (HCV RNA).

[0202] endpoint The co-primary endpoint is: • The percentage of patients who achieved adequate control of their intravascular hemolysis, defined as LDH ≤ 1.5 × ULN, at each of the scheduled time points in between, including weeks 4 and 26; and • Percentage of patients who achieved fluid avoidance, defined as no RBC infusions being administered after baseline according to the protocol, throughout 26 weeks. That was the case.

[0203] The secondary endpoint is: The incidence of breakthrough hemolysis occurring over 26 weeks, defined as an LDH measurement of 2 × ULN or higher (at any time) accompanied by associated signs or symptoms, following an initial outcome of disease control (i.e., LDH ≥ 1.5 × ULN); • The percentage of patients who achieve normalization of their intravascular hemolysis, defined as LDH being ≤ 1.0 × ULN, at each of the scheduled time points in between, including weeks 4 and 26; • The time it takes for LDH to first fall below 1.5 × ULN; • Percentage of days during the period including weeks 4 and 26 when LDH was 1.5 × ULN or less; • Change in LDH levels and percentage change (%) from baseline to 26 weeks; • Rate and number of RBC fluid infusions up to 26 weeks; • Changes in RBC hemoglobin levels from baseline to 26 weeks; • Changes in free hemoglobin levels from baseline to 26 weeks; • Change in CH50 and percentage change (%) from baseline to 26 weeks; • Changes in patient-reported outcomes (FACIT-fatigue, European Agency for Research and Treatment of Cancer [EORTC]-QLQ-30, and EQ-5D-3L) from baseline to 26 weeks; • Incidence and severity of adverse events (TEAEs) and other safety variables observed during the 26-week treatment period; • Total serum REGN3918 concentrations assessed throughout the clinical trial; and • Time course of development of anti-drug antibodies against REGN3918 in patients under treatment That was the case.

[0204] Efficacy indicators / procedures Serum lactate dehydrogenase (LDH). Samples for LDH testing were collected upon arrival at the clinic. Serum LDH levels were measured in the central laboratory. LDH was included in the panel (also tested in the central laboratory) on the day of blood chemistry testing. For patients self-administering, if the test was scheduled on a non-clinic visit day, samples could be collected at home by a nurse during a home visit.

[0205] Updating of IV records. Patients were asked to provide the most up-to-date information on their IV history over the past year since screening. During the study period, the rate and number of RBC IVs administered were recorded in the case report form (CRF). During the study period, RBC IVs were administered according to the algorithm described herein. The rate and number of RBC IVs administered were recorded in the CRF. Hemoglobin levels were obtained before and after IV administration (including values ​​obtained in-situ).

[0206] Total hemolytic complement activity. Samples for the CH50 test were collected upon hospital visit. Serum CH50 levels were measured in the central laboratory. For patients self-administering, if the test was scheduled on a non-clinic visit day, samples could be collected at home by a nurse during a home visit.

[0207] Red blood cell hemoglobin. The red blood cell hemoglobin test was performed using a safety hematology panel collected upon hospital visit, and the test was conducted in the central laboratory.

[0208] Free hemoglobin. The free hemoglobin test was performed in the central laboratory using a safety hematology panel collected upon arrival at the hospital.

[0209] Clinical outcome assessment. COAs were patient self-reported. Clinical outcome assessments (COAs) included functional assessment of chronic disease therapy - fatigue (FACIT-fatigue), two health-related quality of life (HRQoL) questionnaires (EORTC Quality of Life Questionnaire-Core 30 [QLQ-C30] and EQ-5D-3L), and Patient Global Impression of Severity (PGIS) / Patient Global Impression of Change (PGIC).

[0210] The FACIT fatigue scale is a 13-item self-report PRO index that assesses the level of fatigue an individual experienced in their usual daily activities during the previous week. This questionnaire is part of the FACIT Measurement System, a set of questionnaires used to measure health-related quality of life in patients with cancer and other chronic diseases. The FACIT fatigue scale uses a 4-point Leicert scale ranging from 0 (not at all) to 4 (very much). Scores range from 0 to 52, with higher scores indicating greater fatigue. While initially developed to assess fatigue in cancer patients, the FACIT fatigue scale has also been used in trials evaluating the efficacy of eculizumab. The FACIT fatigue scale has been validated in patients with PNH. (Brodsky et al., Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment) of patients with paroxysmal nocturnal hemoglobinuria.Blood 2008;111(4):1840-7;Hillmen et al.,The complement inhibitor eculizumab in paroxysmal nocturnal hemogl obinuria.N Engl J Med 2006;355(12):1233- 43.) FACIT fatigue has been validated in patients with PNH (Weitz et al., Cross-sectiional validation study of patient-reported outcomes in patients with parоxysmal nocturnal haemоglobinuria. Intern Med J 2013;43(3):298-307).

[0211] The EORTC QLQ C30 is a 30-item general questionnaire commonly used to assess health-related quality of life (HRQoL) in cancer patients (Stead et al., Development of an EORTC questionnaire module to be used in health-related quality-of-life assessment for patients with multiple myeloma. European Organization for Research and Treatment of Cancer Study Group). on Quality of Life.Br J Haematol 1999;104(3):605-11;Cocks et al.,An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-MY20)in assessing the Quality of life of patients with multiple myeloma. Eur J Cancer 2007;43(11):1670-8). The EORTC QLQ C30 assesses HRQoL across multiple domains, including overall health status, overall quality of life, functioning (physical, occupational, emotional, cognitive, and social functioning), symptom scales (fatigue, nausea, and vomiting, pain, loss of appetite), and single items (dyspnea, insomnia, constipation, diarrhea, sleep, financial impact). EORTC QLQ 30 was initially developed to assess HRQoL in cancer patients, but has been used in trials evaluating the efficacy of eculizumab. The EORTC QLQ has also been validated in patients with PNH (Brodsky et al.). al.,Multicenter phase 3 study of the co. Complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood 2008;111(4):1840-7; Hillmen et al., The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2006;355(12):1233-43. The EORTC QLQ has also been validated in patients with PNH (Weitz et al., Cross-sectional validation study of patient-reported outcomes in patients with paroxysmal nocturnal hemoglobinuria. Intern Med J 2013;43(3):298-307).

[0212] The EQ-5D-3L is a self-administered, standardized health status index consisting of six questions. The EQ-5D-3L descriptive system assesses five aspects of health: mobility, self-care, daily living activities, pain / discomfort, and anxiety / depression. Each aspect is graded based on a three-level scale: no problem, slightly problematic, and very problematic. The EQ Visual Analog Scale component is a vertical visual analog scale used by patients to rate their health.

[0213] Overall impression of the patient's severity / Overall impression of the patient's change. The assessment consists of three self-administered PRO questions that evaluate a patient's perception of the symptoms of the disease and / or the overall severity of specific symptoms of the disease. Upon arrival at the trial, patients were asked to rate the severity of their PNH symptoms on a 6-point Leicert scale ranging from "no PNH symptoms" to "very severe"; the impact of their PNH symptoms on their ability to perform normal daily activities on a 5-point Leicert scale ranging from "no impact at all" to "very impactful"; and their overall fatigue on a 5-point Leicert scale ranging from "no fatigue" to "very fatigued."

[0214] Overall patient perception changes consist of three self-administered PRO questions that assess patients' perceptions of changes in the overall severity of symptoms of the disease and / or specific symptoms of the disease compared to the start of the trial. At key points during the trial period, patients were asked to rate changes in PNH symptoms, their ability to perform their usual daily activities, and overall fatigue compared to before the start of the trial, using a 7-point Leicert scale ranging from "fairly good" to "no change" to "fairly worse."

[0215] The PGIS and PGIC questions were developed for this trial to enable the interpretation of PRO findings and the investigation of response definitions. Responses to the PGIS and PGIC items served as "anchors" to help interpret mean changes in disease-specific PRO indicators over time and to estimate response definitions. This experimental anchor-based approach is the primary FDA-recommended approach for defining response definitions and analyzing PRO outcomes based on response definitions.

[0216] Clinical trial design This was an open-label, single-treatment, 26-week clinical trial in patients diagnosed with PNH who had either no prior experience with complement inhibitors or had previously received treatment with complement inhibitors but not within the six months prior to their screening visit, and who exhibited signs and symptoms of active PNH.

[0217] This clinical trial had two cohorts: a dose confirmation cohort (Cohort A) and a dose expansion cohort (Cohort B). Dose confirmation was performed in an interim analysis. Inclusion and exclusion criteria and event schedules were identical for Cohort A and Cohort B. During the evaluation period of data obtained from Cohort A, recruitment for the trial continued, and applicants were allocated as follows: if it was decided to extend Cohort A, patients were allocated to Cohort A; if it was decided to proceed to Cohort B, patients were allocated to Cohort B.

[0218] On day 1, patients received a single loading dose of REGN3918, 30 mg / kg intravenously (IV), followed by subcutaneous (SC) doses of 800 mg or less once a week (QW; ±1 day) until 26 weeks.

[0219] Dosage On day 1, a single loading dose of REGN3918, 30 mg / kg IV, was initially selected, followed by 800 mg (SC) once weekly (QW). A minimum concentration of 100 mg / L of REGN3918 was required to maximize the inhibition of C5 activity. The loading dose of 30 mg / kg IV helped to rapidly achieve the steady-state trough concentration required for sustained maximum inhibition of CH50.

[0220] Pharmacokinetics (PK) The PK variable was the total REGN3918 concentration at each time point. The sample collection time was defined in Table 1-1.

[0221] Anti-drug antibodies (ADA) Anti-drug antibody (ADA) variables included ADA status, titer, and time / visit. Samples in this clinical trial were collected at clinic visits as defined in Table 1-1. Blood samples for serum ADA evaluation were collected before drug administration.

[0222] Clinical trial cohort This clinical trial had two cohorts: a dose confirmation cohort (Cohort A) and a dose expansion cohort (Cohort B). Dose confirmation was performed in an interim analysis. Inclusion and exclusion criteria and event schedules were identical for both Cohort A and Cohort B. Recruitment for the trial continued during the evaluation period of data obtained from Cohort A, and applicants were allocated as follows: if it was decided to extend Cohort A, patients were allocated to Cohort A; if it was decided to proceed to Cohort B, patients were allocated to Cohort B. A clinical trial flow chart illustrating the treatment for each cohort is shown in Figure 1.

[0223] In making a decision, clinical data, REGN3918 PK (if available), CH50, total C5, LDH levels achieved in patients who did not achieve ≤1.5 × ULN, and other relevant available data, including safety, were considered as part of the decision-making process.

[0224] The decision to advance from Cohort A to Cohort B was made by the sponsor, in collaboration with the principal investigator, based on the achievement of LDH reduction to ≤1.5 × ULN at 8 weeks and safety, as follows: If all six patients in Cohort A achieved LDH ≤ 1.5 × ULN at week 8 and the dosing regimen was deemed well-tolerated, the dosing regimen was reviewed, and the trial proceeded to Cohort B, or the dosing regimen was modified to test lower doses and / or longer dosing intervals in expanded Cohort A (up to six additional patients). This revision was not considered substantial and therefore did not require formal protocol correction. If one or more patients failed to achieve LDH levels of 1.5 × ULN or less at week 8, the following decision was made after reviewing all data (including clinical and safety data, REGN3918 PK, CH50, total C5, baseline LDH, and achieved LDH levels): ○ Confirm the administration regimen and proceed to Cohort B, or Continue using the selected dosing regimen and expand Cohort A to a maximum of 12 patients, or Increase the dose and / or shorten the dosing interval, and re-evaluate Cohort A. This option requires essential protocol modifications.

[0225] After the initial dose of REGN3918 was administered at the clinical trial site, subsequent doses were continued at the clinical site, by site staff, or at the patient's home by another healthcare professional (where possible), or could be self-administered by the patient or designated personnel.

[0226] Drug administration Patients received a single loading dose of REGN3918, 30 mg / kg IV, on day 1, followed by doses of 800 mg or less every four weeks (±1 day) throughout the treatment period. Weekly subcutaneous administration was 800 mg every four weeks (±1 day) for the first cohort A patients.

[0227] In Cohort A, after administering REGN3918 intravenously as a loading dose at the clinical trial site, subsequent SC administration could be continued by facility staff at the clinical site or by another healthcare professional at the patient's home. From week 8 onward, self-administration by the patient or designated personnel was permitted.

[0228] In Cohort B, subsequent administrations could be continued at the clinic facility, at the patient's home by another healthcare professional, or by the patient / designated personnel. The location and administration options for the SC administration route depended on the preferences of the principal investigator and the patient (e.g., abdomen, thigh, or upper arm), the availability of clinical supplies, and the home healthcare visiting professional. Clinic visits for SC administration were sometimes required and sometimes not.

[0229] If patient / designated personnel self-administration / administration was permitted on-site, sufficient injection training was provided for scheduled injections using REGN3918. Following training, patient / designated personnel self-administration / administration was observed by clinical site staff or visiting healthcare professionals. If this observation was deemed satisfactory, the investigational drug could then be independently administered by the patient / designated personnel for the remainder of the trial. In addition, a patient diary was provided before the start of self-administration (i.e., at week 8 for Cohort A and week 4 for Cohort B). The diary was to be completed after each administration of the investigational drug. Investigational drug kits were distributed upon arrival at the clinical site using a direct-to-patient delivery (DTP) service provider, or transported by healthcare professionals as needed.

[0230] Red blood cell (RBC) infusion During the clinical trial, RBC-assisted fluid administration was to be carried out according to the following predefined criteria for triggering fluid administration; however, the actual number of units administered was at the discretion of the principal investigator: • If the hemoglobin level after baseline is less than 9 g / dL and accompanied by symptoms of anemia, administer RBC fluid; or If the hemoglobin level after baseline is less than 7 g / dL, administer RBC (reactive blood cell) infusion.

[0231] Pre-treatment Registered patients required evidence of meningococcal immunization or vaccination during the screening period, and oral antibiotics were recommended during the treatment period, in accordance with local practices.

[0232] Rules for dosage modification and discontinuation of investigational treatment Individual patient dosage modifications were not permitted. Patients who permanently discontinued the investigational drug but did not withdraw from the trial were asked to return to the clinic for all remaining trial visits. Patients who permanently discontinued the investigational drug and chose to withdraw from the trial were asked to complete the trial evaluation.

[0233] In the following cases, administration of the investigational drug was permanently discontinued: • Evidence of pregnancy; • A serious or severe allergic reaction thought to be related to the investigational drug; • Liver impairment as demonstrated by one or more of the following criteria: ○ Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is greater than 8 × ULN; or ○ ALT or AST levels exceeding 5x ULN for more than 2 weeks; or ○ ALT or AST is greater than 3 × ULN, and total bilirubin is greater than 2 × ULN ( Furthermore, if the international normalized ratio (INR) is greater than 1.5, and no other reason can be found to explain the combined increase in AST / ALT and total bilirubin, such as hepatitis A, B, or C; pre-existing or acute liver disease; or another drug capable of causing the observed injury; • The patient withdraws their consent; • Patient non-compliance (e.g., failure to follow the protocol's instructions regarding hospital visits, evaluations, and / or administration); or • The clinical judgment of the principal investigator that doing so is in the patient's best interest.

[0234] The principal investigator could have considered a temporary discontinuation due to a suspected adverse event (AE). If the principal investigator, based on their best medical judgment, believed that the investigational drug was not involved in the occurrence of the suspected event, they could have resumed treatment with the investigational drug under close and appropriate clinical and / or laboratory monitoring.

[0235] Acute reaction Patients were to be observed for 30 minutes after IV infusion. Emergency equipment and medications for treating IV reactions had to be available for immediate use. All IV reactions had to be reported as adverse events (AEs) and graded. Infusion was to be discontinued if any of the following AEs were observed: cough, chills, rash, itching, urticaria (hives, welts, wheals), diaphoresis (sweating), hypotension, dyspnea (shortness of breath), vomiting, and flushing. Reactions were to be treated symptomatically, and IV infusion could be resumed at 50% of the original rate. If the principal investigator felt there was a medical need to discontinue treatment or IV infusion for reasons other than those listed above, the principal investigator was to use clinical judgment to provide an appropriate response based on representative clinical practice.

[0236] In the event of the following adverse event (AE), intravenous fluid administration should be stopped and not resumed: anaphylaxis. * , laryngeal / pharyngeal edema, severe bronchospasm, chest pain, seizures, severe hypotension, other neurological symptoms (such as impaired consciousness, loss of consciousness, paresthesia, paralysis, etc.); or any other symptoms or signs that, in the opinion of the principal investigator, would warrant discontinuation of IV fluid administration. * Anaphylaxis was considered to occur when the following were observed (Sampson et al.) al., Second symposium on the definition and management of anaphylaxis: summary report--Second National Institute of Allergy and Infectious Disease / Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 2006;117(2):391-7): Acute onset (minutes to hours) of a disease affecting the skin, mucous membranes, or both (e.g., generalized rash, itching or flushing, swelling of the lips, tongue, or uvula), and at least one of the following: respiratory failure (e.g., dyspnea, wheezing bronchospasm, stenosis, decreased maximum expiratory flow, hypoxemia); or symptoms associated with hypotension or end-organ dysfunction (e.g., hypotonia [collapse], syncope, incontinence).

[0237] Patients were to be observed for 30 minutes after the initial SC injection. Emergency equipment and medications for treating systemic reactions had to be available for immediate use at the facility. All injection reactions had to be reported and graded as AEs. Acute systemic reactions after investigational drug (SC) injection were to be treated by determining the appropriate response based on representative clinical practice, using clinical judgment. Local injection site reactions had to be reported and graded as AEs.

[0238] Concomitant medications All treatments administered from the time of informed consent until the end of the final clinical trial visit were considered concomitant medications. This included medications initiated before the trial and continued throughout the trial period.

[0239] Except for those listed below, the following medicines were prohibited: • When blood is drawn, patients must not consume any alcohol within 24 hours prior to their visit to the clinic. Starting on day 1 and throughout the entire trial, patients were instructed not to receive any other complement inhibitor therapies while continuing REGN3918.

[0240] The following medicines and procedures were authorized, subject to the following conditions: • Any medications deemed necessary to treat the adverse event (AE), including systemic corticosteroids, at the discretion of the principal investigator; • Meningococcal vaccine inoculation; • Oral prophylactic antibiotic administration; • Oral contraceptives and hormone replacement therapy can be continued. • Acetaminophen / paracetamol, aspirin, or ibuprofen at the recommended dose according to the local label; Erythropoietin, immunosuppressants, corticosteroids, antithrombotic drugs, anticoagulants, iron supplements, and folic acid are permitted, but should be kept constant throughout the trial whenever possible; any changes to these concomitant medications are at the discretion of the principal investigator and must be consistent with pre-enrollment practices; Furthermore • Any medication necessary for treating the patient's background medical condition.

[0241] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0242] result The dosage (REGN3918, 30 mg / kg intravenously (IV) on day 1, followed by 800 mg subcutaneously (SC) once a week (QW; ±1 day)) was confirmed up to week 8, based only on the initial 6 subjects. The trial was open-label, and therefore LDH was continuously monitored in all subjects as a marker to understand whether patients experienced breakthrough hemolysis.

[0243] All six patients achieved LDH ≤ 1.5 × ULN by day 15 and remained so until day 57 (Figures 5, 6, and 7). Median LDH levels and individual LDH levels (normal and semi-logarithmic scales) are shown in Figures 17, 18, 19, 20, 21, 22, 23, and 24 up to day 57. Figures 21, 22, 23, and 24 reflect the LDH values ​​of nine patients. All six patients normalized after day 29, with the exception of one patient whose LDH was 0.89 on day 29, reached 1.01 on day 43, and then returned to 0.88 on day 57; and another patient whose LDH was 0.90 on day 29, reached 1.19 on day 43, and then returned to 0.91 on day 57 (Figures 8 and 9). See also Table 1-2.

[0244] [Table 4]

[0245] A 51-year-old Asian female patient screened for this trial with a history of PNH, aplastic anemia, and prior 2 units of RBC infusion within the past year. The patient received 2 units of RBC infusion on day 50 of the trial due to symptomatic anemia initiated on day 50 and resolved on day 56. Her pre-infusion hemoglobin (HB) was 7.8 g / dL. The most recent HB available after infusion was 11.8 g / dL on day 57. This infusion is considered protocol-compliant.

[0246] No serious adverse events (SAEs), adverse events of particular interest (AESIs), or fluid response were observed. See Table 1-3.

[0247] [Table 5]

[0248] Serum concentrations of REGN3918 were also evaluated in the subjects. See Figures 9 and 10. Time-course serum concentrations of REGN3918 for individual subjects and median REGN3918 serum concentrations are shown on both a normal and semi-logarithmic scale (Figures 9A, 9B, 10A, and 10B). These data are also broken down by sex (Figures 9C, 9D, 10C, and 10D).

[0249] In subjects treated with REGN3918, an increase in total C5 levels over time was observed. See Figures 11, 12, 13, 14, and 15. Figure 11(A-B) shows the total C5 concentration and median total C5 concentration of individual subjects over time. These data are also decomposed by sex (Figure 12(A-B)). The median ratio increase of total C5 from baseline and the increase in individual subjects over time are shown in Figure 13(A-B). These data are also decomposed by sex (Figure 14(A-B)).

[0250] Similar PK / total C5 ratios were observed in steady state across all six patients. The median ratio was 4.02. Figure 16 (A-F).

[0251] The dataset described in this embodiment provides evidence that REGN3918 has advantageous properties compared to ALXN1210 and eculizumab. Although the data included herein are from only six patients, 100% (6 out of 6 patients) normalized their serum LDH levels. In the clinical trial shown in Figure 25, only about half of the patients treated with ALXN1210 or eculizumab achieved normalization of their LDH levels. [Examples]

[0252] A randomized, double-blind, placebo-controlled Phase I trial of the pharmacokinetics and pharmacodynamics of REGN3918 (a human antibody against complement factor C5) in healthy volunteers. REGN3918 (pozelimab) is a fully human monoclonal immunoglobulin antibody that targets terminal complement protein C5. It inhibits terminal complement activation by blocking C5 cleavage, thereby blocking the formation of membrane invasion complexes (MAC; C5b-9). REGN3918 binds with high affinity to wild-type and variant (R885H / C) human C5. REGN3918 was well-tolerated in primate toxicology studies, even at doses of up to 100 mg / kg / week for up to 26 weeks. This finding supported the implementation of this first-in-human (FIH) clinical trial of REGN3918 in healthy volunteers.

[0253] The primary objective of this clinical trial was to evaluate the safety and tolerability of REGN3918 administered to healthy volunteers using both single-dose escalating IV and SC administration regimens, as well as multi-dose regimens consisting of an IV loading dose plus multiple weekly SC administrations. The secondary objective of this clinical trial was to evaluate the pharmacokinetic and pharmacodynamic profiles of REGN3918.

[0254] A total of 57 participants were randomized into four sequential escalation IV dosing cohorts + two sequential escalation SC cohorts and one subsequent multi-dose cohort (consisting of IV loading dose and weekly SC dosing) (56 participants received investigational treatment). Each cohort consisted of 8 participants randomized to receive either REGN3918 or placebo (6 active drug recipients: 2 placebo recipients). REGN3918 was administered as follows: Cohort 1: 1 mg / kg IV, single dose Cohort 2a: 3 mg / kg IV, single dose • Cohort 2b: 300 mg SC, single dose Cohort 3a: 10 mg / kg IV, single dose • Cohort 3b: 600 mg SC, single dose • Cohort 4: 30 mg / kg IV, single dose Cohort 5: A loading dose of 15 mg / kg IV followed by four repeated SC doses of 400 mg once a week for four weeks. Please refer to Table 2-1 below.

[0255] Adaptation design was implemented to allow for adjustment of dosing levels and intervals, utilizing pharmacokinetic and pharmacodynamic indicators obtained during clinical trials. The pharmacodynamic profile of REGN3918 was evaluated using sheep erythrocyte complement activity assay (CH50 assay) and serum total C5 concentration.

[0256] [Table 6]

[0257] Pharmacokinetics and pharmacodynamics REGN3918 showed a dose-dependent increase upon serum exposure, with serum concentrations tending to be prolonged at IV doses of 10 mg / kg or higher (Figure 2). After SC administration, serum REGN3918 concentrations peaked 4–8 days post-administration, and bioavailability was estimated at approximately 70%. REGN3918 exposure induced dose-dependent CH50 inhibition. In all four IV administration cohorts, suppression of hemolysis was observed 15 minutes post-injection. Maximum suppression of hemolysis was achieved at doses of 3 mg / kg or higher. At 30 mg / kg, maximum suppression of hemolysis was maintained for more than 4 weeks, which is consistent with the observed prolonged REGN3918 concentration after administration. In two SC cohorts, the peak of hemolysis suppression was observed 3–7 days post-administration, which is also consistent with the observed peak serum REGN3918 concentrations. In the multiple-dose cohort 5, complete suppression of CH50 was observed during the 4-week administration period and the 2-week period following the final dose (Figure 3).

[0258] safety REGN3918 was found to be well-tolerated in single doses of up to 30 mg / kg IV and 600 mg SC (Table 2-2). In the multi-dose cohort 5, administration was completed in all subjects, and all safety follow-ups were also completed. A single serious adverse event, salpingitis, occurred in one subject in cohort 5; a serious adverse event occurred after the completion of administration but resolved completely after treatment with a short course of antibiotics.

[0259] [Table 7]

[0260] REGN3918 was generally well-tolerated in both single-dose escalating IV and SC administration regimens, as well as in a single IV loading dose followed by four consecutive weekly doses. Rapid and maximal suppression of complement activity was demonstrated with IV administration at doses of 3 mg / kg or higher, as measured by the sheep erythrocyte CH50 assay. At 30 mg / kg, maximal suppression of hemolysis was maintained for more than four weeks. In a regimen consisting of a 15 mg / kg IV loading dose followed by four consecutive weekly 400 mg SC doses, CH50 suppression was maintained throughout the entire administration period and for two weeks after the final dose.

[0261] Hemolysis assay To further characterize the effect of REGN3918 on alternative complement pathway (AP) activity, the effect of REGN3918 on alternative pathway-mediated hemolysis was investigated using the AH50 assay in a completed first-in-human (FIH) clinical trial. In addition, the effects of REGN3918 in both alternative and classical pathway hemolysis assays were compared ex vivo with those of eculizumab and ravulizumab in pooled normal human serum (NHS) samples.

[0262] Serum collected at multiple time points was used to evaluate the effect of REGN3918 on alternative pathway activity. In ex vivo spike experiments, pooled NHS was used to compare the hemolytic function of REGN3918, eculizumab, and ravulizumab. Alternative pathway (AP) and classical pathway (CP) hemolysis assays were performed based on the lysis of rabbit erythrocytes (RBCs) and sensitized sheep RBCs, respectively. Both assays measure the amount of hemoglobin released from erythrocytes at 412 nm.

[0263] In the FIH trial, baseline AH50 was comparable across treatment groups, with a mean of 110 U / mL (standard deviation = 19, n = 56). REGN3918 exposure induced dose-dependent inhibition of AH50. Peak suppression of hemolysis was observed at end of infusion (EOI) in all four IV administration cohorts. The maximum suppression of hemolysis was approximately -85% from baseline. This was achieved in the 30 mg / kg IV group and the 15 mg / kg IV + 400 mg SC QW repeated dosing group. In the two SC cohorts, peak suppression of hemolysis was observed 3–7 days post-administration, which was consistent with the observed peak concentration of serum REGN3918. In ex vivo spike studies, REGN3918, eculizumab, and rabulizumab were spiked in pooled NHS at 10, 25, or 48% for AP and 5, 10, or 25% for CP. Results from AP hemolysis assays revealed that, at a given concentration of the spiked antibody, the maximum suppression of hemolysis decreased with increasing serum percentage (%) for all antibodies (Figure 4(A-C); Table 2-3). Maximum suppression of hemolysis was consistently higher for REGN3918 than for eculizumab (32-169%) and lower for rabulizumab than for both REGN3918 and eculizumab at all serum percentages (%) tested. Results from the CP hemolysis assay showed that the maximum suppression of hemolysis was similar for all antibodies tested, but ravulizumab required at least a 10-fold higher concentration to achieve a similar effect to the other two anti-C5 antibodies (Figure 4 (D-F); Table 2-4).

[0264] Magnesium is an important cofactor for the activity of AP C3 and C5 convertases. Changing the serum percentage (%) (10%, 25%, or 48%) also changes the magnesium concentration, which affects convertase function. To test whether this constitutes the root cause of the observed differences among the three antibodies tested at different serum percentages, AP assays were performed using 25% NHS and three different concentrations of magnesium. Magnesium concentrations of 1, 1.5, or 2 mM (MgCl2) did not affect the individual antibody performance. Relative differences still existed among the three antibodies tested at the three different magnesium concentrations. While magnesium concentration may still be a contributing factor under the tested conditions, other mechanisms may be involved in the observed relative differences.

[0265] In ex vivo studies using pooled NHS samples, REGN3918 demonstrated robust blockade of both CP and AP hemolysis. Rabulizumab appeared less potent than eculizumab in both CP and AP hemolysis assays. A Phase I healthy volunteer trial of REGN3918 demonstrated dose-dependent, significant inhibition of surrogate route hemolysis, resulting in a maximum suppression of approximately -85% from baseline.

[0266] [Table 8]

[0267] [Table 9]

[0268] [Table 10]

[0269] The sequences of the eculizumab and ravulizumab antibodies used in these assays were as follows: Eculizumab QVQLVQSGAEVKKPGASVKVSCKASGYIFSNYWIQWVRQAPGQGLEWMGEILPGSGSTEYTENFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARYFFGSPNWYFDVWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (Sequence ID 358) DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQNVLNTPLTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Sequence ID 359) Lablisma QVQLVQSGAEVKKPGASVKVSCKASGHIFSNYWIQWVRQAPGQGLEWMGEILPGSGHTEYTENFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARYFFGSPNWYFDVW GQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKC CVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKT ISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHSHYTQKSLSLSLGK (Sequence ID 360) DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQNVLNTPLTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Sequence ID 361) [Examples]

[0270] Switching from eculizumab to REGN3918 results in C5 hu / hu In mice, this resulted in normalization of C5 concentration and sustained suppression of hemolytic activity in ex vivo conditions. To evaluate the efficacy of switching treatment from eculizumab to REGN3918, 15 mg / kg of REGN3918 or culizumab (SEQ ID NOs. 358 and 359) was administered to three groups of C5 hu / huMice were administered three times on days 0, 15, and 29. One group received REGN3918 alone for all three doses, while a second group received eculizumab alone. A third group ("switch group") received eculizumab on day 0, then switched to REGN3918 on days 15 and 29. Cage-side observations and routine wellness checks revealed that the mice were healthy, and all animals survived until their scheduled end date. Blood samples were collected sequentially at multiple points before and after administration throughout the trial period. Cholesterols of REGN3918 and eculizumab max The values ​​were similar after the initial dose (151 μg / mL and 144 μg / mL, respectively); however, REGN3918 alone showed a slower clearance (CL) compared to eculizumab alone, and REGN3918 generally resulted in higher serum concentrations (Figure 4A, Table 4). After switching from eculizumab to REGN3918, the total hIgG concentration profile against time initially resembled the REGN3918 PK profile during the dosing interval after the second switch (Figure 26(A), Table 3-1). These results suggest that switching from eculizumab to REGN3918 has only a limited effect on serum total IgG concentration compared to the concentrations observed when either mAb was administered as a single drug.

[0271] Serum C5 concentrations were also monitored. In mice administered REGN3918, serum C5 concentrations increased up to 1.4 times throughout the trial period. In contrast, eculizumab induced higher serum C5 concentrations after the first, second, and third doses (increases of 1.9, 2.0, and 2.8 times, respectively) (Figure 26(B)). The initial dose of eculizumab administered to the "switch-over group" induced a similar increase in serum C5 concentration as in animals treated with eculizumab monotherapy. After switching to REGN3918 on day 15, serum C5 concentrations in the "switch-over group" temporarily decreased below baseline (70%), but after the final dose of REGN3918, the levels were lower than those in the group treated with REGN3918 monotherapy. It returned to a similar level. C5 excretion accelerated after the switch in administration, which may be consistent with the transient formation of immune complexes containing REGN3918, eculizumab, and C5, as demonstrated in the A4F-MALLS trial. The effect of switching treatment from eculizumab to REGN3918 on the efficacy of blocking complement-mediated hemolysis was also evaluated. Finally, C5 was sacrificed. hu / hu Serum from mice (n=5) was collected before each new dose and 14 days after the third dose, and used in a CP-mediated hemolysis assay. Hemolysis was effectively blocked to a similar degree in serum collected from all three groups after the first, second, and third antibody doses (Figure 26(C)). Blocking of hemolysis was associated with a C5:mAb ratio maintained at less than 1 throughout the trial period (Figure 26(D)). Overall, these results suggest that switching from eculizumab to REGN3918 treatment is generally well tolerated, and ex This suggests a link to the continued suppression of complement activation in vivo.

[0272] [Table 11]

[0273] The REGN3918, eculizumab, and C5 complex primarily contains 1-2 molecules of C5. REGN3918 may be a promising treatment option for patients with rare genetic variants of C5, and may also offer an alternative for patients currently being treated with eculizumab. However, several of them bind to specific epitopes on soluble antigens. The combination of these antibodies may generate higher-order protein complexes that could induce type III hypersensitivity reactions similar to serum sickness. Such conditions are self-limiting, and the size of the complex should be influenced by the molar ratio of antibody to antigen, with the largest complexes generally forming when the components are equimolar or nearly equimolar. Here, the size of the complex formed with REGN3918:eculizumab:C5 in a molar ratio of 5:1:1 was investigated using asymmetric flow field fractionation with multi-angle laser light scattering detection (A4F-MALLS). This molar ratio was selected based on the expected serum concentrations in vivo when the initial administration switch was made in the clinic.

[0274] Representative fractograms generated after A4F-MALLS analysis of the eculizumab / C5 / REGN3918 mixture and each individual component are superimposed in Figure 27. Since the concentration of REGN3918 may be significantly in excess of both C5 and endogenous eculizumab, a major peak representing free REGN3918 (Peak 1; approximately 66% of the total peak area, Table 3-2) was detected in the simulation of the mixture. Several additional minor peaks (Peaks 2-4) corresponding to heteromeric complexes of eculizumab, C5, and REGN3918 were also detected in this sample, confirming that both endogenous eculizumab and REGN3918 can interact with the same molecule of C5 to form an extended antibody-antigen lattice. However, the majority of these complexes separated into two independent peaks (Peaks 2 and 3; approximately 22% of the total peak area) with mean molar masses of approximately 499 kDa and 841 kDa, respectively. Based on the molar mass calculations of the individual components, peaks 2 and 3 could represent 2:1 and 3:2 mAb:C5 heteromeric complexes, respectively. A broad, poorly separated peak (peak 4) was also detected, which could correspond to a heterogeneous distribution of higher-order complexes (approximately 1200–2100 kDa), but it accounted for only about 12% of the total peak area. Considering all of this together, these data suggest that while eculizumab and REGN3918 may form heteromeric complexes with C5, the formation of very large, heterogeneous, immunogenic complexes may be minimal when each component is present at the expected in vivo concentrations at the time of the initial dose switch. Furthermore, the formation of such very large complexes may be transient and should certainly decrease as eculizumab is cleared from the circulation and / or with additional doses of REGN3918.

[0275] [Table 12]

[0276] In addition to offering a promising treatment option for patients with rare C5 variants, REGN3918 also provides an alternative for patients currently being treated with eculizumab. For example, REGN3918 may enable more stable serum C5 levels with a lower frequency of required dosing regimens. In a dosing switch study in humanized C5 mice, switching from eculizumab to REGN3918 was well-tolerated and demonstrated that complement suppression was maintained. However, combining several antibody therapies targeting soluble antigens may generate higher-order immunogenic protein complexes. Using the expected eculizumab:REGN3918:hC5 molar ratio at dosing switch, the A4F-MALS study demonstrated that eculizumab and REGN3918 can form heteromeric complexes with C5. However, the formation of very large, heterogeneous, potentially immunogenic complexes was minimal and may be transient in vivo. These data may support the idea that using excess REGN3918 when switching from eculizumab minimizes the likelihood of inducing serum sickness-like reactions. [Examples]

[0277] An open-label efficacy and safety study of pozelimusb in patients with CD55-deficient protein-losing enteropathy (CHAPLE disease). This was an open-label, single-treatment, 104-week clinical trial in patients aged 1 year or older with active clinical signs and symptoms of CD55-deficient PLE / CHAPLE disease and CD55 loss-of-function mutations (frameshift, nonsense mutations) detected by genotyping. Patients received a single loading dose of pozerimab 30 mg / kg intravenously (IV) on day 1, followed by fixed-dose subcutaneous (SC) (body weight-based) quarterly weeks (±1 day) throughout the treatment period. The trial included a screening period (up to 4 weeks), a subsequent 104-week treatment period from week 0 to week 103, and a follow-up period from week 104 to week 116. Only patients with active PLE were included in the primary analysis. In this trial, active PLE was defined as hypoalbuminemia of ≤3.2 g / dL during the screening period, and one or more of the following symptoms or signs within the past six months, lasting at least seven days (not necessarily consecutive): diarrhea, vomiting, abdominal pain, peripheral or facial edema, infection complicated with hypogammaglobulinemia, or a new thrombotic event.

[0278] Clinical trial period The duration of the clinical trial for patients was approximately 117 weeks (weeks 0 to 116), excluding the screening period.

[0279] Clinical trial group Sample size: A minimum of six patients with active PLE were enrolled. This enrollment was then closed one year after FPFD, or upon enrollment of the 20th patient, whichever came first. Eligible patients with inactive PLE could also be enrolled, but their data were not included in the primary analysis.

[0280] Target population: Patients aged 1 year or older with a clinical diagnosis of CD55-deficient PLE disease, determined by genetic analysis (frameshift, nonsense mutation), and confirmed by CD55 flow cytometry or Western blotting in peripheral blood cells (required only if missense or splice site mutation is suspected) with CD55 loss-of-function mutations. The first two patients had to be 6 years of age or older (exceptions were made for patients under 6 years of age with life-threatening conditions).

[0281] [Table 13]

[0282] Inclusion Criteria To be eligible for enrollment in this clinical trial, patients had to meet the following criteria: 1. Male or female aged 1 year or older. The first two patients recruited must be 6 years of age or older; 2. Clinical diagnosis of CD55-deficient PLE / CHAPLE disease (based on a history of PLE) confirmed by biallelic CD55 loss-of-function mutations (frameshift, nonsense mutations) detected by genotyping. In cases of missense mutations or suspected splice site mutations, CD55-deficient PLE should be confirmed by flow cytometry or Western blotting of peripheral blood cells. These diagnostic tests could be performed as part of the clinical trial screening procedure or as part of the standard clinical evaluation prior to screening; 3. The patient has one of the following diseases: a. Active diseases as defined below: (i) Hypoalbuminemia of 3.2 g / dL or less during the screening period, and (ii) At least one of the following symptoms or signs within the last six months and which may be caused by CD55-deficient PLE, lasting for at least seven days (not necessarily consecutive): diarrhea, vomiting, abdominal pain, peripheral edema or facial edema, or an episode of infection complicated with hypogammaglobulinemia, or a new thromboembolic event. Note: The first two patients enrolled in this clinical trial had to meet inclusion criterion 3a. b. Inactive disease in eculizumab therapy (and the patient's treating physician expects future access to updated eculizumab therapy if necessary), and willingness to discontinue eculizumab during the screening period and initiate pozelimusb at baseline without a break in eculizumab; 4. Having the willingness and ability to visit the clinic and comply with clinical trial-related procedures; 5. Documented informed consent from parents / guardians regarding minor patients; 6. Written consent from minor patients, as appropriate (e.g., those aged 6 or older than the applicable age based on local regulatory requirements); and 7. Patients must be able to understand and complete the trial-related questionnaires independently, or with the assistance of their parent / legal guardian if necessary.

[0283] Exclusion criteria Patients who meet any of the following criteria will be excluded from this trial: 1. History of meningococcal infection. 2. Meningococcal vaccination within 3 years prior to screening is not documented, and the patient does not intend to receive the vaccination during the trial period (in accordance with local practice). (If available). 3. Where applicable, prior to screening, vaccination against Haemophilus influenzae and Streptococcus pneumoniae in accordance with local practices or guidelines is not documented, and the patient is not willing to receive vaccination during the trial period if required in accordance with local practices or guidelines. 4. Presence of comorbidities that cause hypoproteinemia at the start of pozerimab initiation, including liver disease affecting protein loss in urine or protein synthesis by the liver. 5. Comorbid conditions that cause secondary intestinal lymphangiectasia, such as Fontan surgery for congenital heart disease. 6. A recent infection requiring systemic treatment with antibiotics, antivirals, or antifungals (within two weeks of screening, or during the screening period). If the patient has been adequately treated, they may be rescreened. 7. Patients with PLE that have previously been refractory to eculizumab, with the exception of those with the Arg885His variant in the C5 gene. 8. Other hereditary complement deficiencies besides CD55 deficiency are known. 9. A documented history of active, ongoing systemic autoimmune disease. 10. Infectious colitis is known or suspected at the time of screening. Once it has resolved, the patient can be rescreened. 11.30mL / min / 1.73m 2 Patients with an estimated glomerular filtration rate (eGFR) less than 2009 (according to the Chronic Renal Disease-Epidemiology Collaboration Equation 2009 [Adults], or Schwartz's Equation based on creatinine [Pediatric Patients]). 12. Recent unstable medical conditions within the past three months prior to the screening visit, excluding PLE and associated complications. The option of re-screening at three months is invalid. 13. Known hypersensitivity to pozelimusb formulations or any component of the drug. 14. Any clinically significant abnormality identified at screening, such as a history of hepatitis B or C, that would, in the judgment of the principal investigator or co-investigator, preclude safe termination of the trial or limit endpoint evaluation. Patients with a known history of hepatitis B or C were only eligible for enrollment if these conditions were no longer active, as demonstrated by negative results for hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), hepatitis B virus DNA, and hepatitis C virus RNA (HCV RNA), respectively. Note: Testing for hepatitis B and C was not mandatory for enrollment in this trial, but was permitted at the discretion of the principal investigator. 15. Participation in another interventional clinical trial or use of any experimental therapy within 30 days prior to the screening visit or within 5 half-lives of the investigational drug, whichever is longer, with the exception of complement inhibitors. 16. The principal investigator or any investigator in charge of the clinical trial, for any reason, for example: • Being deemed unable to meet certain protocol requirements, such as scheduled visits, and / or Based on the patient, principal investigator, clinical trial physician, pharmacist, clinical trial coordinator, other clinical trial staff, or other persons directly involved in the conduct of the clinical trial, it is determined that the patient is unable to tolerate long-term injections, and / or • The existence of any other actual or anticipated conditions (e.g., geographical, social, etc.) that the principal investigator feels would restrict or limit a patient's participation throughout the trial. Therefore, it is deemed unsuitable for this clinical trial. 17. Patients confined to an institution by order of judicial or administrative authority. 18. Women who are pregnant, breastfeeding, or have a positive pregnancy test at the time of or on day 1 of their screening visit. 19. Pregnant or breastfeeding women. 20. Pregnant women who do not intend to practice highly effective contraception before the start of the first dose / initial treatment, during the trial period, and for at least 21 weeks after the last dose. * and girls after menarche (and who are not abstinent). As a highly effective means of contraception: a. Stable use of combination (estrogen and progestogen-containing) hormonal contraceptives (oral, vaginal, transdermal) or progestogen-only hormonal contraceptives (oral, injectable, implantable) associated with ovulation inhibition, initiated before screening and within two menstrual cycles or more. b. Intrauterine contraceptive device (IUD); Intrauterine hormone-releasing system (IUS) c. Bilateral tubal ligation d. Vasectomy of the partner e. and / or abstinence†,‡ These are some examples. * Postmenopausal women must be amenorrhea for at least 12 months to be considered fertile. Pregnancy tests and contraception are not required for women who have been documented to have undergone a hysterectomy or tubal ligation. † Abstinence is considered a highly effective method only if it is defined as refraining from heterosexual intercourse throughout the entire period of the risk associated with the clinical trial treatment. The reliability of abstinence needs to be evaluated in relation to the duration of the clinical trial and the patient's usual preferred lifestyle. ‡ Regular abstinence (calendar method, symptomatic body temperature method, post-ovulation method), interruption (abortion intercourse), spermicides alone, and lactation-induced amenorrhea (LAM) are not acceptable methods of contraception. It was decided that female condoms and male condoms should not be used together. 21. Intentionally leaving a blank page 22. Evidence of documented unresolved tuberculosis (TB) history or active or latent tuberculosis infection (LTBI) during the screening period. Assessment for active TB and LTBI was to follow local practices or guidelines, including those related to risk assessment, and the use of tuberculin skin tests or T-cell interferon-gamma-release assays.

[0284] Outcome / Endpoint The primary endpoint is the percentage of patients who achieved both of the following: • Normalization of serum albumin as defined below, - Serum albumin levels are within the normal range in at least 70% of measurements performed between weeks 12 and 24, and - Albumin levels were never below 2.5 g / dL at any point between weeks 12 and 24, and - No albumin infusion required between weeks 12 and 24. • At week 24, improvement in the following clinical outcomes that were evaluable for improvement at baseline, provided that other outcomes (i.e., outcomes for which improvement is not evaluable) do not worsen: - Daily bowel movement frequency based on a weekly average, as recorded via e-diary. Improvement is defined as a decrease of 50% or more in daily bowel movement frequency based on a weekly average. Patients eligible for evaluation of improvement are defined as those with an average of 3 or more bowel movements per day at baseline. Worsening is defined as an increase of 30% or more. - Evaluation of facial edema by a physician (based on the 5-point Leicert scale). Improvement is defined as a decrease of 2 points or more. Patients eligible for evaluation of improvement are defined as those with a severity score of at least 2 points out of 5 at baseline. Worsening is defined as an increase of 2 points or more. - Physician assessment of peripheral edema (based on a 5-point Leicert scale). Improvement is defined as a decrease of 2 points or more. Patients eligible for improvement are defined as those with a severity of at least 2 points out of 5 at baseline. Worsening is defined as an increase of 2 points or more. - Patient / caregiver assessment of abdominal pain frequency, evaluated using the PedsQL® GI Symptom Scale's gastric pain and injury subscale. Improvement is defined as an increase of 6 points or more (based on a total subscale score converted from 0 to 100, where a lower score indicates worsening of GI gastric pain and injury). Patients whose improvement is evaluable are defined as those with a baseline score of 70 points or less. Worsening is defined as a decrease of 6 points or more.

[0285] The secondary endpoints are as follows: • Incidence and severity of adverse events (TEAEs) and other safety variables observed during the treatment period from baseline to 104 weeks. • Improvement over 24 weeks of each patient's most bothersome sign / symptom, determined prior to baseline using a semi-structured concept-requesting interview, from among the "core" clinical endpoints consisting of bowel movement frequency, peripheral edema, facial edema, abdominal pain frequency, nausea, vomiting, and stool consistency: - Improvement in nausea and vomiting is defined as a 6-point increase on the nausea and vomiting subscale, which is converted to a 0-100 scale on the PedsQL GI symptom scale, with lower scores indicating worsening nausea and vomiting. Patients can be evaluated for improvement in nausea and vomiting if they have a score of 85 or less on the nausea and vomiting subscale at baseline. - Improvement in stool consistency is defined as a 50% or greater reduction in the number of days per week in which the patient has soft / watery stools. Stool consistency is measured using the Brussels Infant and Toddler Stool Scale. A stool is considered soft / watery if it corresponds to three images of soft or watery stool on the BITSS scale, images and descriptors of category 4 or 5 on the modified Bristol Stool Scale for Children (mBSFS-C), or images and descriptors of category 6 or 7 on the Bristol Stool Scale (BSFS). For improvement in stool consistency to be assessable, the patient must have soft / watery bowel movements at least two days a week at baseline. • The percentage of patients with active disease at baseline who maintain disease control at 48 and 104 weeks, according to the following definitions: - Serum albumin normalization is defined as: serum albumin being within the normal range in at least 70% of measurements between weeks 12 and 48 (and between weeks 12 and 104); no albumin measurement being less than 2.5 g / dL between weeks 12 and 48 (and between weeks 104); and no albumin infusion being required between weeks 12 and 48 (and between weeks 104); and - No worsening of facial or peripheral edema, increased bowel movements, or increased frequency of abdominal pain between weeks 12 and 48 (and 104), using the same definition of worsening as the primary endpoint. - The dosage of any approved concomitant medications used to treat PLE should not be increased at any time, and any approved concomitant medication should not be reintroduced once discontinued, provided that approved concomitant medications are as follows: corticosteroids, immunoglobulins via IV or SC, albumin via IV, biological immunomodulators (anti-TNF, vedolizumab), small molecule immunomodulators (e.g., azathioprine, mesalazine), micronutrients, enteral or parenteral supplementation. • Patients who received eculizumab at baseline, have an inactive disease, and maintain disease control at 24, 48, and 104 weeks according to the definition below. ratio: - Normalization of serum albumin is defined as: serum albumin being within the normal range for at least 70% of measurements between weeks 12 and 24 (and weeks 12 and 48, and weeks 12 and 104); and no albumin measurement falling below 2.5 g / dL between weeks 12 and 24 (and weeks 48, and 104); and no albumin infusion being required between weeks 12 and 24 (and weeks 48, and 104); and - No worsening of facial or peripheral edema, increased bowel movements, or increased frequency of abdominal pain between weeks 12 and 24 (and weeks 48 and 104), using the same definition of worsening as the primary endpoint. - The dosage of any approved concomitant medications used to treat PLE should not be increased at any time, and any approved concomitant medication should not be reintroduced once discontinued, provided that approved concomitant medications are as follows: corticosteroids, immunoglobulins via IV or SC, albumin via IV, biological immunomodulators (anti-TNF, vedolizumab), small molecule immunomodulators (e.g., azathioprine, mesalazine), micronutrients, enteral or parenteral supplements. • Daily bowel movement frequency based on the weekly average, as recorded from the e-diary from baseline to 24 weeks. The number of days / weeks with one or more soft / watery bowel movements, as measured by BSFS for patients 18 years of age or older, mBSFS-C for patients under 18 years of age who have received toilet training, or BITSS for patients who have not received toilet training, as determined from e-diaries from baseline to 24 weeks. • Physician's assessment of facial edema from baseline to 104 weeks (based on a 5-point Leichert scale) • Physician's assessment of peripheral edema from baseline to 104 weeks (based on a 5-point Leichert scale) • Changes in abdominal symptoms, as assessed by the PedsQL® GI Symptom Scale's gastric pain and injury subscale and the food and beverage restriction subscale, from baseline to 104 weeks. • Health-related quality of life as assessed by the PedsQL® General Core Scale from baseline to 104 weeks; in addition, the following subscales were reported individually: - Subscales relating to one's occupation / academics and school function - Physical function subscales • Assessment of ascites from baseline to 24 weeks (assessed by measuring abdominal circumference) • Frequency of albumin infusion up to 104 weeks, expressed as a number per six months. Albumin infusion was permitted during the treatment phase if albumin levels were less than 3.0 g / dL at two consecutive visits and the patient presented with facial or peripheral edema or ascites. Patients who received albumin infusion between weeks 12 and 24 were considered non-responsive to the primary endpoint. • Total albumin, protein, total Ig, IgG, IgM, IgA are expressed as follows: - Absolute values ​​for each scheduled time point, including 24 weeks. - Absolute change and percentage change over time from baseline - Time until normalization occurs for the first time • Vitamin B12, folic acid, iron, iron-binding capacity, ferritin, magnesium, fasting cholesterol / triglycerides as shown below: - Absolute values ​​for each scheduled time point, including 24 weeks. - Changes over time from baseline - Time until normalization occurs for the first time • Blood and stool alpha-1 antitrypsin levels, and changes from baseline to 12 and 24 weeks. • Use and frequency of corticosteroids, immunoglobulins IV or SC, albumin IV, biological immunomodulators (anti-TNF, vedolizumab), small molecule immunomodulators (e.g., azathioprine, mesalazine), micronutrients, enteral or parenteral supplementation, anticoagulants (e.g., low molecular weight heparin), antibiotics (with the exception of antibiotics used for Neisseria prevention), and antiplatelet agents (e.g., low-dose aspirin) from baseline to 104 weeks. • Total number of days hospitalized over the period (percentage of days hospitalized) • Weight and height throughout the period (expressed as z-scores) • Total serum pozeliumab concentration assessed throughout the clinical trial • Incidence of anti-drug antibodies (ADAs) to pozeliumab developed in patients under treatment throughout the period. • Change in total complement activity (CH50) from baseline and percentage change over the period.

[0286] The exploratory outcomes were as follows: • Total plasma C5 concentration throughout the period • Markers of thrombosis: D-dimer and N-terminal prothrombin fragment (F1+2) • Complement assay: sC5b-9 • Changes in GI symptoms over time from baseline, as measured by the Pediatric Quality of Life Inventory (PedsQL®) GI symptom scale (diarrhea subscale, as well as nausea and vomiting subscales). • Changes in the health status and workload of caregivers over time from baseline, as measured by the PedsQL (trademark) Family Impact Module. • Overall impression of changes from baseline to 104 weeks by clinicians (CGIC) • Overall clinical assessment of severity from baseline to 104 weeks (CGIS) • Overall impression of changes from baseline to 104 weeks as reported by patients / caregivers (PGIC / CareGIC) • Overall patient / caregiver assessment of severity from baseline to 104 weeks (PGIS / CareGIS) • If applicable to the age and stage of sexual maturity, Tanner's puberty stage. • Whole exome sequencing (if not already performed)

[0287] Efficacy indicators / procedures Serum albumin, total protein, and immunoglobulins. Samples were collected and tested in the laboratory within a blood chemistry or immunoglobulin panel.

[0288] Physician assessment of edema and ascites. Physicians assessed peripheral edema as follows: After a general physical examination and palpation of all four limbs, the principal investigator rated the overall severity of peripheral edema on a 5-point rating scale (1 meaning no edema, and 5 meaning very severe edema), taking into account both degree and distribution.

[0289] The physician assessed facial edema as follows: After a general facial examination, the principal investigator rated the overall severity of facial edema on a 5-point rating scale (1 meaning no edema, and 5 meaning very severe edema), taking into account both its extent and distribution.

[0290] The severity of ascites was assessed by measuring abdominal circumference as follows: 1. Palpate the lower rib margin (costal margin) and the short Mark with a horizontal line; 2. Palpate the iliac crest and mark it with a short horizontal line; 3. Use a measuring tape to measure the midpoint between two horizontal lines, and mark this midpoint with another short horizontal line; 4. Instruct the patient to cross their arms over their chest to allow access to their waist. Instruct them to stand relaxed and look straight ahead. Ensure the patient does not intentionally extend or retract their arms; 5. Pass the measuring tape around your waist, ensuring it is horizontal and positioned at the midpoint marks on both sides; 6. Ensure the tape is not pulled too tightly. It should stay in place on the skin without causing any indentations. 7. Take the measurement at the end of exhalation; 8. Measure to the nearest 0.1 cm (1 mm); 9. Measure waist circumference three times; and 10. Record all 3 measurements and the mean (average) obtained by adding them together and dividing by 3.

[0291] In cases of abnormal findings, clinical photographs were to be attached to these evaluations, if available. All physician evaluations of patients were to be performed by the same principal investigator until 24 weeks later.

[0292] Clinical trial design This was an open-label, single-treatment, 104-week clinical trial in patients aged 1 year or older with active clinical signs and symptoms of CD55-deficient PLE / CHAPLE disease and CD55 loss-of-function mutations (frameshift, nonsense mutations) detected by genotyping. CD55-deficient PLE was confirmed by flow cytometry of peripheral blood cells in cases of suspected missense or splice site mutations. The first two enrolled patients were 6 years of age or older (with the exception of patients under 6 years of age with life-threatening illnesses).

[0293] A minimum of six patients with active PLE were enrolled. The enrollment was then closed one year after the first patient's initial dose (FPFD) or at the enrollment of the 20th patient, whichever came first. A primary analysis occurred when approximately six patients with active PLE had received six months of treatment. Subsequent analyses occurred one and two years after the initial dose in the last enrolled patient.

[0294] On day 1, the patient received a single loading dose of pozelimab, 30 mg / kg IV, followed by a fixed-dose SC (body weight-based) QW (±1 day) throughout the treatment period.

[0295] The clinical trial consisted of a screening period (up to 4 weeks), a subsequent 104-week treatment period from week 0 to week 103, and a follow-up period from week 104 to week 116. After the completion of the treatment period, patients had the option to enroll in an open-label extension trial that continued until pozeliumab was approved for commercialization in their country (if commercialization had not yet occurred) or until commercialization / development of pozeliumab was completed.

[0296] Active PLE was defined as hypoalbuminemia ≤3.2 g / dL during the screening period, and one or more of the following symptoms or signs within the past six months, lasting at least seven days (not necessarily consecutive): diarrhea, vomiting, abdominal pain, peripheral or facial edema, or an episode of infection complicated with hypogammaglobulinemia, or a new thrombotic event. Patients with active PLE were not receiving current therapy with eculizumab.

[0297] Investigational drug The pozeliumab drug was provided and supplied by the sponsor in sterile, single-use glass vials for IV or SC administration. The drug was initially provided in a vacuum lyophilized form in sterile, single-use glass vials for IV or SC administration (requiring reconstitution with sterile water for injection, and then transfer to a sterile, single-use glass vial), or in pre-filled syringes containing a liquid 200 mg / mL pozeliumab formulation (no reconstitution required) for IV or SC administration.

[0298] The investigational drug was provided by the sponsor. Mixed solutions required for the delivery of vacuum lyophilized or liquid drugs for IV administration were procured locally, or provided by the sponsor as needed.

[0299] Usage / Dosage Patients received a single loading dose of pozelimab-30 mg / kg IV on day 1, followed by SC administration every quarter (±2 days) based on body weight throughout the treatment period. The final dose of the investigational drug was administered at week 103. Subcutaneous administration regimen: • For BW (Body Weight) less than 10kg: 125mg; • For BW (Body Weight) 10kg or more but less than 20kg: 200mg; • For BW (Body Weight) 20kg or more but less than 40kg: 350mg; • For those weighing 40kg or more but less than 60kg: 500mg; • For BW (Body Weight) of 60kg or more: 800mg.

[0300] The location and option of SC administration depended on the preferences of the principal investigator and the patient (e.g., abdomen, thigh, or upper arm), the availability of clinical supplies, and the home healthcare visiting specialist. Clinic visits for SC administration were sometimes necessary and sometimes not.

[0301] Where patient / designated personnel self-administration / administration was permitted on-site, sufficient injection training was provided for scheduled injections of pozeliumab. Following training, patient / designated personnel self-administration / administration was observed by clinical site staff or visiting healthcare professionals. If this observation was deemed satisfactory, the investigational drug could then be independently administered by the patient / designated personnel for the remainder of the trial.

[0302] In addition, a patient diary was provided before the start of self-administration (i.e., on day 29). The diary was to be completed at the time of administration of each investigational drug. Investigational drug kits were distributed to patients upon arrival at the clinical site using a direct-to-patient delivery (DTP) service provider, or transported by healthcare professionals as needed. Detailed information regarding the administration of the investigational drugs was provided in the pharmaceutical manual.

[0303] Pharmacokinetics (PK) Analysis of drug concentration data. The PK endpoint was the total serum pozerimab concentration over time.

[0304] Summary of total drug concentrations and total C5 is presented by nominal time point (i.e., time point specified in the protocol). Individual data are presented by actual time. Plots of pozeliumab and total C5 concentrations are shown over time (linear and logarithmic scales). When the scale is linear, concentrations below the limit of quantification (LLOQ) are set to zero. In the logarithmic scale plots, concentrations below LLOQ are set to LLOQ / 2. Summary of total pozeliumab and total C5 concentrations The measurements may include, but are not limited to, the arithmetic mean, standard deviation, standard error of the mean, coefficient of variation (expressed as a percentage), minimum value, Q1, median, Q3, and maximum value. No formal statistical analysis was performed.

[0305] Analysis of anti-drug antibody data. Anti-drug antibodies were characterized by the type and level of the observed response. Samples positive in the ADA assay were further characterized for neutralizing antibodies (NAb) and ADA titers.

[0306] The anti-drug antibody response classifications and titer classifications evaluated were as follows: • Negative / Pre-existing immunoreactivity; • Responses that occurred under treatment; • Enhanced response under treatment; • NAb response in ADA-positive patients; • Titeral value classification (titer range); - Low (potency less than 1,000) - Moderate (potency between 1,000 and 10,000) - High (potency over 10,000).

[0307] The ADA assay results, along with the ADA and NAb expressed under treatment, and the titers, time points, and administration cohorts / groups shown by patients, are listed. The incidence of ADA and NAb expressed under treatment was assessed as absolute incidence (N) and percentage of patients (%), grouped by ADA titer level.

[0308] The drug concentration plots were examined, and the impact of ADA on individual PK profiles was evaluated. Assessments of the impact of ADA on safety and efficacy were also presented in some cases.

[0309] Before treatment Registered patients required evidence of meningococcal immunization or vaccination during the screening period, and oral antibiotics were recommended during the treatment period, in accordance with local or national practices and the assessment of the principal investigator.

[0310] Vaccination. Registered patients required immunization by meningococcal vaccination. Vaccination was to be administered preferably at least two weeks prior to the initiation of pozerimab, or at a different time in accordance with local practice or national guidelines. Patients were suggested to be vaccinated against serotypes A, C, Y, W, and serotype B, if available. Patients who had previously received and documented meningococcal vaccination were reimmunized in accordance with local practice. Patients were to be closely monitored for early signs and symptoms of meningococcal infection and to be promptly evaluated if infection was suspected. Patients were provided with a patient safety card to describe signs and symptoms of meningococcal infection, along with instructions for potential meningococcal infection and information for non-investigator healthcare providers.

[0311] For pediatric patients, it was recommended, based on local practices, guidelines, and availability, that there be evidence of immunization with Haemophilus influenzae and / or vaccination with Streptococcus pneumoniae during the screening or treatment period. Vaccinations were procured locally by the principal investigator or their designated representative and reimbursed by the sponsor.

[0312] Oral antibiotics. Daily prophylactic oral antibiotics should only be administered if the risks outweigh the benefits. Treatment could be initiated on the day of the first dose, or continued for the duration of the trial, unless it was inconsistent with local practice. Patients who discontinued pozeliumab early were recommended to receive oral prophylactic antibiotics for at least 21 weeks after discontinuation of pozeliumab, or for a period consistent with local guidelines, whichever was longer. For adults, prophylactic antibiotics were suggested to be penicillin V, 500 mg twice daily (BID), and in cases of penicillin allergy, erythromycin, 500 mg, BID, was suggested at the discretion of the principal investigator. For pediatric patients, prophylactic antibiotics were suggested to be penicillin VK, 125 mg orally, BID, for patients under 5 years of age, and 250 mg, BID, for patients 5 years of age and older. If a pediatric patient had a penicillin allergy, the treatment was erythromycin, 125 mg orally, BID, for patients under 3 years of age, and 250 mg orally, BID, for patients 3 years of age and older. Ultimately, the decision regarding prophylactic oral antibiotic administration, duration of prophylactic treatment, selection of oral antibiotics, and administration regimen was left to the discretion of the principal investigator. Oral antibiotics were procured locally by the principal investigator or their designated representative and reimbursed by the sponsor.

[0313] Dosage Modification and Treatment Discontinuation Rules for Clinical Trials Dose Modification. Modification / reduction of the dosing regimen was not permitted for individual patients. If a patient moved to a higher BW group, the dose was to be increased according to the provisions of the dosing regimen. For the purpose of this dose increase, body weight was measured at the time of the trial visit (not with each weekly dose), as specified in the evaluation schedule. Pozelimab was originally supplied in vials as a vacuum lyophilized powder for reconstitution, and therefore a single form supported all body weight-based dosing regimens. The correct number of vials and the volume for SC injection taken were administered by a healthcare practitioner (not necessarily a physician) at the trial site, during the course of the visit, or between visits at a local primary healthcare clinic, or at home; self-administration / administration by the patient / designated person was also permitted in some cases. Each SC dose could be administered by more than two injections if necessary; each injection was not to exceed a volume of 2 mL.

[0314] Discontinuation of investigational drug. Patients who permanently discontinued the investigational drug but did not withdraw from the trial were asked to return to the clinic for all remaining trial visits according to their scheduled appointments. Patients who chose to permanently discontinue the investigational drug and withdraw from the trial could request to complete the trial evaluation.

[0315] Reasons for permanent discontinuation of the investigational drug. The investigational drug was permanently discontinued in the following cases: • A serious or severe allergic reaction thought to be related to the investigational drug; • Liver damage that occurs without evidence of another etiology and is demonstrated by one or more of the following criteria: - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is greater than 8 × ULN, or - For more than two weeks, ALT or AST is greater than 5x ULN, or - No other reason can be found to explain the combined increase in AST / ALT and total bilirubin, such as hepatitis A, B, or C virus; pre-existing or acute liver disease; or another drug capable of causing the observed injury; either ALT or AST is greater than 3 × ULN, and bilirubin is greater than 2 × ULN (or international normalized ratio [INR] is greater than 1.5), or other factors that could explain the combined increase in AST / ALT and total bilirubin. • The patient withdraws their consent; • Patient non-compliance (e.g., failure to follow the protocol's instructions regarding hospital visits, evaluations, and / or administration); or • The clinical judgment of the principal investigator that doing so is in the patient's best interest. Note: Evidence of pregnancy is not considered an automatic reason for permanent discontinuation, and media It was decided to discuss this with the medical monitor. Pregnancy could be a reason for permanent discontinuation of treatment with pozeliumab, if it was deemed undesirable after a benefit-for-risk assessment.

[0316] Reasons for temporary discontinuation of the investigational drug. The principal investigator could have considered temporary discontinuation due to suspected adverse events (AEs). If the principal investigator, based on their best medical judgment, believed that the investigational drug was not involved in the occurrence of the suspected event, they could have resumed treatment with the investigational drug under careful and appropriate clinical and / or laboratory monitoring.

[0317] Management of acute reactions Acute intravenous fluid response. The patient was to be observed for 30 minutes after fluid administration. Emergency equipment and medications for treating fluid responses had to be available for immediate use. All fluid responses had to be reported as adverse events (AEs) and graded using a grading scale.

[0318] Interruption of intravenous fluid administration. Intravenous fluid administration will be interrupted if any of the following adverse events (AEs) are observed: ·cough; • Chills / shivering; Rash, itching; Urticaria (hives, welts, wheals); • Sweating (diaphoresis) (sweating); • Low blood pressure; • Difficulty breathing (shortness of breath); • Vomiting; or ·Flushing.

[0319] The response was treated symptomatically, and intravenous fluid administration could be resumed at 50% of the original rate.

[0320] If the principal investigator felt there was a medical need to discontinue treatment or fluid therapy other than those mentioned above, the principal investigator was to provide appropriate responses based on representative clinical practice, using clinical judgment.

[0321] Discontinuation of intravenous fluid administration. If any of the following adverse events (AEs) occur, the fluid should be stopped and not restarted: Anaphylaxis * ; • Edema of the larynx / pharynx; • Severe bronchospasm; ·Chest pain; • Seizures; • Severe hypotension; Other neurological symptoms (impaired consciousness, loss of consciousness, sensory disturbances, paralysis, etc.); or • In the opinion of the principal investigator, any other symptoms or signs that would cause discontinuation of IV fluid administration * Anaphylaxis should be considered if any of the following are observed (Sampson et al., Second symposium on the definition and management of anaphylaxis: summary report - second National Institute of Allergy). and Infectious Disease / Food Allergy and Anaphylaxis Network Symposium. Ann Emerg Med 2006;47(4):373-80): Acute onset (within minutes to hours) of a disease affecting the skin, mucous membranes, or both (e.g., systemic rash, itching or flushing, swelling of the lip-lingual-uvula), and at least one of the following: • Dyspnea (e.g., shortness of breath, wheezing, bronchospasm, stenosis, decreased maximum expiratory flow, hypoxemia); or Symptoms associated with low blood pressure or end-organ dysfunction (e.g., hypotonia [collapse], syncope, incontinence).

[0322] Systemic injection reactions. Patients were to be observed for 30 minutes after the initial SC injection. Emergency equipment and medications for treating systemic reactions had to be available for immediate use. All injection reactions had to be reported as AEs and graded using a grading scale. Acute systemic reactions after SC injection of the investigational drug were to be treated by determining the appropriate response based on representative clinical practice, using clinical judgment.

[0323] Local injection site reactions. Local injection site reactions were to be reported as AEs and graded according to the Food and Drug Administration (FDA) September 2007 guidance for the industry, a toxicity grading scale for healthy adult and adolescent volunteers enrolled in prophylactic vaccine clinical trials.

[0324] Concomitant medications All treatments administered from the time of informed consent until the end of the final clinical trial visit were considered concomitant medications. This included medications initiated before the trial and continued throughout the trial period.

[0325] Prohibited medicines. Except for those permitted under the following discussion, the following medicines are prohibited: • When blood is drawn, patients must not consume any alcohol within 24 hours prior to their visit to the clinic. From the start of day 1 through the entire trial, patients were instructed not to take eculizumab while continuing to take REGN3918. • The addition of any experimental therapies, including complement inhibitors, even if approved during the clinical trial period; • Vitamin B12 supplementation should not be given during the first four weeks of pozelimusb treatment (i.e., it cannot be started before the fourth week visit).

[0326] Authorized medicines. Authorized medicines are all medicines that are not prohibited. The following medicines and procedures are authorized, subject to the following conditions: • Albumin infusion was permitted only during the screening period for life-threatening severe illnesses, and even after initiation of the investigational drug if albumin levels were less than 3.0 g / dL and accompanied by symptoms of facial or peripheral edema or ascites. This restriction applied only to albumin infusions specifically administered for PLE. • Any medications deemed necessary to treat the AE, including nonsteroidal anti-inflammatory drugs, antihistamines, or topical or systemic corticosteroids, at the discretion of the principal investigator; • Meningococcal vaccine inoculation; • Oral prophylactic antibiotic administration; • Medications for treating type III hypersensitivity reactions • Oral contraceptives and hormone replacement therapy could be continued or initiated during the trial period. ; • Acetaminophen / paracetamol, aspirin, or ibuprofen at the recommended dose according to the local label; • Immunosuppressants, biological therapies, immunoglobulins, corticosteroids, antithrombotic agents, anticoagulants, antibiotics, iron supplements, vitamins, and enteral and parenteral nutritional support were permitted. Any changes to these concomitant medications were at the discretion of the principal investigator. In the context of a response to treatment with pozeliumab in the underlying disease, any discontinuation and / or withdrawal from these medications was permitted at the discretion of the principal investigator; or • Any medication necessary for treating the patient's background medical condition.

[0327] [Table 14-1] [Table 14-2]

[0328] [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4]

[0329] Hematological, chemical (excluding total C5, CH50 sC5b-9, and C5a), urine analysis, and pregnancy test samples were available for analysis by the local / central laboratory. Other tests were performed by the central laboratory or specialized laboratory as outlined in the sample management plan. Detailed instructions for blood sample collection are included in the sample management plan provided to the clinical trial site.

[0330] [Table 16]

[0331] Lipid panel (fasting state) Total cholesterol (LDL and HDL) Triglycerides

[0332] Blood immunoglobulin panel Total Ig, IgG, IgM, IgA

[0333] Micronutrient Panel Vitamin B12, folic acid, iron, iron binding capacity, ferritin

[0334] [Table 17]

[0335] Coagulation panel PT / aPTT (PT / aPTT Prothrombin Time / Activated Partial Thromboplastin Time)

[0336] urine analysis glucose Protein - Note: If protein levels are ++ or higher, promptly check the urinary protein-creatinine ratio. Blood - Note: If blood levels are ++ or higher, perform a microscopic examination immediately.

[0337] Other clinical tests Other clinical tests included the following: Complement hemolysis assay (CH50) Alpha-1 anti-trypsin Pregnancy tests: Serum human chorionic gonadotropin pregnancy test, urine pregnancy test Sample collection, including drug concentration, ADA, and exploratory biomarkers, was described separately.

[0338] 21. Refer to the blood immunoglobulin panel. 22. In accordance with local practices in the country where the clinical trial was conducted, pregnancy testing (urinary human chorionic gonadotropin) was mandatory for all women of sexual maturity age or married women, and, at the discretion of the principal investigator, for unmarried women of sexual maturity age. 23. When it was necessary to comply with local weight-specific limits on blood collection volume, the frequency of blood sampling for this analyte was reduced. The blood collection schedule in the SOE table was designed for patients weighing 20 kg or more. It was anticipated that the frequency of blood sampling would need to be reduced for patients weighing less than 20 kg. For patients weighing 10 kg to 20 kg, a different blood collection schedule was provided in the sample handling manual. For patients weighing less than 10 kg, the priority of blood sampling was presented in the sample handling manual or kit instructions, and samples were to be collected in this order until the volume limit was reached. The chemistry panel was given the highest priority, followed by whole blood count and drug concentration. 24. D-dimers, sometimes including F(1+2), were also found. 25. Samples were to be collected at the baseline visit, however, they could be collected at any time. 26. The kits were available on-site so that chemical panels could be obtained on-site without requiring a visit to the facility. 27. Drug concentrations and ADA samples were to be collected before administration of the investigational drug. Any SAE or any A indicative of an anaphylactic or systemic allergic reaction related to the investigational drug and requiring treatment, or a severe injection site reaction lasting longer than 24 hours. In cases of ESI (Extreme Syndrome Infection), drug concentrations and ADA samples were collected simultaneously with or near the event for any additional analysis. 28. If a patient sample was positive in the pozelimusb ADA assay at week 12 or the first time of analysis, the PK sample at week 4 was allowed to be analyzed in the ADA assay if a sufficient volume was available. 29. The screening period can be extended to approximately 10 weeks for patients with conditions that warrant consideration.

[0339] COVID-19 Given the public health emergency associated with COVID-19, it may have been necessary to implement primary or alternative mechanisms to continue conducting and monitoring clinical trials. Examples of such mechanisms may include, but are not limited to, telephone contact, virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring devices, use of local clinics or testing sites, and home visits by skilled staff. Furthermore, no exemptions for deviations from protocol registration criteria due to COVID-19 were granted. All temporary mechanisms and deviations from planned clinical trial procedures used in response to COVID-19 were documented as COVID-19 related and were valid only for the duration of the public health emergency.

[0340] result Patients receiving the pozeliumab regimen showed some improvement in albumin, total protein, vitamin B12, platelets, fecal α1AT, facial edema, and extremity edema, as well as some indication of improvement in abdominal pain scores and bowel movement frequency; and early signs of reduced hospital stay and reduced steroid use.

[0341] Albumin and total protein. CHAPLE is characterized by the loss of serum proteins, such as albumin, into the gastrointestinal tract, leading to hypoproteinemia (which may be accompanied by edema, ascites, pleural and pericardial effusion, and malnutrition). In healthy individuals, protein loss through the intestinal epithelium plays only a minor role in total protein metabolism. In CHAPLE, gastrointestinal (GI) protein loss can account for up to 60% of the total albumin pool. Patients who received pozerima prednisolone showed more normal levels of serum albumin and total protein, suggesting reduced GI protein loss. Albumin levels improved within a short period after the start of treatment (increasing to above the lower limit of normal (LLN)) and remained above LLN at all time points measured (Figure 28(a)). Monitoring albumin levels in each patient before treatment demonstrated that albumin levels were historically below normal (Figures 28(b)-(e)). In addition, within a short period after the start of treatment, total protein levels improved (increasing to between the lower limit of normal (LLN) and the upper limit of normal (ULN)), and remained within this normal range at all measurement points (Figure 29).

[0342] Vitamin B12. Malabsorption and deficiency of vitamins, such as B12, have been observed in protein-losing enteropathy. Vitamin B12 levels improved over time in patients who received pozelima prednisolone. This is likely due to a reduction in GI malabsorption in CHAPLE patients. These patients did not receive vitamin B12 supplementation. Vitamin B12 levels improved within a short period after the start of treatment and were maintained at elevated levels at all time points measured (Figure 30).

[0343] Platelets. Excessive activation of complement activity can trigger the coagulation cascade. Loss of GPI-anchored complement inhibitory proteins, such as CD55, can lead to... This may lead to terminal-complement-mediated hemolysis, which carries a secondary thrombotic risk. In fact, CHAPLE patients have an increased risk of thrombosis. Patients receiving pozerima prednisolone benefit from a decrease in platelet count. In the short period after the start of treatment, platelet counts decreased and remained at low levels at all time points measured (Figure 31).

[0344] Fecal alpha-1-antitrypsin. Alpha-1-antitrypsin (A1A) is resistant to degradation by digestive enzymes and is therefore used as an endogenous marker for the presence of blood proteins in the intestinal tract. Patients who received pozerima prednisolone showed a decrease in A1A. In the short period after the start of treatment, fecal alpha-1-antitrypsin concentrations decreased in each patient and remained at low levels at all time points measured (Figure 32).

[0345] Facial and peripheral edema. CHAPLE is characterized by excessive loss of serum proteins into the gastrointestinal tract. This leads to decreased serum protein levels, and in severe cases, fluid loss from the vascular lumen and edema. Evidence of reduced edema was observed in patients who received pozelima prednisolone. In the short period following the initiation of treatment, the severity (grade) of facial and peripheral edema generally decreased in patients and remained at low levels at all time points measured (Figures 33 and 34).

[0346] Bowel movement frequency. Patients with Chaple's disease commonly experience diarrhea and excessive bowel movements. These factors have a significant impact on the patient's quality of life and can lead to secondary medical conditions, such as vitamin or electrolyte imbalances. Evidence exists that patients treated with pozerima precipitum achieved improved bowel movement frequency. Shortly after the start of treatment, patients showed initial signs of decreased bowel movement frequency (Figure 35). Therefore, the present invention is intended for patients with C5-related diseases, such as Chaple's disease, (i) One or more intravenous (IV) doses of approximately 30 mg / kg of an antagonist antigen-binding protein that specifically binds to C5 (e.g., pozelimusb); then (ii) One or more subcutaneous (SC) doses (e.g., weekly) of approximately 800 mg of an antagonist antigen-binding protein that specifically binds to C5; or (i) One or more intravenous (IV) doses of approximately 30 mg / kg of an antagonist antigen-binding protein that specifically binds to C5 (e.g., pozelimusb); then (ii) In the following cases: - For those weighing less than 10 kg (BW): 125 mg; - For babies weighing 10kg or more but less than 20kg: 200mg; - For babies weighing 20kg or more but less than 40kg: 350mg; - For BW 40kg or more and less than 60kg: 500mg; and - For BW (Body Weight) of 60kg or more: 800mg Accordingly, one or more subcutaneous (SC) doses (e.g., weekly) of an antagonist antigen-binding protein that specifically binds to C5. By administering it to the patient: • To increase serum albumin levels or reduce their loss through the GI tube; • To increase total serum protein levels or reduce their loss through the GI tube; • To increase serum vitamins (e.g., vitamin B12) even without supplementation of such vitamins or their GI absorption; • To reduce platelet count, or reduce activation of the coagulation cascade, or reduce the incidence of thrombotic events (e.g., heart attack, stroke); • Reduces the loss of alpha-1 antitrypsin through the GI tube; • To treat or prevent edema (e.g., facial or peripheral); • To reduce the frequency of bowel movements, or to treat or prevent diarrhea; • To treat or prevent abdominal pain; Reduce the use of steroids (e.g., corticosteroids such as cortisone, hydrocortisone, or prednisone); • Reduce the incidence of hospitalization; To provide a method for that purpose.

[0347] All references cited herein are incorporated by reference to the same extent as individual publications, database entries (e.g., Genbank sequences or GeneID entries), patent applications, or patents are specifically and individually indicated as being incorporated by reference. This incorporation by reference is intended by the applicant to relate to each publication, database entry (e.g., Genbank sequences or GeneID entries), patent application, or patent, each of which is clearly identified even if such citation is not directly adjacent to the specific incorporation by reference statement. Where there is a specific incorporation by reference statement, its inclusion within this specification does not diminish this general incorporation by reference statement in any way. The citation of references herein does not constitute an acknowledgment that such references are relevant prior art, nor does it constitute any endorsement of the content or date of such publications or documents.

Claims

1. A method for administering an antagonist antigen-binding protein or a pharmaceutical formulation thereof that specifically binds to C5 to a subject suffering from a C5-related disease, comprising the steps of: introducing approximately 30 mg / kg of the antigen-binding protein intravenously into the subject's body one or more times; and optionally, introducing the antigen-binding protein or a pharmaceutical formulation thereof subcutaneously one or more times.

2. A method for administering an antagonist antigen-binding protein or a pharmaceutical preparation thereof that specifically binds to C5, to the body of the target, (i) A step of introducing approximately 30 mg / kg of antigen-binding protein intravenously (IV) once or multiple times; then (ii) A step of introducing approximately 800 mg of antigen-binding protein subcutaneously (SC) once or multiple times; or (i) A step of introducing approximately 30 mg / kg of antigen-binding protein intravenously (IV) once or multiple times; then (ii) Subcutaneously (SC) one or more times administer the antigen-binding protein as follows: The method, including the step of introducing: - For body weight (BW) < 10 kg: 125 mg; - For BW ≥ 10 kg and < 20 kg: 200 mg; - For BW ≥ 20 kg and < 40 kg: 350 mg; - For BW ≥ 40 kg and < 60 kg: 500 mg; and - For BW ≥ 60 kg: 800 mg.

3. The method according to any one of claims 1 to 2, wherein the subject is a human.

4. The method according to any one of claims 1 to 3, wherein the subcutaneous administration is performed once a week.

5. The method according to any one of claims 1 to 4, wherein only a single intravenous dose is administered.

6. The method according to any one of claims 4 to 5, wherein the once-weekly administration is administered approximately 7 days, 7 days (+1 day), 7 days (+2 days), or 7 days (+3 days) after the most recent administration.

7. The method according to any one of claims 1 to 6, applicable to a person suffering from a C5-related disease.

8. The method according to any one of claims 1 to 7, wherein subcutaneous administration is performed on the subject using a pre-filled syringe.

9. A method for treating or preventing CD55-deficient protein-losing enteropathy in a person requiring it: (1) The amino acid sequence described in Sequence ID No. 2 or its heavy chain variable region (HCVR) including HCDR1, HCDR2, and HCDR3, and the amino acid sequence described in Sequence ID No. 10 or its light chain variable region (LCVR) including LCDR1, LCDR2, and LCDR3; (2) an HCVR containing the amino acid sequence described in SEQ ID NO: 18 or its HCDR1, HCDR2, and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 26 or its LCDR1, LCDR2, and LCDR3; (3) The amino acid sequence described in Sequence ID No. 34 or its HCVR including HCDR1, HCDR2 and HCDR3, and the amino acid sequence described in Sequence ID No. 42 or LCVR including LCDR1, LCDR2, and LCDR3; (4) an HCVR containing the amino acid sequence described in SEQ ID NO: 50 or its HCDR1, HCDR2, and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 58 or its LCDR1, LCDR2, and LCDR3; (5) an HCVR containing the amino acid sequence described in SEQ ID NO: 66 or its HCDR1, HCDR2, and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 74 or its LCDR1, LCDR2, and LCDR3; (6) an HCVR containing the amino acid sequence described in SEQ ID NO: 82 or its HCDR1, HCDR2, and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 90 or its LCDR1, LCDR2, and LCDR3; (7) an HCVR containing the amino acid sequence described in SEQ ID NO: 98 or its HCDR1, HCDR2, and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 106 or its LCDR1, LCDR2, and LCDR3; (8) an HCVR containing the amino acid sequence described in SEQ ID NO: 98 or its HCDR1, HCDR2, and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 114 or its LCDR1, LCDR2, and LCDR3; (9) an HCVR containing the amino acid sequence described in SEQ ID NO: 122 or its HCDR1, HCDR2 and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 106 or its LCDR1, LCDR2 and LCDR3; (10) an HCVR containing the amino acid sequence described in SEQ ID NO: 98 or its HCDR1, HCDR2, and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 130 or its LCDR1, LCDR2, and LCDR3; (11) an HCVR containing the amino acid sequence described in SEQ ID NO: 138 or its HCDR1, HCDR2, and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 106 or its LCDR1, LCDR2, and LCDR3; (12) an HCVR containing the amino acid sequence described in SEQ ID NO: 146 or its HCDR1, HCDR2, and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 106 or its LCDR1, LCDR2, and LCDR3; (13) an HCVR containing the amino acid sequence described in SEQ ID NO: 122 or its HCDR1, HCDR2 and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 130 or its LCDR1, LCDR2 and LCDR3; (14) an HCVR containing the amino acid sequence described in SEQ ID NO: 146 or its HCDR1, HCDR2, and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 114 or its LCDR1, LCDR2, and LCDR3; (15) an HCVR containing the amino acid sequence described in SEQ ID NO: 146 or its HCDR1, HCDR2, and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 130 or its LCDR1, LCDR2, and LCDR3; (16) an HCVR containing the amino acid sequence described in SEQ ID NO: 138 or its HCDR1, HCDR2, and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 130 or its LCDR1, LCDR2, and LCDR3; (17) an HCVR containing the amino acid sequence described in SEQ ID NO: 154 or its HCDR1, HCDR2, and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 162 or its LCDR1, LCDR2, and LCDR3; (18) an HCVR containing the amino acid sequence described in SEQ ID NO: 170 or its HCDR1, HCDR2, and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 178 or its LCDR1, LCDR2, and LCDR3; (19) an HCVR containing the amino acid sequence described in SEQ ID NO: 186 or its HCDR1, HCDR2, and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 194 or its LCDR1, LCDR2, and LCDR3; (20) The amino acid sequence described in Sequence ID No. 202 or its HCDR1, HCDR2 HCVR including HCDR3, and LCVR including the amino acid sequence described in Sequence ID No. 210 or its LCDR1, LCDR2, and LCDR3; (21) an HCVR containing the amino acid sequence described in SEQ ID NO: 218 or its HCDR1, HCDR2, and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 226 or its LCDR1, LCDR2, and LCDR3; (22) an HCVR containing the amino acid sequence described in SEQ ID NO: 234 or its HCDR1, HCDR2 and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 242 or its LCDR1, LCDR2 and LCDR3; (23) an HCVR containing the amino acid sequence described in SEQ ID NO: 250 or its HCDR1, HCDR2 and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 258 or its LCDR1, LCDR2 and LCDR3; (24) an HCVR containing the amino acid sequence described in SEQ ID NO: 266 or its HCDR1, HCDR2 and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 258 or its LCDR1, LCDR2 and LCDR3; (25) an HCVR containing the amino acid sequence described in SEQ ID NO: 274 or its HCDR1, HCDR2, and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 282 or its LCDR1, LCDR2, and LCDR3; (26) an HCVR containing the amino acid sequence described in SEQ ID NO: 290 or its HCDR1, HCDR2 and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 298 or its LCDR1, LCDR2 and LCDR3; (27) an HCVR containing the amino acid sequence described in SEQ ID NO: 306 or its HCDR1, HCDR2 and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 314 or its LCDR1, LCDR2 and LCDR3; (28) an HCVR containing the amino acid sequence described in SEQ ID NO: 322 or its HCDR1, HCDR2 and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 330 or its LCDR1, LCDR2 and LCDR3; Furthermore, (29) HCVR containing the amino acid sequence described in SEQ ID NO: 338 or its HCDR1, HCDR2 and HCDR3, and LCVR containing the amino acid sequence described in SEQ ID NO: 346 or its LCDR1, LCDR2 and LCDR3 The method comprising administering a therapeutically effective amount of an antagonist antigen-binding protein that specifically binds to C5, comprising one or more selected from the group consisting of the above.

10. A method for treating or preventing C5-related disease or reducing C5 complement activity in a subject, comprising the step of administering an antagonist antigen-binding protein that specifically binds to C5 to the subject by the method according to any one of claims 1 to 8.

11. The method according to claim 10, wherein C5 complement activity is reduced by about 95–100% when measured by the CH50 assay of complement-mediated sheep erythrocyte lysis.

12. The method according to any one of claims 10 to 11, wherein the C5-related disorder is paroxysmal nocturnal hemoglobinuria (PNH).

13. The method according to any one of claims 10 to 11, wherein the C5-related disease is CD55-deficient protein-losing enteropathy (CHAPLE disease).

14. C5-related diseases are: Adult respiratory distress syndrome; age-related macular degeneration (AMD); allergy; Alport syndrome; Alzheimer's disease; amyotrophic lateral sclerosis (ALS); antiphospholipid syndrome (APS); asthma; atherosclerosis; atypical hemolytic uremic syndrome (aHUS); autoimmune disease; autoimmune Hemolytic anemia (AIHA); balloon angioplasty; bronchoconstriction; bullous pemphigoid; burns; C3 glomerulosis; capillary leak syndrome; cardiovascular disorders; fulminant antiphospholipid syndrome (CAPS); cerebrovascular disorders; CHAPLE disease (CD55 deficiency with complement hyperactivation, vascular thrombosis, and protein-losing enteropathy); chemical injuries; chronic obstructive pulmonary disease (COPD); cold agglutinin disease (CAD); corneal and / or retinal tissue; Crohn's disease; Degos disease; dense deposit disease (DDD); dermatomyositis; diabetes mellitus; diabetic vasculopathy; diabetic macular edema (DME); diabetic nephropathy; diabetes. Disease retinopathy; dilated cardiomyopathy; impaired inappropriate or undesirable complement activation; dyspnea; eclampsia; emphysema; epidermolysis bullosa; epilepsy; fibroplastic pneumoconiosis; frostbite; geographic atrophy (GA); glomerulonephritis; glomerulopathy; Goodpasture syndrome; Graves' disease; Guillain-Barré syndrome; Hashimoto's thyroiditis; complications of hemodialysis; hemolysis, elevated liver enzymes, thrombocytopenia (HELLP) syndrome; hemolytic anemia; hemoptysis; Henoch-Schönlein purpura nephritis; hereditary angioedema; hyperacute allograft rejection; hypersensitivity pneumonitis; idiopathic thrombocytopenic purpura (ITP); IgA nephropathy; immune complex disorders; Immune complex vasculitis; immune complex-associated inflammation; infection; inflammation due to autoimmune disease; inflammatory disorders; hereditary CD59 deficiency; damage from inert dust and / or inorganic substances; interleukin-2-induced toxicity during IL-2 therapy; ischemia-reperfusion injury; Kawasaki disease; lung disease or disorder; lupus nephritis; membranoproliferative glomerulonephritis; membranoproliferative glomerulonephritis; mesenteric artery reperfusion after aortic reconstruction; mesenteric / intestinal circulatory disorders; multifocal motor neuropathy (MMN); multiple sclerosis; myasthenia gravis; myocardial infarction; myocarditis; neuropathy; neuromyelitis optica; obesity; intraocular neovascularization; intraocular blood vessels affecting the choroid Neonatal infection; organoconstriction; parasitic infections; Parkinson's disease; paroxysmal nocturnal hemoglobinuria (PNH); microimmune vasculitis; pemphigus; percutaneous transcatheter coronary angioplasty (PTCA); peripheral vascular disease; pneumonia; post-ischemia-reperfusion; post-pump syndrome in cardiopulmonary bypass; post-pump syndrome in renal bypass; preeclampsia; progressive renal failure; proliferative glomerulonephritis; proteinuria; psoriasis; pulmonary embolism; pulmonary fibrosis; pulmonary infarction; pulmonary vasculitis; recurrent miscarriage; kidney damage; renal ischemia; renal ischemia-reperfusion injury; renal vascular disease; restenosis after stent placement; rheumatoid arthritis (RA); rotational atherosclerosis; schizophrenia; sepsis;The method according to any one of claims 10 to 11, wherein the condition is septic shock; SLE nephritis; smoke damage; spinal cord injury; spontaneous abortion; stroke; systemic inflammatory response to sepsis; systemic lupus erythematosus (SLE); systemic lupus erythematosus-associated vasculitis; Takayasu's arteriovenous arthritis; burns; thrombotic thrombocytopenic purpura (TTP); traumatic brain injury; type 1 diabetes mellitus; typical hemolytic uremic syndrome (tHUS); uveitis; vasculitis; vasculitis associated with rheumatoid arthritis; venous gas embolism (VGE); and / or; xenograft rejection.

15. A method for maintaining a concentration of at least about 100 mg / L of an antagonist antigen-binding protein that specifically binds to C5 in the serum of a subject, and / or maintaining at least 80% suppression of hemolysis in the serum of a subject, the method comprising the step of administering an antagonist antigen-binding protein that specifically binds to C5 to a subject by the method of any one of claims 1 to 8.

16. The method according to claim 15, applicable to individuals suffering from C5-related diseases.

17. The method according to any one of claims 15 to 16, wherein hemolysis is measured in vitro in a CH50 and / or AH50 assay.

18. In subjects with CD55-deficient protein-losing enteropathy: - To normalize and / or increase serum albumin levels, or to reduce its loss through the gastrointestinal tract; - To increase total serum protein levels or reduce their loss through the gastrointestinal tract; - Increases serum vitamin B12 or its gastrointestinal absorption; - Reduces platelet count, or reduces coagulation cascade activation, or thrombotic To reduce the occurrence of an event; - Reduces the loss of alpha-1 antitrypsin through the gastrointestinal tract; - To treat or prevent facial edema and / or peripheral edema; - Reduce the frequency of bowel movements; - To treat or prevent diarrhea; - To treat or prevent abdominal pain; - Reduce the use of corticosteroids; and / or - Reduce the incidence of hospitalization; or A method for reducing therapeutic intervention, comprising the step of administering to a subject an antagonist antigen-binding protein that specifically binds to C5 by the method described in any one of claims 1 to 8; Therapeutic interventions include: (i) Administration of corticosteroids; (ii) Administration of immunoglobulin; (iii) Administration of albumin; (iv) Administration of antitumor necrosis factor alpha therapeutic agents; (v) Administration of immunomodulatory drugs; (vi) Administration of micronutrients; (vii) Administration of enteral or parenteral supplementation; (viiii) Administration of anticoagulants; (ix) Administration of antibiotics; and (x) Administration of antiplatelet agents The method is one or more selected from the group consisting of the following.

19. The method according to claim 18 for increasing serum albumin by at least 1 g / dL and / or normalizing serum albumin to about 3.5 to about 5.5 g / dL.

20. A method for reducing serum lactate dehydrogenase (LDH) levels, intravascular hemolysis, and / or the need for red blood cell transfusion in a subject suffering from paroxysmal nocturnal hemoglobinuria (PNH), the method comprising the step of administering to the subject an antagonist antigen-binding protein that specifically binds to C5 by the method according to any one of claims 1 to 8.

21. (i) The subject has a serum lactate dehydrogenase (LDH) level ≥ 2 × upper limit of normal (ULN); (ii) The subjects have >10% PNH granulocytes (polymorphonucleated nuclei [PMN]); (iii) The subjects are those with hypoalbuminemia of 3.2 g / dL or less; (iv) The subject is suffering from diarrhea; (v) The subject is suffering from vomiting; (vi) The subject is suffering from abdominal pain; (vii) The subjects are those suffering from peripheral edema or facial edema; (viiii) The subjects are those who have had an episode of infection complicated with hypogammaglobulinemia or a thromboembolic event; (ix) The subject is suffering from fatigue; (x) The subject has hemoglobinuria; (xi) The subject is suffering from shortness of breath (difficulty breathing); (xi) The subject is anemic; (xiiii) The subject has a history of major adverse vascular events; (xiv) The subject has a swallowing disorder; and / or (xv) The method according to any one of claims 1 to 20, wherein the subject is suffering from erectile dysfunction.

22. (i) The subjects have biallelelic loss-of-function mutations in CD55; (ii) The subjects are frameshift mutations; missense mutations, splice site mutations, or nonsense mutations in CD55 that are biallelic loss-of-function mutations; (iii) The subjects are those with hypoalbuminemia, where serum albumin is 3.2 g / dL or less; (iv) The subject is suffering from diarrhea; (v) The subject is suffering from vomiting; (vi) The subject is suffering from abdominal pain; (vii) The subjects are those suffering from peripheral edema or facial edema; (viiii) The subject has an episode of infection complicated with hypogammaglobulinemia; and / or (ix) The method according to any one of claims 1 to 21, wherein the subject is suffering from a thrombotic event.

23. The method according to any one of claims 1 to 22, wherein the antagonist antigen-binding protein that specifically binds to C5 is an antibody or an antigen-binding fragment thereof.

24. The method according to any one of claims 1 to 23, wherein the antagonist antigen-binding protein that specifically binds to C5 is REGN3918 (pozelimab).

25. The method according to any one of claims 1 to 24, for patients who have previously taken tesidorumab, eculizumab, and / or ravulizumab.

26. The antagonist antigen-binding proteins that specifically bind to C5 are: (1) The amino acid sequence described in Sequence ID No. 2 or the heavy chain variable region (HCVR) thereof containing HCDR1, HCDR2, and HCDR3, and the amino acid sequence described in Sequence ID No. 10 or the light chain variable region (LCVR) thereof containing LCDR1, LCDR2, and LCDR3; (2) HCVRs containing the amino acid sequence described in SEQ ID NO: 18 or HCDR1, HCDR2, and HCDR3 thereof, and LCVRs containing the amino acid sequence described in SEQ ID NO: 26 or LCDR1, LCDR2, and LCDR3 thereof; (3) HCVRs containing the amino acid sequence described in SEQ ID NO: 34 or HCDR1, HCDR2, and HCDR3 thereof, and LCVRs containing the amino acid sequence described in SEQ ID NO: 42 or LCDR1, LCDR2, and LCDR3 thereof; (4) HCVRs containing the amino acid sequence described in SEQ ID NO: 50 or HCDR1, HCDR2, and HCDR3 thereof, and LCVRs containing the amino acid sequence described in SEQ ID NO: 58 or LCDR1, LCDR2, and LCDR3 thereof; (5) HCVRs containing the amino acid sequence described in SEQ ID NO: 66 or HCDR1, HCDR2, and HCDR3 thereof, and LCVRs containing the amino acid sequence described in SEQ ID NO: 74 or LCDR1, LCDR2, and LCDR3 thereof; (6) HCVRs containing the amino acid sequence described in SEQ ID NO: 82 or HCDR1, HCDR2, and HCDR3 thereof, and LCVRs containing the amino acid sequence described in SEQ ID NO: 90 or LCDR1, LCDR2, and LCDR3 thereof; (7) HCVRs containing the amino acid sequence described in SEQ ID NO: 98 or HCDR1, HCDR2, and HCDR3 thereof, and LCVRs containing the amino acid sequence described in SEQ ID NO: 106 or LCDR1, LCDR2, and LCDR3 thereof; (8) an HCVR containing the amino acid sequence described in SEQ ID NO: 98 or its HCDR1, HCDR2, and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 114 or its LCDR1, LCDR2, and LCDR3; (9) The amino acid sequence described in SEQ ID NO: 122 or the HCVR containing HCDR1, HCDR2 and HCDR3 thereof, and the amino acid sequence described in SEQ ID NO: 106 LCVR including its LCDR1, LCDR2, and LCDR3; (10) an HCVR containing the amino acid sequence described in SEQ ID NO: 98 or HCDR1, HCDR2, and HCDR3 thereof, and an LCVR containing the amino acid sequence described in SEQ ID NO: 130 or LCDR1, LCDR2, and LCDR3 thereof; (11) an HCVR containing the amino acid sequence described in SEQ ID NO: 138 or HCDR1, HCDR2, and HCDR3 thereof, and an LCVR containing the amino acid sequence described in SEQ ID NO: 106 or LCDR1, LCDR2, and LCDR3 thereof; (12) HCVRs containing the amino acid sequence described in SEQ ID NO: 146 or HCDR1, HCDR2, and HCDR3 thereof, and LCVRs containing the amino acid sequence described in SEQ ID NO: 106 or LCDR1, LCDR2, and LCDR3 thereof; (13) an HCVR containing the amino acid sequence described in SEQ ID NO: 122 or its HCDR1, HCDR2, and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 130 or its LCDR1, LCDR2, and LCDR3; (14) HCVRs containing the amino acid sequence described in SEQ ID NO: 146 or HCDR1, HCDR2, and HCDR3 thereof, and LCVRs containing the amino acid sequence described in SEQ ID NO: 114 or LCDR1, LCDR2, and LCDR3 thereof; (15) HCVRs containing the amino acid sequence described in SEQ ID NO: 146 or HCDR1, HCDR2, and HCDR3 thereof, and LCVRs containing the amino acid sequence described in SEQ ID NO: 130 or LCDR1, LCDR2, and LCDR3 thereof; (16) an HCVR containing the amino acid sequence described in SEQ ID NO: 138 or HCDR1, HCDR2, and HCDR3 thereof, and an LCVR containing the amino acid sequence described in SEQ ID NO: 130 or LCDR1, LCDR2, and LCDR3 thereof; (17) HCVRs containing the amino acid sequence described in SEQ ID NO: 154 or HCDR1, HCDR2, and HCDR3 thereof, and LCVRs containing the amino acid sequence described in SEQ ID NO: 162 or LCDR1, LCDR2, and LCDR3 thereof; (18) HCVRs containing the amino acid sequence described in SEQ ID NO: 170 or HCDR1, HCDR2, and HCDR3 thereof, and LCVRs containing the amino acid sequence described in SEQ ID NO: 178 or LCDR1, LCDR2, and LCDR3 thereof; (19) HCVRs containing the amino acid sequence described in SEQ ID NO: 186 or HCDR1, HCDR2, and HCDR3 thereof, and LCVRs containing the amino acid sequence described in SEQ ID NO: 194 or LCDR1, LCDR2, and LCDR3 thereof; (20) an HCVR containing the amino acid sequence described in SEQ ID NO: 202 or its HCDR1, HCDR2, and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 210 or its LCDR1, LCDR2, and LCDR3; (21) an HCVR containing the amino acid sequence described in SEQ ID NO: 218 or its HCDR1, HCDR2, and HCDR3, and an LCVR containing the amino acid sequence described in SEQ ID NO: 226 or its LCDR1, LCDR2, and LCDR3; (22) HCVRs containing the amino acid sequence described in SEQ ID NO: 234 or HCDR1, HCDR2, and HCDR3 thereof, and LCVRs containing the amino acid sequence described in SEQ ID NO: 242 or LCDR1, LCDR2, and LCDR3 thereof; (23) an HCVR containing the amino acid sequence described in SEQ ID NO: 250 or HCDR1, HCDR2 and HCDR3 thereof, and an LCVR containing the amino acid sequence described in SEQ ID NO: 258 or LCDR1, LCDR2 and LCDR3 thereof; (24) an HCVR containing the amino acid sequence described in SEQ ID NO: 266 or HCDR1, HCDR2 and HCDR3 thereof, and an LCVR containing the amino acid sequence described in SEQ ID NO: 258 or LCDR1, LCDR2 and LCDR3 thereof; (25) an HCVR containing the amino acid sequence described in SEQ ID NO: 274 or HCDR1, HCDR2 and HCDR3 thereof, and an LCVR containing the amino acid sequence described in SEQ ID NO: 282 or LCDR1, LCDR2 and LCDR3 thereof; (26) The amino acid sequence described in Sequence ID No. 290 or its HCDR1, HCDR2 HCVR including HCDR3, and LCVR including the amino acid sequence described in Sequence ID No. 298 or its LCDR1, LCDR2, and LCDR3; (27) HCVRs containing the amino acid sequence described in SEQ ID NO: 306 or HCDR1, HCDR2, and HCDR3 thereof, and LCVRs containing the amino acid sequence described in SEQ ID NO: 314 or LCDR1, LCDR2, and LCDR3 thereof; (28) an HCVR containing the amino acid sequence described in SEQ ID NO: 322 or HCDR1, HCDR2 and HCDR3 thereof, and an LCVR containing the amino acid sequence described in SEQ ID NO: 330 or LCDR1, LCDR2 and LCDR3 thereof; Furthermore / or, (29) an HCVR comprising the amino acid sequence described in SEQ ID NO: 338 or therein HCDR1, HCDR2 and HCDR3, and an LCVR comprising the amino acid sequence described in SEQ ID NO: 346 or therein LCDR1, LCDR2 and LCDR3; or Regarding binding to C5, it competes with antigen-binding proteins selected from the group consisting of (1) to (29); or The method according to any one of claims 1 to 25, wherein the antigen-binding protein selected from the group consisting of (1) to (29) binds to the same C5 epitope.

27. The antagonist antigen-binding protein that specifically binds to C5 has the following amino acid sequence: QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNYNPSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWG QGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKT ISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (Sequence ID 368) or its variable region or an immunoglobulin heavy chain containing HCDR1, HCDR2, and HCDR3; Furthermore, Amino acid sequence: AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPSRFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC The method according to any one of claims 1 to 26, wherein the antibody is a monoclonal antibody comprising (SEQ ID NO: 369) or its variable region or an immunoglobulin light chain comprising LCDR1, LCDR2 and LCDR3 thereof.

28. The method according to any one of claims 1 to 27, wherein an antagonist antigen-binding protein that specifically binds to C5 is administered or introduced in combination with a further therapeutic agent.

29. Further therapeutic agents include acetaminophen, albumin infusion, Anklod, angiotensin-converting enzyme inhibitors, antibiotics (e.g., oral antibiotics), further antibodies, anti-CD20 agents, anticoagulants, antifungals, antihypertensives, anti-inflammatory drugs, anti-plasmin-a1, anticonvulsants, antithrombotic agents, anti-TNF-alpha agents, antivirals, argatroban, aspirin, biological agents, bivalirudin, C3 inhibitors, corticosteroids, cyclosporine A, dabigatran, and defibrillator. Ibrotide, E-aminocaproic acid, enteral nutrition, erythromycin, erythropoietin, fibrinolytic agents, folic acid, fondaparinux, heparin, hormone replacement therapy, ibuprofen, hydraparinax, immunosuppressants, infliximab, hydroxymethylglutaryl-CoA reductase inhibitors, iron supplements, repiridine, lipid-lowering agents, magnesium sulfate, meningococcal vaccine, methotrexate, nonsteroidal anti-inflammatory drugs (NSAIDs), oligosaccharides The method according to claim 28, wherein the nucleotides are paracetamol, parenteral nutrition, penicillin, phenindione, contraceptives, prostacyclin, rituximab, thrombin inhibitors, vaccines, vincristine, vitamins and / or warfarin.

30. Further treatments include: DNA oligonucleotides, RNA oligonucleotides, - Single-stranded DNA oligonucleotides, - Single-stranded RNA oligonucleotides, - Double-stranded DNA oligonucleotides, or Double-stranded RNA oligonucleotides It is an oligonucleotide; The method according to claim 28, wherein the oligonucleotide is conjugated to a sugar in some cases.

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