Anti-c5 antibody / c5 irna dosing regimens for treating c5-associated diseases

Abstract

The present disclosure includes methods of treating 05-associated disease or disorder, such as myasthenia gravis, with a combination that includes an antibody or antigen-binding fragment thereof that binds specifically to C5 and a C5 iRNA which is a glycoconjugate that includes a ligand having terminal N-Acetylgalactosamine (GalNAc) residues and / or N-acetylglucosamine (GIcNAc) residues; or with the C5 iRNA monotherapy.

Description

ANTI-C5 ANTIBODY / C5 IRNA DOSING REGIMENS FOR TREATING C5-ASSOCIATED DISEASES This application claims the benefit of U.S. provisional patent application no.63 / 870,664, filed August 26, 2025; U.S. provisional patent application no.63 / 869,961, filed August 25, 2025; U.S. provisional patent application no.63 / 784,847, filed April 7, 2025; U.S. provisional patent application no.63 / 758,703, filed February 14, 2025; and U.S. provisional patent application no.63 / 701,665, filed October 1, 2024; each of which is herein incorporated by reference in its entirety. SEQUENCE LISTING

[0001] The sequence listing of the present application is submitted electronically as an ST.26 formatted xml file with a file name “SeqList11936”, creation date of September 25, 2024, and a size of 503,576 bytes. This sequence listing submitted is part of the specification and is herein incorporated by reference in its entirety. FIELD

[0002] The field of the present disclosure relates to C5 iRNA monotherapies as well as co-formulations and combination therapies that include an antibody or antigen-binding fragment thereof that specifically binds complement component 5 (C5) and a C5 iRNA for use in methods of treating or preventing a C5-associated disease or disorder, such as myasthenia gravis. BACKGROUND

[0003] C5 is a target for several rare diseases, including myasthenia gravis (MG), paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome, and neuromyelitis.

[0004] MG is a rare autoimmune disease of the neuromuscular junction (NMJ) due to the production of antibodies that bind to the acetylcholine receptor (AChR), often leading to complement-mediated damage of the NMJ. Worldwide prevalence of the disease is approximately 200 per million persons, and there are approximately 60,000 patients in the United States. Clinically, the disease is characterized by fatigable muscle weakness. Patients may present with diplopia / ptosis or peripheral muscle fatigable weakness that isoften multifocal or generalized. Generalized myasthenia gravis (gMG) comprises 85% of patients. When gMG affects the intercostal muscles or diaphragm, breathing is affected and the disease can become life-threatening, requiring hospitalization and treatment with mechanical ventilation (myasthenic crisis). Up to 20% of patients have a myasthenic crisis within the first 2 years after diagnosis (Stetefeld et al., Fortschr Neurol Psychiatr 2018; 86(5):301-307; Wendell, Neurohospitalist 2011; 1(1):16-22).

[0005] Evidence suggests that in order to effectively treat paroxysmal nocturnal hemoglobinuria and avoid undesirable hemolysis breakthrough, complete inhibition of complement is necessary. See Peffault de Latour et al., Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab. Blood.2015 Jan 29;125(5):775-83-Epub 2014 Dec 4; Hill et al., Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 2013; 121(25):4985-96; and 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):285-8.

[0006] Evidence has suggested that in order to achieve therapeutic efficacy for treating myasthenia gravis, with a complement 5 inhibitor, complete complement inhibition was necessary. A Phase 2 clinical trial designed to determine whether near-complete complement inhibition is necessary to achieve maximal clinical benefit in patients with generalized myasthenia gravis was conducted. A conclusion reached from the trial was that near-complete complement inhibition was superior to submaximal complement inhibition. See Howard et al., Clinical Effects of the Self-administered Subcutaneous Complement Inhibitor Zilucoplan in Patients With Moderate to Severe Generalized Myasthenia Gravis: Results of a Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial. JAMA Neurol.2020 May 1;77(5):582-592. The dosing of the therapeutic anti-C5 antibodies eculizumab and ravulizumab also suggested that complete complement inhibition in an MG patient, like PNH, was needed for efficacy. Eculizumab (sold as Soliris) and Ravulizumab (sold as Ultomiris) are each approved in the US for treatment of PNH and MG employing the same dosing regimens. SUMMARY

[0007] The present invention provides methods for treating myasthenia gravis where superior efficacy and safety is achieved without complete complement blockade. Thisaspect of the present invention is surprising and unexpected. As mentioned herein, other C5-mediated diseases, such as paroxysmal nocturnal hemoglobinuria (PNH), are believed to require complete inhibition of complement for efficacy. In addition, clinical data from a Phase 2 trial using Zilucoplan (a C5 inhibitor) suggested that better efficacy was associated with greater levels of complement inhibition. This suggested that, to treat MG effectively, maximal complement inhibition was necessary. As stated in the report of the Phase 2 Zilucoplan trial, “Near-complete complement inhibition was associated with a faster onset and greater magnitude of benefit than submaximal complement inhibition, and favorable safety and tolerability were observed”. Howard et al., Clinical Effects of the Self- administered Subcutaneous Complement Inhibitor Zilucoplan in Patients With Moderate to Severe Generalized Myasthenia Gravis: Results of a Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial. JAMA Neurol.2020 May 1;77(5):582-592). The Cemdisiran monotherapy discussed herein demonstrated superior efficacy in the absence of complete complement inhibition. This aspect is favorable since achieving a high degree of efficacy in treating MG without full complement inhibition may lead to a favorable safety profile. Complement inhibition can increase the risk of infection.

[0008] The present invention provides a method for treating or preventing a C5- associated disease or disorder (e.g., myasthenia gravis) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment thereof that binds specifically to C5 (e.g., Pozelimab) in combination with a therapeutically effective amount of a C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form), wherein the combination of the antibody or antigen- binding fragment thereof and the C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) is administered to the subject by: (a) a subcutaneous injection or intravenous infusion of a co-formulation that comprises both (i) the anti-C5 antibody or antigen-binding fragment thereof and (ii) the C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form); (b) subcutaneous injections or intravenous infusions of separate formulations that each comprise either (i) the anti-C5 antibody or antigen-binding fragment thereof or (ii) the C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form); (c) a subcutaneous injection or intravenous infusion of an anti-C5 antibody or antigen-binding fragment thereof; or (d) a subcutaneous injection or intravenous infusion of C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form). In an embodiment of the invention, the method comprises administering, to the subject, one or more: (a) approximately 200 mg (±20 mg)doses of the anti-C5 antibody or antigen-binding fragment thereof (e.g., Pozelimab), and / or approximately 200 mg (±20 mg) C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) or a molar equivalent amount thereof or 10-13 (± 2) micromoles of C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form); (b) approximately 200 mg (±20 mg) doses of C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) or a molar equivalent amount thereof or 10-13 (± 2) micromoles of C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form); (c) approximately 600 mg (±60 mg) doses of C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) or a molar equivalent amount thereof or about 32-35 or 33.8 (±4) micromoles of C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form); (d) approximately 200 mg (±20 mg) doses of anti-C5 antibody or antigen-binding fragment thereof (e.g., Pozelimab); (e) approximately 200 mg (±20 mg) doses of the anti-C5 antibody or antigen-binding fragment thereof (e.g., Pozelimab), about every 4 weeks (±7 days), and approximately 200 mg (±20 mg) C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) or a molar equivalent amount thereof or 10-13 (± 2) micromoles C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form), about every 4 weeks (±7 days); (e) approximately 200 mg (±20 mg) doses of C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) or a molar equivalent amount thereof or 10-13 (± 2) micromoles C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) about every 4 weeks (±7 days); (f) approximately 600 mg (±60 mg) doses of C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) or a molar equivalent amount thereof about every 12 weeks (±7 days) or 84 days (±7 days) or 3 months (±7 days) or 4 times per year (±7 days); (g) approximately 200 mg (±20 mg) doses of anti-C5 antibody or antigen-binding fragment thereof (e.g., Pozelimab) about every 4 weeks (±7 days); or (h) approximately 32-35 or 33.8 (± 4) micromole doses of C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) about every 12 weeks (±7 days) or 84 days (±7 days) or 3 months (±7 days) or 4 times per year (±7 days). In an embodiment of the invention, the method (e.g., for treating MG) comprises administering (e.g., in a saline composition; e.g., by subcutaneous injection, for example, with an autoinjector) one or more doses of approximately 32-35 or 33.8 (± 4) micromoles Cemdisiran salt form; administering one or more doses of approximately 32-35 or 33.8 (± 4) micromoles Cemdisiran salt form once every 12 weeks (±7 days); administering one or more doses of approximately 32-35 or 33.8 micromoles (± 4) Cemdisiran salt form once every 84 days (±7 days); administering one or more doses of approximately 32-35 or 33.8 micromoles (± 4) Cemdisiran salt form once every 3 months(±7 days); administering one or more doses of approximately 600 mg (±60 mg) Cemdisiran salt form; administering one or more doses of approximately 600 mg (±60 mg) Cemdisiran salt form once every 12 weeks (±7 days); administering one or more doses of approximately 600 mg (±60 mg) Cemdisiran salt form once every 84 days (±7 days); administering one or more doses of approximately 600 mg (±60 mg) Cemdisiran salt form once every 3 months (±7 days); administering one or more doses of approximately 32-35 or 33.8 (± 4) micromoles Cemdisiran Na+salt form; administering one or more doses of approximately 32-35 or 33.8 (± 4) micromoles Cemdisiran Na+salt form once every 12 weeks (±7 days); administering one or more doses of approximately 32-35 or 33.8 micromoles (± 4) Cemdisiran Na+salt form once every 84 days (±7 days); administering one or more doses of approximately 32-35 or 33.8 micromoles (± 4) Cemdisiran Na+salt form once every 3 months (±7 days); administering one or more doses of approximately 600 mg (±60 mg) Cemdisiran Na+salt form; administering one or more doses of approximately 600 mg (±60 mg) Cemdisiran Na+salt form once every 12 weeks (±7 days); administering one or more doses of approximately 600 mg (±60 mg) Cemdisiran Na+salt form once every 84 days (±7 days); administering one or more doses of approximately 600 mg (±60 mg) Cemdisiran Na+salt form once every 3 months (±7 days); administering one or more doses of an amount of Cemdisiran salt form that is the molar equivalent of 600 mg (±60 mg) Cemdisiran Na+salt form; administering one or more doses of an amount of Cemdisiran salt form that is the molar equivalent of 600 mg (±60 mg) Cemdisiran Na+salt form once every 12 weeks (±7 days); administering one or more doses of an amount of Cemdisiran salt form that is the molar equivalent of 600 mg (±60 mg) Cemdisiran Na+salt form once every 84 days (±7 days); and / or administering one or more doses of an amount of Cemdisiran salt form that is the molar equivalent of 600 mg (±60 mg) Cemdisiran Na+salt form once every 3 months (±7 days).

[0009] In an embodiment of the invention, the anti-C5 antibody or antigen-binding fragment thereof and the C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) are in a single co-formulation.

[0010] In an embodiment of the invention, one or more doses of the anti-C5 antibody or antigen-binding fragment thereof are administered to the subject subcutaneously; and / or one or more doses of the C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) are administered to the subject subcutaneously. In an embodiment of the invention, the anti- C5 antibody or antigen-binding fragment thereof and the C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) are in separate formulations wherein the C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) is administered before, after, or simultaneously with the anti-C5 antibody or antigen-binding fragment thereof. For example, in an embodiment of the invention, the C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) and the anti-C5 antibody or antigen-binding fragment thereof are administered within 30 minutes or within 1 hour of each other.

[0011] In an embodiment of the invention, the ratio of concentrations (mg / ml) of anti-C5 antibody or antigen-binding fragment thereof and the C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) in the co-formulation is 1:1; e.g., wherein the co-formulation includes about 100 mg / ml (±10 mg / mg) anti-C5 antibody or antigen-binding fragment thereof and the concentration of the C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) in the co-formulation is about 100 mg / ml (±10 mg / mg). In an embodiment of the invention, a co-formulation that includes the anti-C5 antibody or antigen-binding fragment and C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) is administered in a single approximately 2 ml (±0.2 ml) injection. In an embodiment of the invention, the method of the present invention includes steps wherein each dose of the anti-C5 antibody or antigen-binding fragment thereof is administered about every 4 weeks (±1, 2, 3, 4, 5, 6, or 7 days); and / or each dose of the C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) is administered about every 4 weeks (±1, 2, 3, 4, 5, 6, or 7 days). In an embodiment of the invention, a combination administered to a subject includes (i) a co-formulation comprises: the C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) conjugated to a ligand that comprises one or more terminal N-Acetylgalactosamine (GalNAc) and / or N- acetylglucosamine (GlcNAc) residues, the anti-C5 antibody or antigen-binding fragment thereof, and a pharmaceutically acceptable carrier; wherein the co-formulation has a pH of greater than or less than about 6; or (ii) a first formulation comprising the anti-C5 antibody or antigen-binding fragment thereof and a pharmaceutically acceptable carrier; and a second formulation comprising the C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) conjugated to a ligand that comprises one or more terminal N- Acetylgalactosamine (GalNAc) and / or N-acetylglucosamine (GlcNAc) residues, and a pharmaceutically acceptable carrier.

[0012] In an embodiment of the invention, a method the present invention includes the step of receiving, after two or more doses of the C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) which separated by a 12 week (±7 days), 84 day (±7 days) or 3month (±7 days) interval, administering one or more doses of the C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) separated by an interval of greater than or less than said 12 weeks (±7 days), 84 days (±7 days) or 3 months (±7 days), for example, if based on clinical outcomes of the subject and based on the treating physician’s judgment, taking such a step is needed. In an embodiment of the invention, the C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) and the anti-C5 antibody or antigen-binding fragment are in a co-formulation, for example, that has a pH of about 6.5 or a pH within not less than 0.5 to 6.0 or of 6.5 ± 0.2; that comprises a buffer selected from a histidine-based buffer, a citrate-based buffer, a phosphate-based buffer an acetate-based buffer, and combinations thereof; that comprises about 10-35, 35-45, 20-50, 20, 25, 30, 35, 40, 45 or 50 mM buffer; that comprises a viscosity reducer selected from an inorganic salt, an amino acid, and a combination thereof; that comprises a viscosity reducer selected from (D- or L-) arginine, L-arginine HCl, (D- or L-) alanine, proline, (D- or L-) valine, glycine, (D- or L-) serine, (D- or L-) phenylalanine, (D- or L-) lysine, (D- or L-) glutamate and salts thereof, an inorganic salt, NaCl, pyridoxamine, L-ornithine, thiamine phosphoric acid ester chloride dihydrate, benzenesulfonic acid, pyridoxine, and a combination thereof; that comprises about 20-140, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135 or 140 mM viscosity reducer; that comprises a stabilizer which is a polyol or sugar; that comprises a stabilizer selected from trehalose, sorbitol, mannitol, taurine, propane sulfonic acid, L-proline, sucrose, glycerol, threitol, maltitol, polyethylene glycol (PEG), PEG3350, and combinations thereof; that comprises about 0.8-3.6, 0.8, 0.9, 1.0, 1.25, 1.50, 2.0, 2.25, 2.50, 2.75, 3.00, 3.1, 3.2, 3.3, 3.4, 3.5 or 3.6% (w / v) stabilizer; that comprises a non-ionic surfactant selected from a polyoxyethylene glycol alkyl ether; glucoside alkyl ether; polyoxyethylene glycol octylphenol ether; polyoxyethylene glycol alkylphenol ether; glycerol alkyl ester; polyoxyethylene glycol sorbitan alkyl ester; sorbitan alkyl ester; block copolymer of polypropylene glycol; block copolymer of polyethylene glycol; polysorbate; and combinations thereof;that comprises a non-ionic surfactant selected from octaethylene glycol monododecyl ether; pentaethylene glycol monododecyl ether; polyoxypropylene glycol alkyl ether; decyl glucoside, lauryl glucoside, octyl glucoside; triton Χ-100; nonoxynol-9; glyceryl laurate; cocamide ΜΕΑ, cocamide DEA, dodecyldimethylamine oxide; poloxamer; polyethoxylated tallow amine (ΡΟΕΑ); polysorbate-20 (PS20); polysorbate-80 (PS80); and combinations thereof; that comprises about 0.025, 0.05, 0.075, 0.1, 0.125, 0.15, or 0.175% (w / v) non-ionic surfactant; that comprises one or more viscosity reducers; that comprises one or more viscosity reducers at a concentration of about 5 mM to about 100 mM each; that comprises one or more viscosity reducers at a concentration of about 50 mM to about 75 mM each; that comprises a viscosity reducer which is selected from an amino acid, a dicarboxylic acid, an inorganic salt, an ester of citric acid, a xanthine, and combinations thereof; that comprises a viscosity reducer which is selected from arginine, adipic acid, NaCl, lysine, proline, histidine, caffeine, phenylalanine, triethyl citrate; and combinations thereof; that comprises a viscosity reducer which is an amino acid which is the L-enantiomer thereof or the D-enantiomer thereof; that comprises a viscosity reducer which is the conjugate base or salt thereof of an acid viscosity reducer; that comprises about 96% or more anti-C5 antibody or antigen-binding fragment thereof purity as assessed by size exclusion chromatography after about 1 month of storage at 2- 8°C; that comprises about 94% or more C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) purity as assessed by anion exchange chromatography after about 1 month of storage at 2-8°C; that comprises a 1:1 ratio of concentration of C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) to anti-C5 antibody or antigen-binding fragment thereof in milligrams per milliliter; that comprises a viscosity reducer selected from arginine, adipic acid, NaCl, lysine, proline, histidine, caffeine, phenylalanine, triethyl citrate, and combinations thereof; and / orthat comprises a viscosity reducer which is 75 mM arginine, 75 mM adipate, 75 mM NaCl, 75 mM lysine, 75 mM aspartate, 75 mM proline, 50 mM histidine, 50 mM caffeine, 50 mM phenylalanine, 75 mM triethyl citrate, and combinations thereof; wherein, if the buffer is histidine-based, the total histidine concentration of the co-formulation is 50 mM. In an embodiment of the invention, the co-formulation comprises: the C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form); the anti-C5 antibody or antigen-binding fragment thereof; a buffer; a viscosity reducer; a stabilizer; and a non-ionic surfactant; and pH of greater than or less than about 6. In an embodiment of the invention, said combination is administered as a co-formulation, which comprises: Cemdisiran; Pozelimab that was expressed in and isolated from a mammalian host cell that includes beta-hexosaminidase; a buffer; a viscosity reducer; a stabilizer; and a non-ionic surfactant; at a pH of about 6.5; and / or the Cemdisiran is in an aqueous pharmaceutical formulation comprising a buffer and / or NaCl.

[0013] In an embodiment of the invention, the anti-C5 antibody or antigen-binding fragment is Pozelimab which was expressed in a mammalian host cell (e.g., a CHO cell) and / or the C5 iRNA is Cemdisiran (e.g., Cemdisiran Na+form, other salt form or free form) which was chemically synthesized. In an embodiment of the invention, a combination that is administered as a co-formulation, comprises: • no more than about 2.1 parts per million molar ratio of beta-hexosaminidase to anti- C5 antibody or antigen-binding fragment; • no more than about 0.170 micrograms / ml beta-hexosaminidase; • no more than about 0.04 micrograms / ml beta-hexosaminidase; and / or • about 0.04; 0.05; 0.06; 0.0605; 0.063; 0.07; 0.0765; 0.078; 0.08; 0.14; 0.141; 0.15; 0.1525; 0.166; or 0.17 micrograms / ml beta-hexosaminidase; or no more than any of such concentrations.

[0014] In an embodiment of the invention, the anti-C5 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 2, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 18, and a LCVR that comprises the LCDR1,LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 26; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 34, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 42; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 50, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 58; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 66, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 74; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 82, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 90; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 98, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 98, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 114; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 98, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 138, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 146, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106; a HCVR thatcomprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 146, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 114; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 146, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 138, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 154, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 162; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 170, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 178; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 186, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 194; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 202, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 210; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 218, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 226; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 234, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 242; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQID NO: 250, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 258; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 266, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 258; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 274, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 282; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 290, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 298; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 306, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 314; a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 322, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 330; or a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 338, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 346; a heavy chain variable region (HCVR) including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 4, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 6, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 8, and a light chain variable region (LCVR) including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 12, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 14, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 16; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 20, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 22, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 24, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 28, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 30, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 32; aHCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 36, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 38, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 40, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 46, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 48; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 52, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 54, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 56, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 60, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 62, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 64; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 68, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 70, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 72, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 76, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 78, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 80; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 84, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 86, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 88, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 92, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 94, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 96; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 100, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 102, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 104, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 108, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 110, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 112; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 100, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 102, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 104, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQID NO: 116, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 118, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 120; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 124, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 126, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 128, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 108, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 110, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 112; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 100, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 102, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 104, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 132, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 134, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 136; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 140, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 142, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 144, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 108, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 110, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 112; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 148, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 150, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 152, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 108, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 110, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 112; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 124, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 126, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 128, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 132, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 134, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 136; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 148, an HCDR2that comprises the amino acid sequence set forth in SEQ ID NO: 150, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 152, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 116, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 118, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 120; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 148, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 150, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 152, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 132, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 134, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 136; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 140, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 142, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 144, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 132, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 134, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 136; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 156, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 158, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 160, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 164, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 166, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 168; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 172, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 174, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 176, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 180, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 182, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 184; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 188, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 190, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 192, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 196, an LCDR2that comprises the amino acid sequence set forth in SEQ ID NO: 198, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 200; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 204, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 206, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 208, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 212, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 214, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 216; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 220, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 222, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 224, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 228, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 230, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 232; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 236, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 238, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 240, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 244, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 246, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 248; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 252, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 254, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 256, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 260, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 262, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 264; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 268, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 270, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 272, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 260, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 262, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 264; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 276, an HCDR2that comprises the amino acid sequence set forth in SEQ ID NO: 278, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 280, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 284, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 286, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 288; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 292, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 294, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 296, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 300, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 302, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 304; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 308, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 310, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 312, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 316, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 318, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 320; a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 324, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 326, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 328, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 332, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 334, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 336; or a HCVR including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 340, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 342, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 344, and a LCVR including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 348, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 350, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 352; a heavy chain variable region (HCVR) that comprises the amino acid sequence set forth in SEQ ID NO: 2, a light chain variable region (LCVR) that comprises the amino acid sequence set forth in SEQ ID NO: 10; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 18, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 26; a HCVR thatcomprises the amino acid sequence set forth in SEQ ID NO: 34, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 42; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 50, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 58; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 66, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 74; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 82, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 90; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 98, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 98, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 114; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 98, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 138, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 146, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 146, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 114; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 146, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 138, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 154, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 162; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 170, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 178; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 186, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 194; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 202, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 210; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 218, a LCVR that comprises the amino acid sequenceset forth in SEQ ID NO: 226; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 234, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 242; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 250, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 258; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 266, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 258; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 274, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 282; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 290, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 298; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 306, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 314; a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 322, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 330; or a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 338, a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 346.

[0015] In an embodiment of the invention, the anti-C5 antibody or antigen-binding fragment comprises a heavy chain including the amino acid sequence: QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNYN PSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWGQGTLVTVSSA STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNV FSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 358); optionally, lacking the C-terminal lysine; and a light chain including the amino acid sequence: AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPSR FAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 359); for example, wherein the anti-C5 antibody or antigen-binding fragment thereof is Pozelimab.

[0016] In an embodiment of the invention, the C5 iRNA comprises an RNA strand that is complementary to an mRNA transcribed from the C5 gene sense strand DNAsequence AAGCAAGATATTTTTATAATA (SEQ ID NO: 407; nucleotides 782-802 of SEQ ID NO: 360). In an embodiment of the invention, the C5 iRNA is a double-stranded ribonucleic acid (dsRNA) agent including a sense strand and an antisense strand; wherein the antisense strand comprises a region of complementarity including at least 17 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of 5’UAUUAUAAAAAUAUCUUGCUUUU3’ (SEQ ID NO: 364); and wherein the dsRNA agent comprises at least one modified nucleotide. In an embodiment of the invention, the C5 iRNA is a double-stranded ribonucleic acid (dsRNA) agent including a sense strand and an antisense strand; wherein the antisense strand comprises 5'- asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3', and the antisense strand comprises 5'- usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3'; wherein a, g, c and u are 2'-0-methyl (2'-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2'-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; s is a phosphorothioate linkage; and wherein the sense strand is conjugated at the 3'-terminus to the ligand . In an embodiment of the invention,the C5 iRNA is a duplex comprising [(2S,4R)-1-{1-[(2-acetamido-2-deoxy-β- Dgalactopyranosyl) oxy]-16,16-bis({3-[(3-{5-[(2-acetamido-2- deoxy-β-D- galactopyranosyl)oxy]pentanamido}propyl)amino]-3- oxopropoxy}methyl)-5,11,18-trioxo-14- oxa-6,10,17- triazanonacosan-29-oyl}-4-hydroxypyrrolidin-2-yl]methyl hydrogen all-P-ambo- 2'-O-methyl-P-thioadenylyl-(3'→5')-2'-Omethyl- P-thioadenylyl-(3'→5')-2'-deoxy-2'- fluoroguanylyl- (3'→5')-2'-O-methylcytidylyl-(3'→5')-2'-deoxy-2'-fluoroadenylyl- (3'→5')-2'-O- methyladenylyl-(3'→5')-2'-deoxy-2'-fluoroguanylyl- (3'→5')-2'-O-methyladenylyl-(3'→5')-2'-deoxy-2'-fluorouridylyl- (3'→5')-2'-deoxy-2'-fluoroadenylyl-(3'→5')-2'-deoxy-2'- fluorouridylyl- (3'→5')-2'-O-methyluridylyl-(3'→5')-2'-deoxy-2'- fluorouridylyl-(3'→5')-2'-O-methyluridylyl- (3'→5')-2'-Omethyluridylyl-( 3'→5')-2'-deoxy-2'-fluoroadenylyl-(3'→5')-2'-Omethyluridylyl-( 3'→5')-2'-deoxy-2'-fluoroadenylyl-(3'→5')-2'-Omethyladenylyl-( 3'→5')-2'-O-methyluridylyl- (3'→5')-2'-Omethyl- 3'-adenylate and all-P-ambo-thymidylyl-(5'→3')- thymidylyl-(5'→3')-2'-O- methyl-P-thiouridylyl-(5'→3')-2'-Omethyl- P-thiouridylyl-(5'→3')-2'-O-methyluridylyl-(5'→3')- 2'-Omethyluridylyl-( 5'→3')-2'-O-methylcytidylyl-(5'→3')-2'-deoxy-2'- fluoroguanylyl-(5'→3')- 2'-O-methyluridylyl-(5'→3')-2'-deoxy-2'- fluorouridylyl-(5'→3')-2'-O-methylcytidylyl-(5'→3')-2'- deoxy-2'- fluorouridylyl-(5'→3')-2'-O-methyladenylyl-(5'→3')-2'-Omethyluridylyl-( 5'→3')-2'-O- methyladenylyl-(5'→3')-2'-deoxy-2'- fluoroadenylyl-(5'→3')-2'-O-methyladenylyl-(5'→3')-2'- deoxy-2'- fluoroadenylyl-(5'→3')-2'-O-methyladenylyl-(5'→3')-2'-Omethyluridylyl-( 5'→3')-2'- deoxy-2'-fluoroadenylyl-(5'→3')-2'-Omethyluridylyl-( 5'→3')-2'-deoxy-2'-fluoro-P-thiouridylyl- (5'→3')- 2'-deoxy-2'-fluoro-P-thioadenylyl-(5'→3')-2'-O-methyluridine. In an embodiment of the invention, the C5 iRNA is Cemdisiran, for example, the Na+salt form, another salt form or free form. In an embodiment of the invention, the anti-C5 antibody or antigen-binding fragment thereof is Pozelimab and / or the C5 iRNA is Cemdisiran (preferably Na+form).

[0017] The methods of the present invention relate to treatment or prevention of a C5-asociated disease or disorder. In an embodiment of the invention, the C5-asociated disease or disorder is selected from adult respiratory distress syndrome (ARDS); age- related macular degeneration (AMD); allergy; Alport's syndrome; Alzheimer's disease; an autoimmune disease; an immune complex disorder; an inflammatory disorder; angiopathic thrombosis and protein-losing enteropathy); asthma; atherosclerosis; bronchoconstriction; bullous pemphigoid; C3 glomerulopathy; capillary leak syndrome; CHAPLE disease (CD55 deficiency with hyperactivation of complement); a chemical injury due to irritant gasses and / or chemicals; chronic obstructive pulmonary disease (COPD); complement activation due to a burn; complement activation due to frostbite; complement activation due to obesity; complement activation due to sepsis; Crohn's disease; diabetes; diabetic macular edema (DME); diabetic nephropathy; diabetic retinopathy; a disorder of inappropriate or undesirable complement activation; dry AMD; dyspnea; emphysema; epilepsy; fibrogenic dust disease; geographic atrophy (GA); glomerulopathy; Goodpasture's Syndrome; Guillain- Barre Syndrome; a hemodialysis complication; hemolytic anemia; hemoptysis; hereditary angioedema; hyperacute allograft rejection; hypersensitivity pneumonitis; immune complex- associated inflammation; an infectious disease; inflammation of an autoimmune disease;inherited CD59 deficiency; an injury due to inert dusts and / or minerals; interleukin-2 induced toxicity during IL-2 therapy; a lung disease or disorder; lupus nephritis; membranoproliferative glomerulonephritis; membranoproliferative nephritis; mesenteric artery reperfusion after aortic reconstruction; multiple sclerosis; myasthenia gravis; myocardial infarction; a neurological disorder; neuromyelitis optica; ocular angiogenesis; an ocular disease; an organic dust disease; a parasitic disease; Parkinson's disease; paroxysmal nocturnal hemoglobinuria (PNH); pneumonia; a post-ischemic reperfusion condition; a proteinuric kidney disease; progressive kidney failure; psoriasis; pulmonary embolisms and infarcts; pulmonary fibrosis; pulmonary vasculitis; a renal disorder; renal ischemia; renal ischemia-reperfusion injury; rheumatoid arthritis; schizophrenia; SLE nephritis; a smoke injury; stroke; systemic inflammatory response in post-pump syndrome due to cardiopulmonary bypass or renal bypass; systemic lupus erythematosus (SLE); a thermal injury; a traumatic brain injury; uveitis; vasculitis; wet AMD; xenograft rejection; and combinations thereof. Preferably, the C5-associated disease or disorder is myasthenia gravis; for example, the myasthenia gravis is generalized myasthenia gravis, ocular myasthenia gravis, Class I myasthenia gravis, Class II myasthenia gravis, Class IIa myasthenia gravis, Class IIb myasthenia gravis, Class III myasthenia gravis, Class IIIa myasthenia gravis, Class IIIb myasthenia gravis, Class IV myasthenia gravis, Class IVa myasthenia gravis, Class IVb myasthenia gravis, Class V myasthenia gravis, Early-onset myasthenia gravis, Late-onset myasthenia gravis, Thymoma-associated myasthenia gravis, myasthenia gravis with anti-MuSK antibodies, Ocular myasthenia gravis characterized by symptoms from periocular muscles, and / or myasthenia gravis with no detectable AChR and MuSK antibodies.

[0018] The present invention includes embodiments wherein the subject has been diagnosed with myasthenia gravis (e.g., generalized myasthenia gravis, ocular myasthenia gravis, Class I myasthenia gravis, Class II myasthenia gravis, Class IIa myasthenia gravis, Class IIb myasthenia gravis, Class III myasthenia gravis, Class IIIa myasthenia gravis, Class IIIb myasthenia gravis, Class IV myasthenia gravis, Class IVa myasthenia gravis, Class IVb myasthenia gravis, Class V myasthenia gravis, Early-onset myasthenia gravis, Late-onset myasthenia gravis, Thymoma-associated myasthenia gravis, myasthenia gravis with anti-MuSK antibodies, Ocular myasthenia gravis characterized by symptoms from periocular muscles, and / or myasthenia gravis with no detectable AChR and MuSK antibodies).

[0019] The present invention provides a method for treating or preventing a C5-associated disease or disorder (e.g., MG) in a subject in need thereof comprising administering, to the subject, a dose of C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) wherein one week after said administering, the subject serum CH50 decreases by about 33%, two weeks after said administering, the subject serum CH50 decreases by about 56%,four week after said administering ,the subject serum CH50 decreases by about 77%; relative to before the administration. The present invention provides a method for treating or preventing a C5-associated disease or disorder in a subject in need thereof comprising administering, to the subject, a dose of C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) wherein the subject serum CH50 decreases by at least 33, 56, 74 or 77%, for example, wherein the CH50 decreases by 1, 2, 4, 8, 16, 20 or 24 weeks after treatment initiation.

[0020] In an embodiment of the invention, a subject in a method set forth herein has been diagnosed with myasthenia gravis by a method comprising an electrophysiologic test, a repetitive nerve stimulation (RNS) test, a single-fiber electromyography (SFEMG) test, an Edrophonium (Tensilon) test, an Ice-pack test, Chest computed tomography (CT), and / or Magnetic resonance imaging (MRI). In an embodiment of the invention, a method of the present invention further includes the step of diagnosing the subject with myasthenia gravis.

[0021] In an embodiment of the invention, a subject has myasthenia gravis and one or more criteria selected from: (a) a history of abnormal neuromuscular transmission by repetitive nerve stimulation; (b) a history of abnormal neuromuscular transmission by single-fiber electromyography; (c) a history of a positive anticholinesterase test; and (d) improvement in symptoms with anticholinesterase treatment. In an embodiment of the invention, the subject has myasthenia gravis and is positive for anti-acetylcholinesterase (anti-AChR) antibodies or anti-Lipoprotein receptor-related protein 4 (anti-LRP4) antibodies. In an embodiment of the invention, a method of the present invention further includes administering to the subject one or more further therapeutic agents (e.g., a chemotherapeutic agent, an anti-coagulant, warfarin, aspirin, heparin, phenindione, fondaparinux, idraparinux, a thrombin inhibitor, argatroban, lepirudin, bivalirudin, dabigatran, an anti-inflammatory drug, a corticosteroid, a non-steroidal anti-inflammatory drug (NSAID), an antihypertensive, an angiotensin-converting enzyme inhibitor, an immunosuppressive agent, vincristine, cyclosporine A, methotrexate, a fibrinolytic agent ancrod, E-aminocaproic acid, antiplasmin-a1, prostacyclin, defibrotide, a lipid-lowering agent, an inhibitor ofhydroxymethylglutaryl CoA reductase, an anti-CD20 agent, rituximab, an anti-TNFalpha agent, infliximab, an anti-seizure agent, magnesium sulfate, a C3 inhibitor and an anti- thrombotic agent). In an embodiment of the invention, the further therapeutic agent is not an anti-CD20 antibody, an anti-FcRN antibody, and / or an androgen deprivation therapy. The present invention may include a step of administering to the subject an initial loading dose (e.g., by intravenous infusion) of C5 iRNA (e.g., Cemdisiran Na+form, other salt form or free form) and / or antibody or fragment thereof that binds specifically to C5.

[0022] In an embodiment of the invention, a method of the present invention is continued up until or terminated when: the subject becomes pregnant; the subject contracts a serious meningococcal infection; the subject suffers a liver impairment as confirmed by a repeat test on 1 or more of the following criteria and no other reason can be found to explain the following lab abnormalities:− ALT (Alanine aminotransferase) or AST (Aspartate aminotransferase) level >8× ULN (upper limit of normal), or − ALT or AST level >5× ULN for >2 weeks, or − ALT or AST level >3× ULN and total bilirubin >2× ULN (or INR (international normalized ratio) >1.5); and / or the subject makes a suicide attempt.

[0023] In an embodiment of the invention, the subject has received (previously or during the course of treatment) one or more of: an anticholinesterase agent, an immunosuppressive drug, a C5 complement inhibitor, a neonatal Fc receptor blocker, prednisone, tacrolimus, rituximab, eculizumab, ravulizumab, efgartigimod, rozanolixizumab, pyridostigmine, plasmapheresis (PLEX) and / or intravenous IgG.

[0024] In an embodiment of the invention, during said treatment, the subject is monitored for: Meningococcal infection; Serious infection; Sepsis; Embryofetal toxicity; Immunogenicity; Anti-drug antibody formation; Any clinical Consequences of large Drug- Target-Drug immune complexes in subjects who switch from Eculizumab or Ravulizumab to Pozelimab; Liver transaminase elevations; and / or Injection site reaction; and, optionally, treatment is terminated or suspended if one or more are observed.

[0025] In an embodiment of the invention, during or after treatment, the subject achieves one or more of: Improvement in Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score from baseline to week 24; Improvement in Quantitative Myasthenia Gravis (QMG) score from baseline to week 24; ≥3-point improvement from baseline to week 24 on the MG-ADL; ≥5-point improvement from baseline to week 24 on the QMG; At least a 2-point MG-ADL improvement on 2 or more consecutive assessments on the MG-ADL spanning 4 or more weeks during the double-blind treatment period (DBTP); Minimal symptomexpression (MSE), defined by a score of 0 to 1 on the MG-ADL at week 24; Improvement in the Myasthenia Gravis Composite (MGC) total score from baseline to week 24; Improvement in Myasthenia Gravis Quality of Life (MG-QOL15r) total score from baseline to week 24; Improvement point threshold of ≥2, 4, 5, 6, 7, 8, 9, or 10 on MG-ADL at week 24; Improvement point threshold of ≥3, 4, 6, 7, 8, 9, or 10 on QMG at week 24; Reduced incidence and severity of treatment-related adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) in comparison to placebo through week 24; Improvement from baseline in MG-ADL total score by visit; Improvement from baseline in QMG total score by visit; Reduced time to achievement of a 3-point improvement from baseline on the MG-ADL in comparison to placebo; Reduced time to achievement of a 5-point improvement from baseline on the QMG in comparison to placebo; Improvement from baseline in the physical performance measures of hand grip strength, supine leg lift, supine head lift, onset of dysarthria, and all timed items of the QMG; Improvement from baseline in individual domains (ocular, bulbar, respiratory, and gross motor / limb impairment) of the MG-ADL; Improvement from baseline in sentinel domains (ocular, facial, bulbar, gross motor, axial, and respiratory) of the QMG; Improvement from baseline in continuous variable measures from the MGC; Improvement from baseline in timed step count, cadence, and other exploratory measures using a wearable device; Increased total MG-ADL score and secondary efficacy endpoints in comparison to placebo through week 48 and through week 120; Improvement in patient-reported fatigue as measured by the Neuro-QoL-Fatigue from baseline to week 24; Improvement from baseline in patient-reported health status as measured by the EuroQol-5 Dimensions-5 Levels (EQ- 5D-5L); Reduced number of myasthenic crises (including impending crises), days of hospitalization due to MG, and / or procedures related to MG from time periods prior to randomization; Improvement from baseline and percent change from baseline in alternative pathway hemolytic activity assay (AH50) and total C5 over time; Reduced use of rescue therapy from baseline to week 24; Increase in corticosteroid dosage from baseline to week 24; Decrease in corticosteroid dosage from baseline to week 24; Reduced incidence and severity of adverse events through the end of study in comparison to placebo; Improvement from baseline in Modified MGFA Post-Intervention Status (MG-PIS) at week 24, week 48, and week 120; A percent change in serum CH50 by week 1, week 2, week 4, week 12 or week 24, after treatment initiation with Pozelimab monotherapy (200 mg, q4w) of about - 18.49, -9.19, -7.06, -6 or -7.31, U / ml, respectively; A percent change in serum CH50 byweek 1, week 2, week 4, week 12 or week 24 after treatment initiation with Pozelimab (PZ) and Cemdisiran (CMD) combination (200 mg PZ + 200 CMD, q4w) of about -63.31, -83.53, -84.62, -98.91 or -99.57, U / ml, respectively; A percent change in serum CH50 by week 1, week 2, week 4, week 12 or week 24 after treatment initiation with Cemdisiran monotherapy (600 mg, q12w) of about -32.62, -55.75, -76.77, -73.53 or -76.61, U / ml, respectively; A change in MG-ADL total score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab monotherapy (200 mg, q4w) of about -1.31, -1.98, -2.59, -2.66, -2.80, -2.59 or -2.77, respectively; A change in MG-ADL total score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab (PZ) + Cemdisiran (CMD) combination (200 mg PZ + 200 mg CMD, q4w) of about -2.56, -3.08, -3.38, -3.76, -3.75, -3.91 or -3.96, respectively; A change in MG-ADL total score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Cemdisiran monotherapy (600 mg, q12w) of about -2.50, -3.22, -3.96, -4.31, -4.14, - 4.59 or -4.52, respectively; An absolute MD-ADL score, by week, 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab (200 mg, q4w), of about 8.50, 7.87, 7.08, 7.13, 6.94, 7.15 or 6.92, respectively; An absolute MD-ADL score, by week, 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab (PZ) + Cemdisiran (CMD) (200 mg PZ + 200 mg CMD, q4w), of about 6.91, 6.25, 5.84, 5.45, 5.33, 5.22 or 5.08, respectively; An absolute MD-ADL score, by week, 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Cemdisiran (600 mg, q12w), of about 6.52, 5.81, 5.08, 4.70, 4.81, 4.44 or 4.53, respectively; A change in QMG total score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab monotherapy (200 mg, q4w) of about -0.83, -0.73, -1.58, -1.78, -1.44, -1.77 or -1.55, respectively; A change in QMG total score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab (PZ) and Cemdisiran (CMD) combination (200 mg PZ + 200 CMD, q4w) of about -2.11, -2.77, -2.56, -3.07, -3.27, -3.18 or -3.32, respectively; A change in QMG total score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Cemdisiran monotherapy (600 mg, q12w) of about -1.95, -2.60, -3.91, -3.94, -4.11, -3.92 or -4.24, respectively; An absolute MD-ADL score, by week, 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab monotherapy (200 mg, q4w), of about 15.33, 15.54, 14.38, 14.41, 14.47, 14.19 or 14.31, respectively; An absolute MD-ADL score, by week, 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab (PZ) + Cemdisiran (CMD) (200 mg PZ + 200 mg CMD, q4w) (200 mg, q4w), of about 13.84, 12.85, 12.94, 12.33, 11.97, 11.98 or 11.94, respectively; An absolute MD-ADL score, by week, 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Cemdisiran monotherapy (600 mg, q12w), of about 13.64, 12.98, 11.69,11.64, 11.45, 11.76 or 11.44, respectively; A change in MGC score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab (PZ) + Cemdisiran (CMD) combination (200 mg PZ + 200 mg CMD, q4w) of about -4.31, -4.77, -5.49, -5.89, -5.85, -6.01 or -6.04, respectively; A change in MGC score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Cemdisiran monotherapy (600 mg, q12w) of about -4.49, -5.22, -6.55, -7.55, - 7.57, -7.69 or -7.78, respectively; A change in MGC score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab (PZ) monotherapy (200 mg, q4w) of about -1.64, - 2.13, -3.34, -3.47, -3.30, -3.57 or -3.19, respectively; A change in MG-QoL15r score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab (PZ) + Cemdisiran (CMD) combination (200 mg PZ + 200 mg CMD, q4w) of about -2.44, -2.86, -4.00, -3.79, - 3.86, -3.91 or -4.25, respectively; A change in MG-QoL15r score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Cemdisiran monotherapy (600 mg, q12w) of about -1.43, -2.67, -4.08, -4.31, -4.52, -4.65 or -4.68, respectively; and / or A change in MG-QoL15r score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab (PZ) monotherapy (200 mg, q4w) of about -1.65, -1.26, -0.92, -1.76, -1.49, -0.70 or -1.58, respectively.

[0026] The present invention provides a method for treating myasthenia gravis, preferably, generalized myasthenia gravis (gMG) in an adult patient who is anti-acetylcholine receptor (AChR) or anti-low-density lipoprotein receptor-related protein 4 (LRP4) antibody positive comprising administering about 600 mg Cemdisiran sodium form or a molar equivalent of another salt form of Cemdisiran or Cemdisiran free form, by subcutaneous injection every about once every 12 weeks or 3 months wherein the Cemdisiran Na+form is represented bythe chemical structure:wherein the Cemdisiran Na+form is in an aqueous composition which is an aqueous pharmaceutical formulation comprising a pharmaceutically acceptable carrier which is, for example, water for Injection, USP and sodium hydroxide and / or phosphoric acid, pH ~7.0. In an embodiment of the invention, the Cemdisiran Na+form is in a sterile, preservative- free, clear, colorless to yellow solution in glass vials, free from visible particulates. In an embodiment of the invention, the Cemdisiran is in one or more vials. In an embodiment of the invention, the 600 mg Cemdisiran Na+form or molar equivalent is in three separate vials including about 200 mg Cemdisiran Na+form or molar equivalent. In an embodiment of the invention, the 600 mg Cemdisiran Na+form or molar equivalent is administered in 2 injections with a volume of 1.5 ml each or 3 injections of 1 ml each or a single injection with a full dose. In an embodiment of the invention, the full 600 mg Cemdisiran Na+form dose, or molar equivalent, is in three separate vials. In an embodiment of the invention, vials containing the Cemdisiran are refrigerated, wherein the method includes the steps of removing the vials from refrigeration and allowing the vials to sit for at least 15 minutes at20ºC to 25ºC (68ºF to 77ºF) before use. In an embodiment of the invention, the method includes one or more of the steps of inspecting the aqueous composition, visually, for particulate matter and discoloration prior to administration discarding the aqueous composition if it is cloudy, discolored or contains particulate matter; gently swirling the vials comprising the aqueous composition in an upright position but not shaking the vials; subcutaneously administering the Cemdisiran, e.g., with a 25 gauge to 27 gauge, ½ inch or5 / 8-inch stainless steel needle, e.g., with Luer-Lok; withdrawing 3 ml of the aqueous composition, comprising the Cemdisiran Na+form, with a 21 gauge withdrawal needle, e.g., with Luer-Lok, equally into two syringes each containing about 1.5 mL or 3 syringes with 1 ml each; changing the withdrawal needle on each syringe to an injection needle fulfilling the following criteria: 25 gauge to 27 gauge and1 / 2or5 / 8-inch stainless steel needle, e.g., with Luer-Lok; administering the subcutaneous injections, each at a different injection site, for example, into the thigh, back of the upper arm, or abdomen, on opposite sides or at least 2 cm apart, but not injecting into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact; observing the subject for 30 minutes following completion of the first 600 mg Cemdisiran Na+form dose; and / or administering the subcutaneous injection within 4 hours of preparation.

[0027] Water for injection (WFI) is an excipient in the production of parenteral and other preparations where the product endotoxin content must be controlled. See U.S. Pharmacopeia (USP) 37, General Information / <1231> Water for Pharmaceutical Purposes.

[0028] For example, the present invention provides a method for treating generalized myasthenia gravis (gMG) in an adult patient who is anti-acetylcholine receptor (AChR) or anti-low-density lipoprotein receptor-related protein 4 (LRP4) antibody positive comprising: removing the 3 glass vials containing the Cemdisiran Na+form which is in a sterile, preservative-free, clear, colorless to yellow solution free from visible particulates wherein each vial contains 200 mg Cemdisiran Na+form in 1 mL with water for injection, USP and sodium hydroxide and / or phosphoric acid, pH ~7.0, from refrigeration and allowing the vials to sit for at least 15 minutes at room temperature 20ºC to 25ºC (68ºF to 77ºF) before use; inspecting the solution visually for particulate matter and discoloration prior to any administration; discarding the solution if it is cloudy, discolored or contains particulate matter; gently swirling the vials in an upright position, but not shaking the vials; withdrawing 3 mL of the solution equally into two syringes (each containing 1.5 mL) or 3 syringes with 1ml each with a withdrawal needle (21 gauge needle with Luer-Lok); changing the withdrawal needle on each syringe to an injection needle fulfilling the following criteria: • 25 gauge to 27 gauge; and • 1 / 2 or 5 / 8-inch stainless steel needle with Luer-Lok; and, within 4 hours, administering 600 mg Cemdisiran Na+form by two separate subcutaneous 1.5 ml injections or three separate 1 ml injections of the solution consecutively, each at a different injection site, into the thigh, back of the upper arm, or abdomen, on opposite sides or at least 2 cm apart, but not injecting into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact, every 12 weeks or 3 months; wherein the Cemdisiran Na+form is represented by the chemical structure:and observing the subject for 30 minutes following administering of the first dose of 600 mg (3 ml) Cemdisiran Na+form. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] The accompanying drawings, which are incorporated herein and constitute part of this specification, are illustrative of particular embodiments of the present disclosure and do not limit the scope of the present disclosure. The drawings are intended for use in conjunction with the explanations in the following detailed description. The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawings will be provided by the Office upon request and payment of the necessary fee.

[0030] Figure 1. Study Flow Diagram for the study described in Example 1. Abbreviations are as follows: Q4W: every 4 weeks; Q12W :every 12 weeks; SC: subcutaneous administration; “Combination”: Pozelimab about 200 mg Q4W + Cemdisiran about 200 mg Q4W. Day 1 is the start of double-blind SC Q4W treatment. W24 is primary endpoint: Myasthenia Gravis-Activities of Daily Living (MG-ADL). From Day 1 to W36 all treatments are added onto the patient’s existing treatment, as applicable, for MG. W52 is start of open-label combination SC Q4W. W60 is start of open-label Cemdisiran. W108 is last dose of Cemdisiran. W116 is last dose of combination. During the extension period (after week 24 PEP) PBO patients were re-randomize to cemdi mono (Cemdisiran monotherpay) or combo (combination pozelimab + Cemdisiran therapy).

[0031] Figure 2. Cemdisiran Structure

[0032] Figure 3. Comparison of Treatment Efficacy (primary and secondary endpoints) between Patients Receiving Cemdisiran Monotherapy and Combination Treatment (Forest Plot). MSE: Minimal symptom expression (score of 0 or 1 on MG-ADL); Stable responders: Achievement of a consistent response on the MG-ADL, defined as a patient with a ≥2- point reduction (improvement) in MG-ADL total score on 2 or more consecutive assessments spanning 4 or more weeks during the DBTP. MGC: Myasthenia Gravis Composite; MG- QOL15r: Myasthenia Gravis Quality of Life revised. See Example 1.

[0033] Figure 4. Mean CH50 Change (%) from Baseline over Time in Placebo, Pozelimab, Combination and Cemdisiran arms. See Example 1.

[0034] Figure 5. Total C5 concentration in Plasma over Time in Placebo, Pozelimab, Combination and Cemdisiran arms. LLOQ is indicated by the dashed line. Below LOQ values are set to LLOQ / 2. See Example 1.

[0035] Figure 6. Least Squares Mean Change in Myasthenia Gravis-Activities of Daily Living (MG-ADL) Score from Baseline over Time in Placebo, Pozelimab, Combination and Cemdisiran arms. Least square means are adjusted for intercurrent events (i.e., rescue therapy, and discontinue study due to AE) and baseline differences. The number of subjects per arm is based on the raw data prior to addressing intercurrent events. See Example 1.

[0036] Figure 7. Myasthenia Gravis-Activities of Daily Living (MG-ADL) Score over Time (mean absolute values) in Placebo, Pozelimab, Combination and Cemdisiran arms. Raw observed data without adjusting for intercurrent events (i.e., includes data post-rescue) and without any imputation. No adjustments for baseline differences (i.e., not LS means). See Example 1.

[0037] Figure 8. Observed Mean Change in Myasthenia Gravis-Activities of Daily Living (MG-ADL) Score from Baseline over Time in Placebo, Pozelimab, Combination and Cemdisiran arms. Raw observed data without adjusting for intercurrent events (i.e., includes data post-rescue) and without any imputation. No adjustments for baseline differences (i.e., not LS means). See Example 1.

[0038] Figure 9. Least Squares Mean Change in Quantitative Myasthenia Gravis (QMG) Score from Baseline over Time in Placebo, Pozelimab, Combination and Cemdisiran arms. Least square means are adjusted for intercurrent events (i.e., rescue therapy, and discontinue study due to AE) and baseline differences. The number of subjects per arm is based on the raw data prior to addressing intercurrent events. See Example 1.

[0039] Figure 10. Quantitative Myasthenia Gravis (QMG) Total Score (mean) over Time in Placebo, Pozelimab, Combination and Cemdisiran arms. Raw observed data without adjusting for intercurrent events (i.e., includes data post-rescue) and without any imputation. No adjustments for baseline differences (i.e., not LS means). See Example 1.

[0040] Figure 11. Observed Mean Change in Quantitative Myasthenia Gravis (QMG) Score from Baseline over Time in Placebo, Pozelimab, Combination and Cemdisiran arms. Raw observed data without adjusting for intercurrent events (i.e., includes data post-rescue) and without any imputation. No adjustments for baseline differences (i.e., not LS means). See Example 1.

[0041] Figure 12. Percentage of Responders Achieving a Change in Myasthenia Gravis-Activities of Daily Living (MG-ADL) Score (of 2, 3, 4, 5, 6, 7, 8, 9 or 10) in Cemdisiran, Combination and Placebo Arms. Percents on top of the bars are the proportion of participants who had at least the indicated point reduction (improvement) in their MG- ADL total score. MCID: Minimal clinically important difference. See Example 1.

[0042] Figure 13. Percentage of Responders Achieving a Change in Quantitative Myasthenia Gravis (QMG) Score (of 3, 4, 5, 6, 7, 8, 9 or 10) in Cemdisiran, Combination and Placebo Arms. Percents on top of the bars are the proportion of participants who had at least the indicated point reduction (improvement) in their QMG total score. MCID: Minimal clinically important difference. See Example 1.

[0043] Figure 14. Serum concentration of Pozelimab over time in patients receiving Pozelimab or Pozelimab and Cemdisiran. *Mean (+SD) Concentrations of Total Pozelimab in Serum Over Time (Log-Scaled). **The concentration records that were collected the first time after the participants did not receive the dose per protocol were excluded. LLOQ indicated with dashed line. See Example 1.

[0044] Figure 15 (A&B). Serum concentration of (A) Cemdisiran and (B) Cemdisiran metabolite, AS(N-2)3’Cemdisiran, over time in Pozelimab + Cemdisiran arm and Cemdisiran arm. (A) ***The concentration records that were collected the first time after the participants did not receive the dose per protocol were excluded. ****Predose and postdose concentrations are jittered to show peak and trough concentrations separately. (B) *Mean (+SD) Concentrations of Cemdisiran and metabolite in Plasma Over Time (Log-Scaled). **Below LLOQ value is set to LLOQ / 2. See Example 1.

[0045] Figure 16. Mean (±SD) Percent Change from Baseline in Concentrations of Total C5 in Plasma by Nominal Time, Treatment Group and Study (Study ALN-CC5-001, part A, single ascending dose (SAD) and R3918-MG-2018). See Example 1.

[0046] Figure 17. Mean (±SD) Concentrations of Total C5 in Plasma by Nominal Time, Treatment Group and Study (Study ALN-CC5-001, part A, single ascending dose (SAD) and R3918-MG-2018). See Example 1.

[0047] Figure 18. Total C5 Concentration (+SD) in Plasma in Placebo, Combination, Cemdisiran and Pozelimab Arms. *Below LOQ values are set to LLOQ / 2. See Example 1.

[0048] Figure 19. Mean (±SD) Percent Change from Baseline in CH50 in Serum Over Time in Placebo, Combination, Cemdisiran and Pozelimab Arms. See Example 1.

[0049] Figure 20. Mean (±SD) CH50 in Serum by Nominal Time in Participants with gMG in Placebo, Combination, Cemdisiran and Pozelimab Arms. See Example 1. DETAILED DESCRIPTION

[0050] The present invention provides, in part, a method for treating or preventing a C5- associated disease or disorder (e.g., generalized myasthenia gravis (gMG)), for example in an adult subject in need thereof who is anti-acetylcholine receptor (AChR) or anti-low- density lipoprotein receptor-related protein 4 (LRP4) antibody positive) including the steps of administering, to the subject, a therapeutically effective amount of C5 iRNA (preferably, Cemdisiran, for example, at a dose of about 600 mg which may be administered one or more times every 12 weeks) or a combination of an antibody or antigen-binding fragment thereof that binds specifically to C5 (preferably Pozelimab) and C5 iRNA (preferably, Cemdisiran).

[0051] The following discussion omits or only briefly describes conventional features of the disclosed technology that are apparent to those skilled in the art. Reference to various embodiments does not limit the scope of the claims attached hereto. Additionally, any examples set forth in this specification are intended to be non-limiting and merely set forth some of the many possible embodiments for the appended claims. Further, particular features described herein can be used in combination with other described features in each of the various possible combinations and permutations. A person of ordinary skill in the art would know how to use the instant invention, in combination with routine experiments, to achieve other outcomes not specifically disclosed in the examples or the embodiments.

[0052] Unless otherwise specifically defined herein, all terms are to be given their broadest possible interpretation including meanings implied from the specification as well as meanings understood by those skilled in the art and / or as defined in dictionaries, treatises, etc. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art in the field of the disclosed technology. It must also be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless otherwise specified, and that the terms "includes" and / or "including," when used in this specification, specify the presence of stated features, elements, and / or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups thereof. Additionally, methods, equipment, andmaterials similar or equivalent to those described herein can also be used in the practice or testing of the disclosed technology. Antigen-Binding Proteins

[0053] The present invention includes methods and compositions including anti-C5 antigen-binding proteins such as antibodies and antigen-binding fragments thereof.

[0054] The term "antibody", as used herein, refers to immunoglobulin molecules including four polypeptide chains, two heavy chains (HCs) and two light chains (LCs), inter- connected by disulfide bonds (e.g., IgG)-for example 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; Crovalimab; Eculizumab, Tesidolumab, Mubodina or Ravulizumab; preferably, Pozelimab. In an embodiment of the disclosure, each antibody heavy chain (HC) comprises a heavy chain variable region (“HCVR” or “VH”) ( e.g., any of SEQ ID NOs: 2; 18; 34; 50; 66; 82; 98; 122; 138; 146; 154; 170; 186; 202; 218; 234; 250; 266; 274; 290; 306; 322; or 338; or a variant thereof) and a heavy chain constant region; and each antibody light chain (LC) comprises a light chain variable region (“LCVR or “VL”) ( e.g., any of 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 a variant thereof) and a light chain constant region (CL). The VHand VLregions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VHand VLcomprises three CDRs and four FRs. Preferably an anti-C5 antibody or antigen-binding fragment thereof in a co- formulation of the present disclosure was expressed and isolated from a mammalian host cell such as a Chinese hamster ovary (CHO) cell.

[0055] Antibodies as set forth herein include, for example, monoclonal, recombinant, chimeric, human and / or humanized antibodies.

[0056] In an embodiment of the disclosure, the assignment of amino acids to each framework or CDR domain is in accordance with the definitions of Sequences of Proteins of Immunological Interest, Kabat, et al.; National Institutes of Health, Bethesda, Md.; 5thed.; NIH Publ. No.91-3242 (1991); Kabat (1978) Adv. Prot. Chem.32:1-75; Kabat, et al., (1977)J. Biol. Chem.252:6609-6616; Chothia, et al., (1987) J. Mol. Biol.196:901-917 or Chothia, et al., (1989) Nature 342:878-883. Thus, the present disclosure includes antibodies and antigen-binding fragments including the CDRs of a VHand the CDRs of a VL, which VHand VLcomprise amino acid sequences as set forth herein (or a variant thereof), wherein the CDRs are as defined according to Kabat and / or Chothia.

[0057] In an embodiment of the disclosure, an anti-C5 antigen-binding protein, e.g., anti- C5 antibody or antigen-binding fragment thereof, comprises a heavy chain constant domain, e.g., of the type IgA ( e.g., IgA1 or IgA2), IgD, IgE, IgG ( e.g., IgG1, IgG2, IgG3 and IgG4 ( e.g., including a S228P and / or S108P mutation)) or IgM. In an embodiment of the disclosure, an antigen-binding protein, e.g., antibody or antigen-binding fragment thereof, comprises a light chain constant domain, e.g., of the type kappa or lambda. The present disclosure includes antigen-binding proteins including the variable domains set forth 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; Crovalimab; Eculizumab, Tesidolumab, Mubodina or Ravulizumab; preferably, Pozelimab) which are linked to a heavy and / or light chain constant domain, e.g., as set forth above.

[0058] Pozelimab is sold commercially as Veopoz.

[0059] "Isolated" antigen-binding proteins (e.g., antibodies or antigen-binding fragments thereof), polypeptides, polynucleotides and vectors, are at least partially free of other biological molecules from the cells or cell culture from which they are produced. Such biological molecules include nucleic acids, proteins, other antibodies or antigen-binding fragments thereof, lipids, carbohydrates, or other material such as cellular debris and growth medium. An isolated antigen-binding protein may further be at least partially free of expression system components such as biological molecules from a host cell or of the growth medium thereof. Generally, the term "isolated" is not intended to refer to a complete absence of such biological molecules (e.g., minor or insignificant amounts of impurity may remain) or to an absence of water, buffers, or salts or to components of a pharmaceutical formulation that includes the antigen-binding proteins (e.g., antibodies or antigen-binding fragments thereof).

[0060] In an embodiment of the disclosure, an antibody or antigen-binding fragment thereof that binds specifically to complement factor 5 (C5) protein, interacts with one or more amino acids contained within NMATGMDSW (SEQ ID NO: 353) (or at least 1, 2, 3, 4 or 5 amino acids therein); or WEVHLVPRRKQLQFALPDSL (SEQ ID NO: 354) (or at least 1, 2, 3, 4 or 5 amino acids therein), as determined by hydrogen / deuterium exchange. In an embodiment of the disclosure, an antibody or antigen-binding fragment thereof that binds specifically to complement factor 5 (C5) protein interacts with one or more amino acids contained within the alpha chain and / or the beta chain of C5, as determined by hydrogen / deuterium exchange. For example, in an embodiment of the disclosure, the antibody or antigen-binding fragment thereof does not interact with an amino acid of the C5a anaphylatoxin region of C5, as determined by hydrogen / deuterium exchange. In an embodiment of the disclosure, an antibody or antigen-binding fragment thereof that binds specifically to complement factor 5 (C5) protein interacts with an amino acid sequence selected from the group consisting of (a) NMATGMDSW (SEQ ID NO: 353); (b) ATGMDSW (SEQ ID NO: 355); (c) WEVHLVPRRKQLQ (SEQ ID NO: 356); (d) WEVHLVPRRKQLQFALPDSL (SEQ ID NO: 354); and (e) LVPRRKQLQ (SEQ ID NO: 357).

[0061] The sequence of anti-C5 antibodies and antigen-binding fragments thereof (e.g., LCVRs and HCVRs or LCDRs and HCDRs thereof) that may be included in a co- formulation or used in a method are set forth below. Table A. Anti-C5 Antibody Chain Amino Acid Sequences* Antibody SEQ ID NOs R3H4H12166P2 98 100 102 104 114 116 118 120 H4H12166P3 122 124 126 128 106 108 110 112See WO2017 / 218515

[0062] Polynucleotides encoding the chains set forth in Table A are set forth below in Table B. Table B. Anti-C5 Antibody Chain Nucleotide Sequences* Antibody SEQ ID NOs R3H4H12166P97 99 101 103 105 107 109 111H4H12166P297 99 101 103 113 115 117 119See WO2017 / 218515 H2M11683N HCVR QVQLVESGGGVVQPGRSLRLSCVASGFTFSSYGIHWVRQAPGKGLEWVAVIWDDGNNINY SDSVKGRFIISRDNSRKTVYLQMNSLRGEDTAVYYCARDAPIAPVPDYWGQGTLVTVSS (SEQ ID NO: 2) HCDR1, HCDR2 and HCDR3 are set forth below, respectively:Gly Phe Thr Phe Ser Ser Tyr Gly; Ile Trp Asp Asp Gly Asn Asn Ile; and Ala Arg Asp Ala Pro Ile Ala Pro Val Pro Asp Tyr LCVR DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLDTGVPS RFSGSGSGTEFTLTISSLQPDDFATYYCQQYNTYSYTFGLGTKLEIK (SEQ ID NO: 10) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Ser Ile Ser Ser Trp; Lys Ala Ser; and Gln Gln Tyr Asn Thr Tyr Ser Tyr Thr H2M11686N HCVR QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGNTIKY ADSMKGRFTISRDNAKKSLFVEMNSLRAEDTAVYYCARYKSSSDYFDHWGQGTLVTVSS (SEQ ID NO: 18) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Phe Thr Phe Ser Asp Tyr Tyr; Ile Ser Ser Ser Gly Asn Thr Ile; and Ala Arg Tyr Lys Ser Ser Ser Asp Tyr Phe Asp His LCVR EIVLTQSPATLSLSPGERATLSCRASQSVRSYLAWYQQKPGQAPRLLIYDASNRATAIPA RFSGSGSGTDFTLTISSLEPEDLAVYYCQQSGNWPLTFGGGTKVEIK (SEQ ID NO: 26) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Ser Val Arg Ser Tyr; Asp Ala Ser; and Gln Gln Ser Gly Asn Trp Pro Leu Thr H4H12159PHCVR QVQLVESGGGVVQPGRSLRLSCGASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGNNKYY ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDSEVAPVGDYWGQGTLVTVSS (SEQ ID NO: 34) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Phe Thr Phe Ser Thr Tyr Gly; Ile Trp Asp Asp Gly Asn Asn Lys; and Ala Arg Asp Ser Glu Val Ala Pro Val Gly Asp Tyr LCVR DIQMTQSPSTLSASVGDRVTIICRASQSINRWLAWYQQKPGKAPKLLIYKASSLESGVPS RFSGSGSGTEFTLTISSLQPDDFAAYYCQQYNDYSYTFGQGTKLEIK (SEQ ID NO: 42) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Ser Ile Asn Arg Trp; Lys Ala Ser; and Gln Gln Tyr Asn Asp Tyr Ser Tyr Thr H4H12161P HCVR EVQLVESGGDLVQPGGSLRLSCAASGFTFSDHYMDWVRQAPGKGLDWIGRIRNKANAYNT EYAASVRGRFTISRDDSQNLLYLQMNSLKTDDTAVYYCVRVWNYAYFAMDVWGQGTTVTV SS (SEQ ID NO: 50) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Phe Thr Phe Ser Asp His Tyr; Ile Arg Asn Lys Ala Asn Ala Tyr Asn Thr; and Val Arg Val Trp Asn Tyr Ala Tyr Phe Ala Met Asp Val LCVR DIQMTQSPSSLSASVGDRVTITCRSSQNIGIFLNWYQQKPGEAPNLLISAASSLHSGVPS RFSGSGSGTDFTLTIGSLQPEDFATYYCQQTYNTIFTFGPGTKVDIK (SEQ ID NO: 58) LCDR1, LCDR2 and LCDR3 are set forth below, respectively:Gln Asn Ile Gly Ile Phe; Ala Ala Ser; and Gln Gln Thr Tyr Asn Thr Ile Phe Thr H4H12163P HCVR EVQLVESGGDLVQPGGSLRLSCAASGFTFSSYAMNWVRQGPGKGLEWVSAISGRGDSTYY ADSVKGRLTISRDNSKNTLYLQMNSLRAEDTAVYYCVKEGEQLVYWYFDLWGRGTLVTVSS (SEQ ID NO: 66) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Phe Thr Phe Ser Ser Tyr Ala; Ile Ser Gly Arg Gly Asp Ser Thr; and Val Lys Glu Gly Glu Gln Leu Val Tyr Trp Tyr Phe Asp Leu LCVR DIQMTQSPSSLSASVGDRVTITCRASQTISNFLHWYQQKPGKAPKLLIYAASSLQSGVPS RFSGSGSGTDFTLTISSLQPEDFSTYFCQQSYTTPLTFGGGTKVEIK (SEQ ID NO: 74) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Thr Ile Ser Asn Phe; Ala Ala Ser; and Gln Gln Ser Tyr Thr Thr Pro Leu Thr H4H12164P HCVR EVQLVESGGGLVRSGGSLRLSCAASGFTFNRYAMTWVRQAPGKGLEWVSAISGSGSSTYY TDSVKGRFTISRDNSKNSVDLQMHSLRVEDTAIYYCARGTTVTTGYGMDVWGQGTTVTVS S (SEQ ID NO: 82) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Phe Thr Phe Asn Arg Tyr Ala; Ile Ser Gly Ser Gly Ser Ser Thr; and Ala Arg Gly Thr Thr Val Thr Thr Gly Tyr Gly Met Asp ValLCVR DIQMTQSPSSLSASVGDRVTFTCQASQDITNSLNWYQQKPGRAPKLLIYDASYLKAGVPS RFSGSGSGTDFTFTISSLQPEDIATYYCQQYDDLPYTFGQGTKLEIK (SEQ ID NO: 90) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Asp Ile Thr Asn Ser; Asp Ala Ser; and Gln Gln Tyr Asp Asp Leu Pro Tyr Thr H4H12166P HCVR QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNYN PSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWGQGTLVTVSS (SEQ ID NO: 98) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Asp Ser Val Ser Ser Ser Tyr; Ile Tyr Tyr Ser Gly Ser Ser; and Ala Arg Glu Gly Asn Val Asp Thr Thr Met Ile Phe Asp Tyr LCVR AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPS RFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIK (SEQ ID NO: 106) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Gly Ile Arg Asn Asp; Ala Ala Ser; and Leu Gln Asp Phe Asn Tyr Pro Trp Thr H4H12166P2 HCVR QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNYN PSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWGQGTLVTVSS (SEQ ID NO: 98) HCDR1, HCDR2 and HCDR3 are set forth below, respectively:Gly Asp Ser Val Ser Ser Ser Tyr; Ile Tyr Tyr Ser Gly Ser Ser; and Ala Arg Glu Gly Asn Val Asp Thr Thr Met Ile Phe Asp Tyr LCVR AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPS RFAGRGSGTDFTLTISSLQPEDFATYYCHQDFNYPWTFGQGTKVEIK (SEQ ID NO: 114) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Gly Ile Arg Asn Asp; Ala Ala Ser; and His Gln Asp Phe Asn Tyr Pro Trp Thr H4H12166P3 HCVR QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNYN PSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREHNVDTTMIFDYWGQGTLVTVSS (SEQ ID NO: 122) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Asp Ser Val Ser Ser Ser Tyr; Ile Tyr Tyr Ser Gly Ser Ser; and Ala Arg Glu His Asn Val Asp Thr Thr Met Ile Phe Asp Tyr LCVR AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPS RFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIK (SEQ ID NO: 106) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Gly Ile Arg Asn Asp; Ala Ala Ser; and Leu Gln Asp Phe Asn Tyr Pro Trp Thr H4H12166P4HCVR QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNYN PSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWGQGTLVTVSS (SEQ ID NO: 98) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Asp Ser Val Ser Ser Ser Tyr; Ile Tyr Tyr Ser Gly Ser Ser; and Ala Arg Glu Gly Asn Val Asp Thr Thr Met Ile Phe Asp Tyr LCVR AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPS RFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWHFGQGTKVEIK (SEQ ID NO: 130) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Gly Ile Arg Asn Asp; Ala Ala Ser; and Leu Gln Asp Phe Asn Tyr Pro Trp His H4H12166P5 HCVR QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNYN PSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIHDYWGQGTLVTVSS (SEQ ID NO: 138) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Asp Ser Val Ser Ser Ser Tyr; Ile Tyr Tyr Ser Gly Ser Ser; and Ala Arg Glu Gly Asn Val Asp Thr Thr Met Ile His Asp Tyr LCVR AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPS RFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIK (SEQ ID NO: 106) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Gly Ile Arg Asn Asp;Ala Ala Ser; and Leu Gln Asp Phe Asn Tyr Pro Trp Thr H4H12166P6 HCVR QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNYN PSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDHTMIFDYWGQGTLVTVSS (SEQ ID NO: 146) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Asp Ser Val Ser Ser Ser Tyr; Ile Tyr Tyr Ser Gly Ser Ser; and Ala Arg Glu Gly Asn Val Asp His Thr Met Ile Phe Asp Tyr LCVR AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPS RFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIK (SEQ ID NO: 106) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Gly Ile Arg Asn Asp; Ala Ala Ser; and Leu Gln Asp Phe Asn Tyr Pro Trp Thr H4H12166P7 HCVR QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNYN PSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREHNVDTTMIFDYWGQGTLVTVSS (SEQ ID NO: 122) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Asp Ser Val Ser Ser Ser Tyr; Ile Tyr Tyr Ser Gly Ser Ser; and Ala Arg Glu His Asn Val Asp Thr Thr Met Ile Phe Asp Tyr LCVRAIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPS RFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWHFGQGTKVEIK (SEQ ID NO: 130) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Gly Ile Arg Asn Asp; Ala Ala Ser; and Leu Gln Asp Phe Asn Tyr Pro Trp His H4H12166P8 HCVR QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNYN PSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDHTMIFDYWGQGTLVTVSS (SEQ ID NO: 146) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Asp Ser Val Ser Ser Ser Tyr; Ile Tyr Tyr Ser Gly Ser Ser; and Ala Arg Glu Gly Asn Val Asp His Thr Met Ile Phe Asp Tyr LCVR AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPS RFAGRGSGTDFTLTISSLQPEDFATYYCHQDFNYPWTFGQGTKVEIK (SEQ ID NO: 114) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Gly Ile Arg Asn Asp; Ala Ala Ser; and His Gln Asp Phe Asn Tyr Pro Trp Thr H4H12166P9 HCVR QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNYN PSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDHTMIFDYWGQGTLVTVSS (SEQ ID NO: 146) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Asp Ser Val Ser Ser Ser Tyr;Ile Tyr Tyr Ser Gly Ser Ser; and Ala Arg Glu Gly Asn Val Asp His Thr Met Ile Phe Asp Tyr LCVR AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPS RFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWHFGQGTKVEIK (SEQ ID NO: 130) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Gly Ile Arg Asn Asp; Ala Ala Ser; and Leu Gln Asp Phe Asn Tyr Pro Trp His H4H12166P10 HCVR QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNYN PSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIHDYWGQGTLVTVSS (SEQ ID NO: 138) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Asp Ser Val Ser Ser Ser Tyr; Ile Tyr Tyr Ser Gly Ser Ser; and Ala Arg Glu Gly Asn Val Asp Thr Thr Met Ile His Asp Tyr LCVR AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPS RFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWHFGQGTKVEIK (SEQ ID NO: 130) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Gly Ile Arg Asn Asp; Ala Ala Ser; and Leu Gln Asp Phe Asn Tyr Pro Trp His H4H12167P HCVRQVQLVESGGGLVKPGGSLRLSCAASGFTFSDSYMSWIRQAPGKGLEWISYIGSSGNTFYY ADSVKGRFTISRDNANNLLYLQMTSLRAEDTAVYYCAREEGDFWSAVDSWGQGTLVTVSS (SEQ ID NO: 154) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Phe Thr Phe Ser Asp Ser Tyr; Ile Gly Ser Ser Gly Asn Thr Phe; and Ala Arg Glu Glu Gly Asp Phe Trp Ser Ala Val Asp Ser LCVR DIQLTQSPSFLSASVGDRVTITCWASQGISSYLAWYQQKPGKAPKLLIHTASTLQSGVPS RFSGSGSGTEFTLTISNLQPEDFATYYCQQLNSYPFTFGPGTKVDIK (SEQ ID NO: 162) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Gly Ile Ser Ser Tyr; Thr Ala Ser; and Gln Gln Leu Asn Ser Tyr Pro Phe Thr H4H12168P HCVR QVQLVESGGGVVQPGGSLRLSCAASGFTFGGHAMHWVRQAPGKGLEWLAVISSDGSNKQY ADSVKGRFTISRDNPKNTLYLQMNSLRVGDTAIYYCAKEVAPRYYYYGLDVWGQGTTVTV SS (SEQ ID NO: 170) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Phe Thr Phe Gly Gly His Ala; Ile Ser Ser Asp Gly Ser Asn Lys; and Ala Lys Glu Val Ala Pro Arg Tyr Tyr Tyr Tyr Gly Leu Asp Val LCVR DIQMTQSPSSLSASVGDRVTITCRASQDISNFLAWYQQKPGKVPKLLIYTASTLQSGVPS RFSGSGSGTDFTLTVSSLQPEDVATYYCQKYAGALTFGPGTKVDIK (SEQ ID NO: 178) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Asp Ile Ser Asn Phe;Thr Ala Ser; and Gln Lys Tyr Ala Gly Ala Leu Thr H4H12169P HCVR EVQLVESGGGLAQPGGSLRLSCAASGFTFRSYAMSWVRQAPGKGPEWVSGIGGNGVTTYY ADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCVQGGLGGYFTGYWGQGTLVTVSS (SEQ ID NO: 186) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Phe Thr Phe Arg Ser Tyr Ala; Ile Gly Gly Asn Gly Val Thr Thr; and Val Gln Gly Gly Leu Gly Gly Tyr Phe Thr Gly Tyr LCVR DIQMTQSPSSLSASVGDRVTITCRASQSISTYLNWYQQNPGKAPKLLIFDASSLQSGVPS RFSGSGSGTDFTLTIRGLQPEDFATYYCQQSYSAPLTFGGGTKVEIK (SEQ ID NO: 194) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Ser Ile Ser Thr Tyr; Asp Ala Ser; and Gln Gln Ser Tyr Ser Ala Pro Leu Thr H4H12170P HCVR QVQLVESGGGVVQPGRSLRLSCAASGFTFSGYGMHWVRQAPGKGLEWVALIWLDGSNDYY ADSVKGRFTISRDNSKNTLYLQMNRLRAEDTAVYYCARDGPVAAIPDYWGQGTLVTVSS (SEQ ID NO: 202) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Phe Thr Phe Ser Gly Tyr Gly; Ile Trp Leu Asp Gly Ser Asn Asp; and Ala Arg Asp Gly Pro Val Ala Ala Ile Pro Asp Tyr LCVRDIQMTQSPSTLSASVGDRVTITCRASQSISRWLAWYQLKPGKAPKLLIYKASSLESGVPS RFSGSGSGTDFTLTISSLQPDDFATYYCQQYNTYSYTFGQGTKLEIK (SEQ ID NO: 210) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Ser Ile Ser Arg Trp; Lys Ala Ser; and Gln Gln Tyr Asn Thr Tyr Ser Tyr Thr H4H12171P HCVR EVQLVESGGGVVRPGGSLRLSCAASGFTFDEYGMTWVRQVPGKGLEWVSGITWNGGFTDY TDSVKGRFTSSRDNAKNSLYLQMNSLRAEDTALYYCARDGYSSSWGAYDIWGQGTMVTVSS (SEQ ID NO: 218) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Phe Thr Phe Asp Glu Tyr Gly; Ile Thr Trp Asn Gly Gly Phe Thr; and Ala Arg Asp Gly Tyr Ser Ser Ser Trp Gly Ala Tyr Asp Ile LCVR DIQMTQSPSSLSASVGDRVTITCRASQSISTYLNWYQQKPGKAPKLLIYAASSLQSGVPL RFSGSGSGTDFTLTISSLQPEDFASYFCQQSYSTPYTFGQGTKLEIK (SEQ ID NO: 226) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Ser Ile Ser Thr Tyr; Ala Ala Ser; and Gln Gln Ser Tyr Ser Thr Pro Tyr Thr H4H12175P HCVR EVQLVESGGGVVQPGGSLRLSCAASGFTFNDYAMHWVRQAPGKGLEWVSLISGDGGNTYY ADSVKGRLTISRDNSKNSLYLQMNSLRTEDTALYYCAKDKGWNFGYFDLWGRGTLVTVSS (SEQ ID NO: 234) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Phe Thr Phe Asn Asp Tyr Ala;Ile Ser Gly Asp Gly Gly Asn Thr; and Ala Lys Asp Lys Gly Trp Asn Phe Gly Tyr Phe Asp Leu LCVR DIQMTQSPSSLSTSVGDRVTITCRASQNIDTYLNWYQQKPGKAPKLLIYDASSLQSGVPS RFSGSGSGTDFTLTITSLQPEDFATYYCQQNDNILHPLTFGGGTKVEIK (SEQ ID NO: 242) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Asn Ile Asp Thr Tyr; Asp Ala Ser; and Gln Gln Asn Asp Asn Ile Leu His Pro Leu Thr H4H12176P2 HCVR EVQLVESGGGLVQPGGSLRLSCAASGFHSNRYWMDWVRQAPGKGLEWVANIKQDGSEENY VDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDRSTSWVPYWFFDLWGRGTLVTVSS (SEQ ID NO: 250) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Phe His Ser Asn Arg Tyr Trp; Ile Lys Gln Asp Gly Ser Glu Glu; and Ala Arg Asp Arg Ser Thr Ser Trp Val Pro Tyr Trp Phe Phe Asp Leu LCVR DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 258) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Ser Ile Ser Ser Tyr; Ala Ala Ser; and Gln Gln Ser Tyr Ser Thr Pro Pro Ile Thr H4H12177P2 HCVREVQLVESGGGVVQRGESLRLSCSASDFIFKDYAMYWVRQIPGKGLEWISLISGDGDTTWY GDSVKGRFTISRDNNENSLFLQMNDLRTEDTAMYYCARDMGWNFFQLQYWGQGTLVTVSS (SEQ ID NO: 266) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Asp Phe Ile Phe Lys Asp Tyr Ala; Ile Ser Gly Asp Gly Asp Thr Thr; and Ala Arg Asp Met Gly Trp Asn Phe Phe Gln Leu Gln Tyr LCVR DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 258) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Ser Ile Ser Ser Tyr; Ala Ala Ser; and Gln Gln Ser Tyr Ser Thr Pro Pro Ile Thr H4H12183P2 HCVR QVQLQESGPALVKPSQTLSLTCTVSGGSIIRGSTYWSWVRQFPGKGLEWIGYSYYSGTAY YNPSLESRATISVDTSKNQFSLNLKSVTAADTAVYYCTREIGVAGLFDIWGQGTLVTVSS (SEQ ID NO: 274) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Gly Ser Ile Ile Arg Gly Ser Thr Tyr; Ser Tyr Tyr Ser Gly Thr Ala; and Thr Arg Glu Ile Gly Val Ala Gly Leu Phe Asp Ile LCVR EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIP DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK (SEQ ID NO: 282) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala; Gly Ala Ser Ser Arg Ala Thr; andGln Gln Tyr Gly Ser Ser Pro Trp Thr H2M11682N HCVR QEQLVQSGAEVKKPGASVKVSCKASGYTFTGYYIHWVRQAPGLGLEWMGWINPNSGGTKY AQKFQGRVTMTRDTSINTAYMELKRLKSDDSAVYYCARDAPPHDVFDIWGQGTLVTVSS (SEQ ID NO: 290) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Tyr Thr Phe Thr Gly Tyr Tyr; Ile Asn Pro Asn Ser Gly Gly Thr; and Ala Arg Asp Ala Pro Pro His Asp Val Phe Asp Ile LCVR DIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKRLIYAASSLQIGVPS RFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPLTFGGGTKVEIK (SEQ ID NO: 298) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Gly Ile Arg Asn Asp; Ala Ala Ser; and Leu Gln His Asn Ser Tyr Pro Leu Thr H2M11684N HCVR QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGAYHWSWIRQHPGKGLEWIGYIYYNGDTY YNPSLKSRVTISVDTSKNQFFLKVTSVTAADTAMYYCAGEKQLTAFDIWGQGTLVTVSS (SEQ ID NO: 306) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Gly Ser Ile Ser Ser Gly Ala Tyr His; Ile Tyr Tyr Asn Gly Asp Thr; and Ala Gly Glu Lys Gln Leu Thr Ala Phe Asp Ile LCVR VIQMTQSPSSLSASVGDRVTITCRASQDINNFLNWYQQKLGKAPKLLISDASNLQTGVPS RFSGSGSGTDFTFTISSLQPEDIAAYYCQQYDHFPYTFGQGTRLENN(SEQ ID NO: 314) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Asp Ile Asn Asn Phe; Asp Ala Ser; and Gln Gln Tyr Asp His Phe Pro Tyr Thr H2M11694N HCVR EVQLVESGGGVVRPGGSLRLSCAASGFTFDDYGMTWVRQAPGKGLEWVSGINWNGDSTEY SDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAFYHCARENNWNFYFDYWGQGTLVTVSS (SEQ ID NO: 322) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Phe Thr Phe Asp Asp Tyr Gly; Ile Asn Trp Asn Gly Asp Ser Thr; and Ala Arg Glu Asn Asn Trp Asn Phe Tyr Phe Asp Tyr LCVR EIVMTQSPATLSVSRGERATLSCRASQSVSSNLAWYQQKLGQAPRLLIYGASTRATGIPA RFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPWTFGQGTKVEIK (SEQ ID NO: 330) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Ser Val Ser Ser Asn; Gly Ala Ser; and Gln Gln Tyr Asn Asn Trp Pro Trp Thr H2M11695N HCVR QVHLVQSGAEVKKPGASVKVSCKVSGNTLTELSMHWVRQAPGKGLEWMGGFDPEDGDTIY SQKFQGRVTLTEDTSTDTAYMELSSLRSEDTAVYYCSTVGGPTSDCWGQGTLVTVSS (SEQ ID NO: 338) HCDR1, HCDR2 and HCDR3 are set forth below, respectively: Gly Asn Thr Leu Thr Glu Leu Ser; Phe Asp Pro Glu Asp Gly Asp Thr; andSer Thr Val Gly Gly Pro Thr Ser Asp Cys LCVR DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKVLIFDASNLEPGVPS RFSGSGSGTDFTFTIISLQPEDIATYYCQQYDNLPITFGQGTRLDIK (SEQ ID NO: 346) LCDR1, LCDR2 and LCDR3 are set forth below, respectively: Gln Asp Ile Ser Asn Tyr; Asp Ala Ser; and Gln Gln Tyr Asp Asn Leu Pro Ile Thr CDRs underscored

[0063] In an embodiment of the disclosure, an antibody or antigen-binding fragment thereof that binds specifically to C5, which is in a co-formulation of the present disclosure comprises: (1) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 2 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10 (or a variant thereof); (2) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 18 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 26 (or a variant thereof); (3) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 34 (or a variant thereof), anda LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 42 (or a variant thereof); (4) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 50 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 58 (or a variant thereof); (5) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 66 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 74 (or a variant thereof); (6) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 82 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 90 (or a variant thereof); (7) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 98 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106 (or a variant thereof); (8) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 98 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 114 (or a variant thereof); (9)a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106 (or a variant thereof); (10) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 98 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof); (11) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 138 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106 (or a variant thereof); (12) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 146 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106 (or a variant thereof); (13) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof); (14) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 146 (or a variant thereof), anda LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 114 (or a variant thereof); (15) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 146 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof); (16) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 138, and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof); (17) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 154 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 162 (or a variant thereof); (18) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 170 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 178 (or a variant thereof); (19) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 186 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 194 (or a variant thereof); (20)a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 202 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 210 (or a variant thereof); (21) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 218 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 226 (or a variant thereof); (22) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 234 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 242 (or a variant thereof); (23) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 250 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 258 (or a variant thereof); (24) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 266 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 258 (or a variant thereof); (25) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 274 (or a variant thereof), anda LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 282 (or a variant thereof); (26) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 290 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 298 (or a variant thereof); (27) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 306 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 314 (or a variant thereof); (28) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 322 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 330 (or a variant thereof); and / or (29) a HCVR that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 338 (or a variant thereof), and a LCVR that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 346 (or a variant thereof).

[0064] In an embodiment of the disclosure, an antibody or antigen-binding fragment thereof that binds specifically to C5, which is in a co-formulation of the present disclosure comprises: (a) a heavy chain variable region includingan HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 4 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 6 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 8 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 12 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 14 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 16 (or a variant thereof); (b) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 20 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 22 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 24 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 28 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 30 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 32 (or a variant thereof); (c) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 36 (or a variant thereof),an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 38 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 40 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 44 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 46 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 48 (or a variant thereof); (d) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 52 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 54 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 56 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 60 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 62 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 64 (or a variant thereof); (e) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 68 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 70 (or a variant thereof),an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 72 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 76 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 78 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 80 (or a variant thereof); (f) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 84 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 86 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 88 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 92 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 94 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 96 (or a variant thereof); (g) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 100 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 102 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 104 (or a variant thereof), and a light chain variable region includingan LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 108 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 110 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 112 (or a variant thereof); (h) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 100 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 102 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 104 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 116 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 118 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 120 (or a variant thereof); (i) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 124 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 126 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 128 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 108 (or a variant thereof),an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 110 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 112 (or a variant thereof); (j) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 100 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 102 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 104 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 132 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 134 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 136 (or a variant thereof); (k) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 140 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 142 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 144 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 108 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 110 (or a variant thereof),an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 112 (or a variant thereof); (l) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 148 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 150 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 152 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 108 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 110 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 112 (or a variant thereof); (m) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 124 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 126 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 128 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 132 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 134 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 136 (or a variant thereof); (n)a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 148 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 150 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 152 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 116 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 118 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 120 (or a variant thereof); (o) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 148 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 150 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 152 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 132 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 134 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 136 (or a variant thereof); (p) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 140 (or a variant thereof),an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 142 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 144 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 132 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 134 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 136 (or a variant thereof); (q) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 156 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 158 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 160 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 164 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 166 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 168 (or a variant thereof); (r) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 172 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 174 (or a variant thereof),an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 176 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 180 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 182 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 184 (or a variant thereof); (s) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 188 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 190 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 192 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 196 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 198 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 200 (or a variant thereof); (t) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 204 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 206 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 208 (or a variant thereof), and a light chain variable region includingan LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 212 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 214 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 216 (or a variant thereof); (u) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 220 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 222 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 224 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 228 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 230 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 232 (or a variant thereof); (v) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 236 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 238 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 240 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 244 (or a variant thereof),an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 246 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 248 (or a variant thereof); (w) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 252 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 254 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 256 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 260 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 262 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 264 (or a variant thereof); (x) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 268 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 270 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 272 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 260 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 262 (or a variant thereof),an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 264 (or a variant thereof); (y) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 276 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 278 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 280 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 284 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 286 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 288 (or a variant thereof); (z) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 292 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 294 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 296 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 300 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 302 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 304 (or a variant thereof); (aa)a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 308 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 310 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 312 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 316 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 318 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 320 (or a variant thereof); (ab) a heavy chain variable region including an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 324 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 326 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 328 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 332 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 334 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 336 (or a variant thereof); and / or (ac) a heavy chain variable region includingan HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 340 (or a variant thereof), an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 342 (or a variant thereof), an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 344 (or a variant thereof), and a light chain variable region including an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 348 (or a variant thereof), an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 350 (or a variant thereof), an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 352 (or a variant thereof).

[0065] In an embodiment of the disclosure, an antibody or antigen-binding fragment thereof that binds specifically to C5, which is in a co-formulation of the present disclosure comprises: (i) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 2 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 10 (or a variant thereof); (ii) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 18 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 26 (or a variant thereof); (iii) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 34 (or a variant thereof), anda light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 42 (or a variant thereof); (iv) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 50 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 58 (or a variant thereof); (v) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 66 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 74 (or a variant thereof); (vi) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 82 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 90 (or a variant thereof); (vii) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 98 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 106 (or a variant thereof); (viii) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 98 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 114 (or a variant thereof); (ix)a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 122 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 106 (or a variant thereof); (x) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 98 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof); (xi) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 138 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 106 (or a variant thereof); (xii) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 146 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 106 (or a variant thereof); (xiii) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 122 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof); (xiv) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 146 (or a variant thereof), anda light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 114 (or a variant thereof); (xv) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 146 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof); (xvi) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 138 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof); (xvii) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 154 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 162 (or a variant thereof); (xviii) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 170 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 178 (or a variant thereof); (xix) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 186 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 194 (or a variant thereof); (xx)a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 202 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 210 (or a variant thereof); (xxi) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 218 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 226 (or a variant thereof); (xxii) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 234 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 242 (or a variant thereof); (xxiii) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 250 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 258 (or a variant thereof); (xxiv) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 266 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 258 (or a variant thereof); (xxv) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 274 (or a variant thereof), anda light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 282 (or a variant thereof); (xxvi) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 290 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 298 (or a variant thereof); (xxvii) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 306 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 314 (or a variant thereof); (xxviii) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 322 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 330 (or a variant thereof); and / or (xxix) a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 338 (or a variant thereof), and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 346 (or a variant thereof).

[0066] In an embodiment of the disclosure, an antibody or antigen-binding fragment thereof that binds specifically to C5, which is in a co-formulation of the present disclosure comprises a heavy chain including the amino acid sequence: QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNYN PSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWGQGTLVTVSSA STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNV FSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 358); and a light chain including the amino acid sequence: AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPSR FAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 359); such an antibody may be referred to herein as Pozelimab or REGN3918 (variable regions and CDRs underscored). See Proposed INN: List 120, WHO Drug Information, Vol.32, No.4, 2018.

[0067] “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” or “H2M11695N”, unless otherwise stated, refer to anti-C5 antigen-binding proteins, e.g., antibodies and antigen-binding fragments thereof (including multispecific antigen-binding proteins), that bind specifically to C5, including an immunoglobulin heavy chain or variable region thereof (VH) including the amino acid sequence specifically set forth herein corresponding to Table A herein or Table 1 of WO2017 / 218515 (and the sequences set forth therein), to 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 or H2M11695N (e.g., SEQ ID NO: 2; 18; 34; 50; 66; 82; 98; 98; 122; 98; 138; 146; 122; 146; 146; 138; 154; 170; 186; 202; 218; 234; 250; 266; 274; 290; 306; 322 or 338) (or a variant thereof), and / or an immunoglobulin light chain or variable region thereof (VL) including the amino acid sequence specifically set forth herein corresponding to Table A herein or Table 1 of WO2017 / 218515 (and the sequences set forth therein), to 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 or H2M11695N (e.g., SEQ ID NO: 10; 26; 42; 58; 74; 90; 106; 114; 106; 130; 106; 106; 130; 114; 130; 130; 162; 178; 194; 210; 226; 242; 258; 258; 282; 298; 314; 330 or 346) (or a variant thereof); and / or that comprise a heavy chain or VHthat comprises the CDRs thereof (CDR-H1 (or a variant thereof), CDR-H2 (or a variant thereof) and CDR-H3 (or a variant thereof)) and / or a light chain or VLthat comprises the CDRs thereof (CDR-L1 (or a variant thereof), CDR-L2 (or a variant thereof) and CDR-L3 (or a variant thereof)). In an embodiment of the disclosure, the VHis linked to an IgG constant heavy chain domain (e.g., IgG1 or IgG4 (e.g., IgG4 (S228P mutant))) and / or the VLis linked to a lambda or kappa constant light chain domain.

[0068] An “anti-C5” antibody or antigen-binding fragment thereof or antibody or antigen- binding fragment thereof that “binds specifically” to C5 binds to human C5 with a KDof at least 1 nM (i.e., 1 nM or a higher affinity), e.g., about 0.1 or 0.2 nM.

[0069] In an embodiment of the disclosed technology, an anti-C5 antibody or antigen- binding fragment thereof is missing the C-terminal Lysine from the heavy chain. Interfering RNA (iRNA)

[0070] The present invention includes methods and compositions including the use of C5 iRNAs such as Cemdisiran (e.g., Cemdisiran Na+form, other salt form or free form), for example for treating or preventing MG.

[0071] In an embodiment of the invention, the C5 iRNA, e.g., Cemdisiran, is in an aqueous solution including water for Injection, US Pharmcopeia (USP) and sodium hydroxide and / or phosphoric acid to adjust the pH to ~7.0.

[0072] The present disclosure provides a co-formulation that includes an anti-C5 antibody or antigen-binding fragment thereof (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; Crovalimab; Eculizumab, Tesidolumab, Mubodina or Ravulizumab; preferably, Pozelimab); and an iRNA which effects the RNA-induced silencingcomplex (RISC)-mediated cleavage of RNA transcripts of a C5 gene (C5 iRNA), e.g. Cemdisiran (e.g., Cemdisiran / Pozelimab). The C5 gene may be within a cell, e.g., a cell within a subject, such as a human. The present disclosure provides iRNA agents for inclusion in a co-formulation of the disclosure which effect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of a complement component C5 gene.

[0073] Dosages of Cemdisiran specifically cited herein include embodiments wherein an equivalent molar amount of the Cemdisiran free form or a corresponding salt form is administered.

[0074] As discussed in detail herein, the present invention also includes a method for treating or preventing a C5 associated disease or disorder, preferably MG, comprising administering a therapeutically effective amount of Cemdisiran, e.g., Na+salt form or another salt form or free form.

[0075] The present invention also includes a method for treating or preventing a C5 associated disease or disorder, preferably MG, comprising administering about 567 or 566.6 mg (±57 mg) of the Cemdisiran free form or an equivalent molar amount of the free molecule but in a salt form, e.g., Na+form, about every 12 weeks (±7 days).

[0076] Cemdisiran is a chemically synthesized double-stranded oligonucleotide glycoconjugate that is covalently linked to a ligand containing 3 GalNAc residues to facilitate targeted delivery to the liver. All nucleosides are modified with 2′-deoxy, 2′-methoxy, or 2′- fluoro groups and are connected through 3′ to 5′ phosphodiester linkages, thus forming the sugar-phosphate backbone of the oligonucleotide.

[0077] The sense strand (A-125167) contains 21 nucleotides and the antisense strand (A-125647) contains 25. The 3′-end of the sense strand is conjugated to a triantennary GalNAc moiety (referred to as L96) through a phosphodiester linkage.

[0078] The antisense strand (A-125647) contains four phosphorothioate linkages, two consecutive phosphorothioate linkages at the 3′ end and two at the 5′ end. The sense strand (A-125167) contains two phosphorothioate linkages at the 5′ end. The 21 nucleotides of the sense strand hybridize with the complementary 21 nucleotides of the antisense strand, thus forming 21 nucleotide base pairs duplex with a 4-base overhang at the 3′-end of the antisense strand. The bases involved in base pair formation are connected with a center dot (see chemical structure below). Cemdisiran is preferably in asalt form, e.g., the Na+salt form, but the present disclosure includes embodiments including Cemdisiran in the free acid form as well as in other salt forms, e.g., Ca2+or Mg2+salts.

[0079] Cemdisiran, including salt forms thereof, may be associated with a lipid nanoparticle (LNP) delivery system, e.g., including lipids PEG-DMG (1,2-dimyristoyl- rac‑glycero‑3-[methoxy(polyethylene glycol)-2000]), PEG-DMPE (1,2-dimyristoyl- sn‑glycero‑3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]), DSPC (1,2- distearoyl-sn‑glycero‑3-phosphocholine) or DOPE (1,2-dioleoyl-sn‑glycero‑3- phosphoethanolamine). In an embodiment of the invention, the Cemdisiran is not associated with a LNP.

[0080] When expressing, herein, the concentration of RNAi in a composition, such as a co-formulation of the present disclosure, in terms of mass per volume (e.g., mg / ml), the RNAi is in a salt form or a free acid form. Preferably, when referring to Cemdisiran as such, the Cemdisiran is in salt form, preferably Na+salt form. Na+counter-ions are present due to the net-negatively charged ribonucleotide phosphate backbone. The quantity of Cemdisiran free acid form can be obtained by multiplying the Cemdisiran Na+salt form concentration by 0.9443. For example, about 566.6 or 567 mg of a 600 mg quantity of Cemdisiran Na+form is the Cemdisiran free form.

[0081] Some embodiments of the present invention refer to a quantity of Cemdisiran free form which is in a salt form, e.g., 567 mg of Cemdisiran free form which is in Na+salt form. This would refer to a quantity of Cemdisiran Na+ form wherein the amount of free form component of Cemdisiran (not including the Na+) is 567 mg.

[0082] In addition, an amount of Cemdisiran salt form which is the molar equivalent to an amount of Cemdisiran Na+form can be calculated based on the molecular weight of Cemdisiran Na+form of the duplex molecule which is summarized below in Table C. For example, 600 mg of Cemdisiran Na+salt is about 0.00003376143 moles (about 3.38 X 10-5moles or 33.8 micromoles). Table C. Cemdisiran Molecular Weight ALN-62643A-125167 A-125647 )Molecular weight of the 16,782.56 Da 8682 Da 8100 Da free acid [free form.

[0084] In an embodiment of the invention, the C5 iRNA is ALN-62643.

[0085] In an embodiment of the invention the C5 iRNA has the structure shown below wherein A-125167 is on top (5’-3’) and A-125647 is on bottom (3’-5’): Af, Gf and Uf = 2’-F ribonucleosides Am, Cm and Um- 2’-OMe ribonucleosides dT=thymidine S=phosphorothioate L96 isSee Figure 2.

[0086] SEQ ID NO: 406 is 5’AAGCAAGAUAUUUUUAUAAUA3’ with the modified bases and phosporothioate linkages described above. SEQ ID NO: 369 is 5’UAUUAUAAAAAUAUCUUGCUUUUTT3’ with the modified bases and phosporothioate linkages described above.

[0087] The present invention includes methods of use a C5 iRNA comprising a double stranded RNA, which may include one or more overhanging bases, including nucleotidestrands 5’AAGCAAGAUAUUUUUAUAAUA3’ (SEQ ID NO: 406) and 5’UAUUAUAAAAAUAUCUUGCUUUUTT3’ (SEQ ID NO: 369); wherein one more of the nucleoside bases is 2′-deoxy, 2′-methoxy and / or 2′-fluoro modified; which may include one more sugar ligands.

[0088] In an embodiment of the disclosure the C5 iRNA (e.g., dsRNA) is characterized by the strand structures: (3’-5’) A=A=G-C-A-A-G-A-U-A-U-U-U-U-U-A-U-A-A-U-A-R1 . . . . . . . . . . . . . . . . . . . . . (5’-3’) Z-Z-U=U=U-U-C-G-U-U-C-U-A-U-A-A-A-A-A-U-A-U-U=A=U [3’-5’ and 5’-3’ refers to polarity of the internucleotide bonds] wherein, X is 2’-deoxy-2’-fluoro X is 2’-O-methyl Z is thymidineIn an embodiment of the invention ,the C5 iRNA is Cemdisiran. See International Nonproprietary Names for Pharmaceutical Substances (INN) (Proposed INN: List 114),WHO Drug Information, Vol.29, No.4, 2015; or CAS No.1639267-24-5. See also "Abbreviations and Symbols for Nucleic Acids, Polynucleotides and their Constituents" Pure and Applied Chemistry, vol.40, no.3, 1974, pp.277-331. See FDA UNII (Unique Ingredient Identifiers (UNIIs)) record S66Z65E10T or X0DZ4POQ4K.

[0089] The C5 iRNAs that can be included in co-formulations of the disclosure and / or used in methods for treating or preventing MG include an RNA strand (e.g., the antisense strand) having a region which is about 30 nucleotides or less in length, e.g., at least 15, 15- 30, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15- 17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19- 29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20- 27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21- 24, 21-23, or 21-22 nucleotides in length, which region is substantially complementary to at least part of an mRNA transcript of a C5 gene.

[0090] In an embodiment of the disclosure, a C5 iRNA is a glycoconjugate that includes a double stranded RNA complementary to a region of C5 which is conjugated (e.g., by a linker) to a terminal mono-, or bi-, tri-antennary N-acetylgalactosamine (GalNAc) group, preferably triantennary N-acetylgalactosamine.

[0091] In an embodiment of the disclosure, an iRNA agent which may be included in a co-formulation of the present disclosure and / or used in methods for treating or preventing MG, includes a single stranded RNA that interacts with a target RNA sequence, e.g., a C5 target mRNA sequence, to direct the cleavage of the target RNA. Without wishing to be bound by theory, it is believed that long double stranded RNA introduced into cells is broken down into siRNA by a Type III endonuclease known as Dicer (Sharp et al. (2001) Genes Dev.15:485). Dicer, a ribonuclease-III-like enzyme, processes the dsRNA into 19-23 base pair short interfering RNAs (siRNAs) with characteristic two base 3' overhangs (Bernstein, et al., (2001) Nature 409:363). The siRNAs are then incorporated into an RNA-induced silencing complex (RISC) where one or more helicases unwind the siRNA duplex, enabling the complementary antisense strand to guide target recognition (Nykanen, et al., (2001) Cell 107:309). Upon binding to the appropriate target mRNA, one or more endonucleases within the RISC cleave the target to induce silencing (Elbashir, et al., (2001) Genes Dev.15:188). Thus, in one aspect the disclosure relates to a siRNA generated within a cell and which promotes the formation of a RISC complex to effect silencing of the target gene, i.e., a C5gene. Accordingly, the term "siRNA" is also used herein to refer to an iRNA as described above.

[0092] In another embodiment, the iRNA agent which may be included in a co- formulation of the present disclosure and / or used in methods for treating or preventing MG may be a single-stranded siRNA that is introduced into a cell or organism to inhibit a target mRNA. Single-stranded iRNA agents bind to the RISC endonuclease, Argonaute 2, which then cleaves the target mRNA. The single-stranded siRNAs are generally 15-30 nucleotides and are chemically modified. The design and testing of single-stranded siRNAs are described in U.S. Pat. No.8,101,348 and in Lima et al., (2012) Cell 150: 883-894, the entire contents of each of which are hereby incorporated herein by reference. Any of the antisense nucleotide sequences described herein may be used as a single-stranded siRNA as described herein or as chemically modified by the methods described in Lima et al., (2012) Cell 150:883-894.

[0093] In another embodiment, an iRNA for use in the compositions, uses, and methods of the disclosure is a double-stranded RNA and is referred to herein as a "double stranded iRNA agent," "double-stranded RNA (dsRNA) molecule," "dsRNA agent," or "dsRNA". The term "dsRNA", refers to a complex of ribonucleic acid molecules, having a duplex structure including two anti-parallel and substantially complementary nucleic acid strands, referred to as having "sense" and "antisense" orientations with respect to a target RNA, i.e., a C5 gene. In some embodiments of the disclosure, a double-stranded RNA (dsRNA) triggers the degradation of a target RNA, e.g., an mRNA, through a post-transcriptional gene- silencing mechanism referred to herein as RNA interference or RNAi.

[0094] In an embodiment of the disclosure, the iRNA is a double-stranded ribonucleic acid (dsRNA) wherein the dsRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises nucleotides (e.g., at least 15 contiguous nucleotides) differing by no more than 3 nucleotides from the nucleotide sequence of C5 (open reading frame underscored): tatatccgtg gtttcctgct acctccaacc atgggccttt tgggaatact ttgtttttta 60 atcttcctgg ggaaaacctg gggacaggag caaacatatg tcatttcagc accaaaaata 120 ttccgtgttg gagcatctga aaatattgtg attcaagttt atggatacac tgaagcattt 180 gatgcaacaa tctctattaa aagttatcct gataaaaaat ttagttactc ctcaggccat 240 gttcatttat cctcagagaa taaattccaa aactctgcaa tcttaacaat acaaccaaaa 300 caattgcctg gaggacaaaa cccagtttct tatgtgtatt tggaagttgt atcaaagcat 360ttttcaaaat caaaaagaat gccaataacc tatgacaatg gatttctctt cattcataca 420 gacaaacctg tttatactcc agaccagtca gtaaaagtta gagtttattc gttgaatgac 480 gacttgaagc cagccaaaag agaaactgtc ttaactttca tagatcctga aggatcagaa 540 gttgacatgg tagaagaaat tgatcatatt ggaattatct cttttcctga cttcaagatt 600 ccgtctaatc ctagatatgg tatgtggacg atcaaggcta aatataaaga ggacttttca 660 acaactggaa ccgcatattt tgaagttaaa gaatatgtct tgccacattt ttctgtctca 720 atcgagccag aatataattt cattggttac aagaacttta agaattttga aattactata 780 aaagcaagat atttttataa taaagtagtc actgaggctg acgtttatat cacatttgga 840 ataagagaag acttaaaaga tgatcaaaaa gaaatgatgc aaacagcaat gcaaaacaca 900 atgttgataa atggaattgc tcaagtcaca tttgattctg aaacagcagt caaagaactg 960 tcatactaca gtttagaaga tttaaacaac aagtaccttt atattgctgt aacagtcata 1020 gagtctacag gtggattttc tgaagaggca gaaatacctg gcatcaaata tgtcctctct 1080 ccctacaaac tgaatttggt tgctactcct cttttcctga agcctgggat tccatatccc 1140 atcaaggtgc aggttaaaga ttcgcttgac cagttggtag gaggagtccc agtaacactg 1200 aatgcacaaa caattgatgt aaaccaagag acatctgact tggatccaag caaaagtgta 1260 acacgtgttg atgatggagt agcttccttt gtgcttaatc tcccatctgg agtgacggtg 1320 ctggagttta atgtcaaaac tgatgctcca gatcttccag aagaaaatca ggccagggaa 1380 ggttaccgag caatagcata ctcatctctc agccaaagtt acctttatat tgattggact 1440 gataaccata aggctttgct agtgggagaa catctgaata ttattgttac ccccaaaagc 1500 ccatatattg acaaaataac tcactataat tacttgattt tatccaaggg caaaattatc 1560 cactttggca cgagggagaa attttcagat gcatcttatc aaagtataaa cattccagta 1620 acacagaaca tggttccttc atcccgactt ctggtctatt acatcgtcac aggagaacag 1680 acagcagaat tagtgtctga ttcagtctgg ttaaatattg aagaaaaatg tggcaaccag 1740 ctccaggttc atctgtctcc tgatgcagat gcatattctc caggccaaac tgtgtctctt 1800 aatatggcaa ctggaatgga ttcctgggtg gcattagcag cagtggacag tgctgtgtat 1860 ggagtccaaa gaggagccaa aaagcccttg gaaagagtat ttcaattctt agagaagagt 1920 gatctgggct gtggggcagg tggtggcctc aacaatgcca atgtgttcca cctagctgga 1980 cttaccttcc tcactaatgc aaatgcagat gactcccaag aaaatgatga accttgtaaa 2040 gaaattctca ggccaagaag aacgctgcaa aagaagatag aagaaatagc tgctaaatat 2100 aaacattcag tagtgaagaa atgttgttac gatggagcct gcgttaataa tgatgaaacc 2160 tgtgagcagc gagctgcacg gattagttta gggccaagat gcatcaaagc tttcactgaa 2220 tgttgtgtcg tcgcaagcca gctccgtgct aatatctctc ataaagacat gcaattggga 2280 aggctacaca tgaagaccct gttaccagta agcaagccag aaattcggag ttattttcca 2340 gaaagctggt tgtgggaagt tcatcttgtt cccagaagaa aacagttgca gtttgcccta 2400 cctgattctc taaccacctg ggaaattcaa ggcgttggca tttcaaacac tggtatatgt 2460 gttgctgata ctgtcaaggc aaaggtgttc aaagatgtct tcctggaaat gaatatacca 2520 tattctgttg tacgaggaga acagatccaa ttgaaaggaa ctgtttacaa ctataggact 2580 tctgggatgc agttctgtgt taaaatgtct gctgtggagg gaatctgcac ttcggaaagc 2640ccagtcattg atcatcaggg cacaaagtcc tccaaatgtg tgcgccagaa agtagagggc 2700 tcctccagtc acttggtgac attcactgtg cttcctctgg aaattggcct tcacaacatc 2760 aatttttcac tggagacttg gtttggaaaa gaaatcttag taaaaacatt acgagtggtg 2820 ccagaaggtg tcaaaaggga aagctattct ggtgttactt tggatcctag gggtatttat 2880 ggtaccatta gcagacgaaa ggagttccca tacaggatac ccttagattt ggtccccaaa 2940 acagaaatca aaaggatttt gagtgtaaaa ggactgcttg taggtgagat cttgtctgca 3000 gttctaagtc aggaaggcat caatatccta acccacctcc ccaaagggag tgcagaggcg 3060 gagctgatga gcgttgtccc agtattctat gtttttcact acctggaaac aggaaatcat 3120 tggaacattt ttcattctga cccattaatt gaaaagcaga aactgaagaa aaaattaaaa 3180 gaagggatgt tgagcattat gtcctacaga aatgctgact actcttacag tgtgtggaag 3240 ggtggaagtg ctagcacttg gttaacagct tttgctttaa gagtacttgg acaagtaaat 3300 aaatacgtag agcagaacca aaattcaatt tgtaattctt tattgtggct agttgagaat 3360 tatcaattag ataatggatc tttcaaggaa aattcacagt atcaaccaat aaaattacag 3420 ggtaccttgc ctgttgaagc ccgagagaac agcttatatc ttacagcctt tactgtgatt 3480 ggaattagaa aggctttcga tatatgcccc ctggtgaaaa tcgacacagc tctaattaaa 3540 gctgacaact ttctgcttga aaatacactg ccagcccaga gcacctttac attggccatt 3600 tctgcgtatg ctctttccct gggagataaa actcacccac agtttcgttc aattgtttca 3660 gctttgaaga gagaagcttt ggttaaaggt aatccaccca tttatcgttt ttggaaagac 3720 aatcttcagc ataaagacag ctctgtacct aacactggta cggcacgtat ggtagaaaca 3780 actgcctatg ctttactcac cagtctgaac ttgaaagata taaattatgt taacccagtc 3840 atcaaatggc tatcagaaga gcagaggtat ggaggtggct tttattcaac ccaggacaca 3900 atcaatgcca ttgagggcct gacggaatat tcactcctgg ttaaacaact ccgcttgagt 3960 atggacatcg atgtttctta caagcataaa ggtgccttac ataattataa aatgacagac 4020 aagaatttcc ttgggaggcc agtagaggtg cttctcaatg atgacctcat tgtcagtaca 4080 ggatttggca gtggcttggc tacagtacat gtaacaactg tagttcacaa aaccagtacc 4140 tctgaggaag tttgcagctt ttatttgaaa atcgatactc aggatattga agcatcccac 4200 tacagaggct acggaaactc tgattacaaa cgcatagtag catgtgccag ctacaagccc 4260 agcagggaag aatcatcatc tggatcctct catgcggtga tggacatctc cttgcctact 4320 ggaatcagtg caaatgaaga agacttaaaa gcccttgtgg aaggggtgga tcaactattc 4380 actgattacc aaatcaaaga tggacatgtt attctgcaac tgaattcgat tccctccagt 4440 gatttccttt gtgtacgatt ccggatattt gaactctttg aagttgggtt tctcagtcct 4500 gccactttca cagtgtacga ataccacaga ccagataaac agtgtaccat gttttatagc 4560 acttccaata tcaaaattca gaaagtctgt gaaggagccg cgtgcaagtg tgtagaagct 4620 gattgtgggc aaatgcagga agaattggat ctgacaatct ctgcagagac aagaaaacaa 4680 acagcatgta aaccagagat tgcatatgct tataaagtta gcatcacatc catcactgta 4740 gaaaatgttt ttgtcaagta caaggcaacc cttctggata tctacaaaac tggggaagct 4800 gttgctgaga aagactctga gattaccttc attaaaaagg taacctgtac taacgctgag 4860 ctggtaaaag gaagacagta cttaattatg ggtaaagaag ccctccagat aaaatacaat 4920ttcagtttca ggtacatcta ccctttagat tccttgacct ggattgaata ctggcctaga 4980 gacacaacat gttcatcgtg tcaagcattt ttagctaatt tagatgaatt tgccgaagat 5040 atctttttaa atggatgcta aaattcctga agttcagctg catacagttt gcacttatgg 5100 actcctgttg ttgaagttcg tttttttgtt ttcttctttt tttaaacatt catagctggt 5160 cttatttgta aagctcactt tacttagaat tagtggcact tgcttttatt agagaatgat 5220 ttcaaatgct gtaactttct gaaataacat ggccttggag ggcatgaaga cagatactcc 5280 tccaaggtta ttggacaccg gaaacaataa attggaacac ctcctcaaac ctaccactca 5340 ggaatgtttg ctggggccga aagaacagtc cattgaaagg gagtattaca aaaacatggc 5400 ctttgcttga aagaaaatac caaggaacag gaaactgatc attaaagcct gagtttgctt 5460 tcaaaaaaaa aaaaaaaaaa 5480 (SEQ ID NO: 360), and the antisense strand comprises nucleotides (e.g., at least 15 contiguous nucleotides) differing by no more than 3 nucleotides from the nucleotide sequence of: tttttttttt ttttttttga aagcaaactc aggctttaat gatcagtttc ctgttccttg 60 gtattttctt tcaagcaaag gccatgtttt tgtaatactc cctttcaatg gactgttctt 120 tcggccccag caaacattcc tgagtggtag gtttgaggag gtgttccaat ttattgtttc 180 cggtgtccaa taaccttgga ggagtatctg tcttcatgcc ctccaaggcc atgttatttc 240 agaaagttac agcatttgaa atcattctct aataaaagca agtgccacta attctaagta 300 aagtgagctt tacaaataag accagctatg aatgtttaaa aaaagaagaa aacaaaaaaa 360 cgaacttcaa caacaggagt ccataagtgc aaactgtatg cagctgaact tcaggaattt 420 tagcatccat ttaaaaagat atcttcggca aattcatcta aattagctaa aaatgcttga 480 cacgatgaac atgttgtgtc tctaggccag tattcaatcc aggtcaagga atctaaaggg 540 tagatgtacc tgaaactgaa attgtatttt atctggaggg cttctttacc cataattaag 600 tactgtcttc cttttaccag ctcagcgtta gtacaggtta cctttttaat gaaggtaatc 660 tcagagtctt tctcagcaac agcttcccca gttttgtaga tatccagaag ggttgccttg 720 tacttgacaa aaacattttc tacagtgatg gatgtgatgc taactttata agcatatgca 780 atctctggtt tacatgctgt ttgttttctt gtctctgcag agattgtcag atccaattct 840 tcctgcattt gcccacaatc agcttctaca cacttgcacg cggctccttc acagactttc 900 tgaattttga tattggaagt gctataaaac atggtacact gtttatctgg tctgtggtat 960 tcgtacactg tgaaagtggc aggactgaga aacccaactt caaagagttc aaatatccgg 1020 aatcgtacac aaaggaaatc actggaggga atcgaattca gttgcagaat aacatgtcca 1080 tctttgattt ggtaatcagt gaatagttga tccacccctt ccacaagggc ttttaagtct 1140 tcttcatttg cactgattcc agtaggcaag gagatgtcca tcaccgcatg agaggatcca 1200 gatgatgatt cttccctgct gggcttgtag ctggcacatg ctactatgcg tttgtaatca 1260 gagtttccgt agcctctgta gtgggatgct tcaatatcct gagtatcgat tttcaaataa 1320 aagctgcaaa cttcctcaga ggtactggtt ttgtgaacta cagttgttac atgtactgta 1380 gccaagccac tgccaaatcc tgtactgaca atgaggtcat cattgagaag cacctctact 1440ggcctcccaa ggaaattctt gtctgtcatt ttataattat gtaaggcacc tttatgcttg 1500 taagaaacat cgatgtccat actcaagcgg agttgtttaa ccaggagtga atattccgtc 1560 aggccctcaa tggcattgat tgtgtcctgg gttgaataaa agccacctcc atacctctgc 1620 tcttctgata gccatttgat gactgggtta acataattta tatctttcaa gttcagactg 1680 gtgagtaaag cataggcagt tgtttctacc atacgtgccg taccagtgtt aggtacagag 1740 ctgtctttat gctgaagatt gtctttccaa aaacgataaa tgggtggatt acctttaacc 1800 aaagcttctc tcttcaaagc tgaaacaatt gaacgaaact gtgggtgagt tttatctccc 1860 agggaaagag catacgcaga aatggccaat gtaaaggtgc tctgggctgg cagtgtattt 1920 tcaagcagaa agttgtcagc tttaattaga gctgtgtcga ttttcaccag ggggcatata 1980 tcgaaagcct ttctaattcc aatcacagta aaggctgtaa gatataagct gttctctcgg 2040 gcttcaacag gcaaggtacc ctgtaatttt attggttgat actgtgaatt ttccttgaaa 2100 gatccattat ctaattgata attctcaact agccacaata aagaattaca aattgaattt 2160 tggttctgct ctacgtattt atttacttgt ccaagtactc ttaaagcaaa agctgttaac 2220 caagtgctag cacttccacc cttccacaca ctgtaagagt agtcagcatt tctgtaggac 2280 ataatgctca acatcccttc ttttaatttt ttcttcagtt tctgcttttc aattaatggg 2340 tcagaatgaa aaatgttcca atgatttcct gtttccaggt agtgaaaaac atagaatact 2400 gggacaacgc tcatcagctc cgcctctgca ctccctttgg ggaggtgggt taggatattg 2460 atgccttcct gacttagaac tgcagacaag atctcaccta caagcagtcc ttttacactc 2520 aaaatccttt tgatttctgt tttggggacc aaatctaagg gtatcctgta tgggaactcc 2580 tttcgtctgc taatggtacc ataaataccc ctaggatcca aagtaacacc agaatagctt 2640 tcccttttga caccttctgg caccactcgt aatgttttta ctaagatttc ttttccaaac 2700 caagtctcca gtgaaaaatt gatgttgtga aggccaattt ccagaggaag cacagtgaat 2760 gtcaccaagt gactggagga gccctctact ttctggcgca cacatttgga ggactttgtg 2820 ccctgatgat caatgactgg gctttccgaa gtgcagattc cctccacagc agacatttta 2880 acacagaact gcatcccaga agtcctatag ttgtaaacag ttcctttcaa ttggatctgt 2940 tctcctcgta caacagaata tggtatattc atttccagga agacatcttt gaacaccttt 3000 gccttgacag tatcagcaac acatatacca gtgtttgaaa tgccaacgcc ttgaatttcc 3060 caggtggtta gagaatcagg tagggcaaac tgcaactgtt ttcttctggg aacaagatga 3120 acttcccaca accagctttc tggaaaataa ctccgaattt ctggcttgct tactggtaac 3180 agggtcttca tgtgtagcct tcccaattgc atgtctttat gagagatatt agcacggagc 3240 tggcttgcga cgacacaaca ttcagtgaaa gctttgatgc atcttggccc taaactaatc 3300 cgtgcagctc gctgctcaca ggtttcatca ttattaacgc aggctccatc gtaacaacat 3360 ttcttcacta ctgaatgttt atatttagca gctatttctt ctatcttctt ttgcagcgtt 3420 cttcttggcc tgagaatttc tttacaaggt tcatcatttt cttgggagtc atctgcattt 3480 gcattagtga ggaaggtaag tccagctagg tggaacacat tggcattgtt gaggccacca 3540 cctgccccac agcccagatc actcttctct aagaattgaa atactctttc caagggcttt 3600 ttggctcctc tttggactcc atacacagca ctgtccactg ctgctaatgc cacccaggaa 3660 tccattccag ttgccatatt aagagacaca gtttggcctg gagaatatgc atctgcatca 3720ggagacagat gaacctggag ctggttgcca catttttctt caatatttaa ccagactgaa 3780 tcagacacta attctgctgt ctgttctcct gtgacgatgt aatagaccag aagtcgggat 3840 gaaggaacca tgttctgtgt tactggaatg tttatacttt gataagatgc atctgaaaat 3900 ttctccctcg tgccaaagtg gataattttg cccttggata aaatcaagta attatagtga 3960 gttattttgt caatatatgg gcttttgggg gtaacaataa tattcagatg ttctcccact 4020 agcaaagcct tatggttatc agtccaatca atataaaggt aactttggct gagagatgag 4080 tatgctattg ctcggtaacc ttccctggcc tgattttctt ctggaagatc tggagcatca 4140 gttttgacat taaactccag caccgtcact ccagatggga gattaagcac aaaggaagct 4200 actccatcat caacacgtgt tacacttttg cttggatcca agtcagatgt ctcttggttt 4260 acatcaattg tttgtgcatt cagtgttact gggactcctc ctaccaactg gtcaagcgaa 4320 tctttaacct gcaccttgat gggatatgga atcccaggct tcaggaaaag aggagtagca 4380 accaaattca gtttgtaggg agagaggaca tatttgatgc caggtatttc tgcctcttca 4440 gaaaatccac ctgtagactc tatgactgtt acagcaatat aaaggtactt gttgtttaaa 4500 tcttctaaac tgtagtatga cagttctttg actgctgttt cagaatcaaa tgtgacttga 4560 gcaattccat ttatcaacat tgtgttttgc attgctgttt gcatcatttc tttttgatca 4620 tcttttaagt cttctcttat tccaaatgtg atataaacgt cagcctcagt gactacttta 4680 ttataaaaat atcttgcttt tatagtaatt tcaaaattct taaagttctt gtaaccaatg 4740 aaattatatt ctggctcgat tgagacagaa aaatgtggca agacatattc tttaacttca 4800 aaatatgcgg ttccagttgt tgaaaagtcc tctttatatt tagccttgat cgtccacata 4860 ccatatctag gattagacgg aatcttgaag tcaggaaaag agataattcc aatatgatca 4920 atttcttcta ccatgtcaac ttctgatcct tcaggatcta tgaaagttaa gacagtttct 4980 cttttggctg gcttcaagtc gtcattcaac gaataaactc taacttttac tgactggtct 5040 ggagtataaa caggtttgtc tgtatgaatg aagagaaatc cattgtcata ggttattggc 5100 attctttttg attttgaaaa atgctttgat acaacttcca aatacacata agaaactggg 5160 ttttgtcctc caggcaattg ttttggttgt attgttaaga ttgcagagtt ttggaattta 5220 ttctctgagg ataaatgaac atggcctgag gagtaactaa attttttatc aggataactt 5280 ttaatagaga ttgttgcatc aaatgcttca gtgtatccat aaacttgaat cacaatattt 5340 tcagatgctc caacacggaa tatttttggt gctgaaatga catatgtttg ctcctgtccc 5400 caggttttcc ccaggaagat taaaaaacaa agtattccca aaaggcccat ggttggaggt 5460 agcaggaaac cacggatata 5480 (SEQ ID NO: 361).

[0095] The present disclosure includes an iRNA which can be used in methods for treating or preventing MG and / or included in a co-formulation of the present disclosure that is a double-stranded ribonucleic acid (dsRNA) agent (e.g., having a complementarity region of 19-23 nucleotides in length and / or having a strand length of no more than 30 nucleotides) that inhibits expression of complement component C5, wherein the dsRNA agent comprisesa sense strand and an antisense strand, the antisense strand including a region of complementarity which comprises at least 17 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of 5'-UAUUAUAAAAAUAUCUUGCUUUU- 3' (SEQ ID NO: 364), wherein one or more of the dsRNA nucleotides are modified. The dsRNA agent may include at least one modified nucleotide e.g., with 2′-deoxy, 2′-methoxy, and / or 2′-fluoro groups; for example, where substantially all of the nucleotides of the sense strand and antisense strand are modified nucleotides. Moreover, the sense strand can be conjugated to a ligand attached at the 3'-terminus, e.g., terminally modified with a triantennary GalNAc moiety.

[0096] The modified nucleotides that may be included in a dsRNA which may be used in a co-formulation of the present invention or in a method for treating or preventing MG may include a 3'-terminal deoxy-thymine (dT) nucleotide, a 2'-O-methyl modified nucleotide, a 2'- fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, a 2'-amino-modified nucleotide, a 2'-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base including nucleotide, a nucleotide including a 5'-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or a dodecanoic acid bisdecylamide group. The dsRNA may include a phosphorothioate and / or methylphosphonate internucleotide linkage.

[0097] A dsRNA is double stranded, but may include one or more overhangs, such as at the 3’ end of one or more strands (e.g., 2 or more nucleotides of overhang).

[0098] Double stranded RNAs of the present disclosure may include a ligand (e.g., a N- acetylgalactosamine (GalNAc) derivative ). In an embodiment of the disclosure, the lstrand of the dsRNA.

[0099] In one aspect, the present disclosure provides a double-stranded ribonucleic acid (dsRNA) agent that inhibits expression of complement component C5 which can be included in a co-formulation of the present disclosure and / or used in methods for treating or preventing MG, wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the sense strand comprises the nucleotide sequence 5’- AAGCAAGAUAUUUUUAUAAUA-3’ (SEQ ID NO: 365) and wherein the antisense strand comprises the nucleotide sequence 5’-UAUUAUAAAAAUAUCUUGCUUUU-3’ (SEQ ID NO: 364), e.g., wherein one or more of the dsRNA nucleotides are modified; e.g., with 2′-deoxy, 2′-methoxy, and / or 2′-fluoro groups and / or terminally modified with a triantennary GalNAc moiety. In one embodiment, the dsRNA agent comprises at least one modified nucleotide, as described herein.

[0100] In one aspect, the present disclosure provides a double stranded iRNA agent, which can be included in a co-formulation of the present disclosure and / or used in methods for treating or preventing MG, that inhibits expression of complement component C5 wherein the double stranded iRNA agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO: 365 and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO: 364, wherein substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand are modified nucleotides, and wherein the sense strand is conjugated to a ligand attached at the 3' -terminus. In one embodiment, the dsRNA agent comprises at least one modified nucleotide, as described herein.

[0101] In one embodiment, substantially all of the nucleotides of the sense strand are modified nucleotides selected from the group consisting of a 2'-O-methyl modification, a 2'- fluoro modification and a 3'-terminal deoxy-thymine (dT) nucleotide. In another embodiment, substantially all of the nucleotides of the antisense strand are modified nucleotides selected from the group consisting of a 2'-O-methyl modification, a 2'-fluoro modification and a 3'-terminal deoxy-thymine (dT) nucleotide. In another embodiment, the modified nucleotides are a short sequence of deoxy-thymine (dT) nucleotides. In another embodiment, the sense strand comprises two phosphorothioate internucleotide linkages at the 5' -terminus. In one embodiment, the antisense strand comprises two phosphorothioateinternucleotide linkages at the 5'-terminus and two phosphorothioate internucleotide linkages at the 3'-terminus. In yet another embodiment, the sense strand is conjugated to one or more GalNAc derivatives attached through a branched bivalent or trivalent linker at the 3'-terminus.

[0102] In one embodiment, at least one of the modified nucleotides is selected from the group consisting of a 3'-terminal deoxy-thymine (dT) nucleotide, a 2'-O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, a locked nucleotide, a basic nucleotide, a 2'-amino-modified nucleotide, a 2'-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base including nucleotide, a nucleotide 20 including a 5'-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or a dodecanoic acid bisdecylamide group.

[0103] In another embodiment, the modified nucleotides comprise a short sequence of 3'-terminal deoxy-thymine (dT) nucleotides (e.g., 2).

[0104] In one embodiment, the region of complementarity is at least 17 nucleotides in length. In another embodiment, the region of complementarity is between 19 and 21 nucleotides in length. In one embodiment, the region of complementarity is 19 nucleotides in length. In one embodiment, each strand is no more than 30 nucleotides in length. In one embodiment, at least one strand comprises a 3' overhang of at least 1 nucleotide. In another embodiment, at least one strand comprises a 3' overhang of at least 2 nucleotides. In one embodiment, the dsRNA agent further comprises a ligand. In one embodiment, the ligand is conjugated to the 3' end of the sense strand of the dsRNA agent. In one embodiment, the ligand is an N-acetylgalactosamine (GalNAc) derivative. In one embodiment, the ligand is[0gated to the ligand as shown in the following schematic, ,

[0106] In an embodiment of the present disclosure, the C5 iRNA includes an RNA strand that is complementary to an mRNA transcribed from the C5 gene sense strand DNA sequence AAGCAAGATATTTTTATAATA (SEQ ID NO: 407), for example, wherein the iRNA is a dsRNA that includes another hybridized RNA strand.

[0107] In another aspect, the present disclosure provides a double-stranded ribonucleic acid (dsRNA) agent that inhibits expression of complement component C5, wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the sense strand comprises the nucleotide sequence 5’AAGCAAGAUAUUUUUAUAAUA3’ (SEQ ID NO: 366) and wherein the antisense strand comprises the nucleotide sequence5’UAUUAUAAAAAUAUCUUGCUUUUdTdT3’ (SEQ ID NO: 367).

[0108] In another aspect, the present disclosure provides a double-stranded ribonucleic acid (dsRNA) agent that inhibits expression of complement component C5, wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the sense strand comprises the nucleotide sequence 5’AAGCAAGAUAUUUUUAUAAUA3’ with the modified bases and phosporothioate linkages described above (SEQ ID NO: 406) (i.e., asasGfcAfaGfaUfAfUfuUfuuAfuAfaua), and wherein the antisense strand comprises the nucleotide sequence 5’UAUUAUAAAAAUAUCUUGCUUUUTT5’ with the modified bases and phosporothioate linkages described above (SEQ ID NO: 369) (i.e., usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT), wherein the 3′-end of the sense strand is conjugated to L96.

[0109] In an embodiment of the disclosure, the sense or antisense strands of a dsRNA that can be included in a formulation of the present disclosure comprises sequences selected from the group consisting of A-118320, A-118321, A-118316, A-118317, A- 118332, A-118333, A-118396, A-118397, A-118386, A-118387, A-118312, A-118313, A- 118324, A-118325, A-119324, A-119325, A-119332, A-119333, A-119328, A-119329, A- 119322, A-119323, A-119324, A-119325, A-119334, A-119335, A-119330, A-119331, A- 119326, A-119327, A-125167, A-125173, A-125647, A-125157, A-125173, and A-125127. In one embodiment, the dsRNA agent comprises at least one modified nucleotide. Table D. Sense and Anti-sense RNA strands of C5 dsRNAs (unmodified and modified strands shown) A-118320 aagcaagaua uuuuuauaau aA-118317 auuauaguga guuauuuugu caa anti-sense strandanti-sense strand (SEQ ID NO: 383)A-119334 guuccggaua uuugaacuuu u sense strandanti-sense strand (SEQ ID NO: 404)Af=2'-fluoroadenosine-3'-phosphate Afs=2'-fluoroadenosine-3'-phosphorothioate As=adenosine-3'-phosphorothioate C=cytidine-3'-phosphate Cf=2'-fluorocytidine-3'-phosphate Cfs=2'-fluorocytidine-3'-phosphorothioate Cs=cytidine-3'-phosphorothioate G=guanosine-3'-phosphate Gf=2'-fluoroguanosine-3'-phosphate Gfs=2'-fluoroguanosine-3 '-phosphorothioate Gs=guanosine-3'-phosphorothioate Τ=5'-methyluridine-3'-phosphate Tf=2'-fluoro-5-methyluridine-3 '-phosphate Tfs=2'-fluoro-5-methyluridine-3 '-phosphorothioate Ts=5-methyluridine-3'-phosphorothioate U=Uridine-3'-phosphate Uf=2'-fluorouridine-3'-phosphate Ufs=2'-fluorouridine-3'-phosphorothioate Us=uridine-3'-phosphorothioate Ν=any nucleotide (G, A, C, Τ or U) a=2'-0-methyladenosine-3'-phosphate as=2'-0-methyladenosine-3'-phosphorothioate c=2'-0-methylcytidine-3 '-phosphate cs=2'-0-methylcytidine-3 '-phosphorothioate g= 2'-0-methylguanosine-3 '-phosphategs= 2'-0-methylguanosine-3 '-phosphorothioate t= 2'-0-methyl-5-methyluridine-3'-phosphate ts= 2'-0-methyl-5-methyluridine-3'-phosphorothioate u= 2'-0-methyluridine-3'-phosphate us= 2'-0-methyluridine-3'-phosphorothioate s= phosphorothioate linkage L96= N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol Hyp - (GalNAc-alkyl)3(dt)= deoxy-thymine

[0110] In an embodiment of the disclosure, the dsRNA comprises the two following pairs of strands: A-118320 & A-118321; A-118316 & A-118317; A-118332 & A-118333; A-118396 & A-118397; A-118386 & A-118387; A-118312 & A-118313; A-118324 & A-118325; A-119324 & A-119325; A-119332 & A-119333; A-119328 & A-119329; A-119322 & A-119323; A-119324 & A-119325; A-119334 & A-119335; A-119330 & A-119331; A-119326 & A-119327; A-125167 & A-125173 or A-125647; A-125157 & A-125173 or A-125647; A-125127 & A-125173 or A-125647; and / or A-125167 & A-125647.

[0111] In an embodiment of the disclosure, the C5 iRNA (e.g., Cemdisiran) comprises one or more galactosamines, e.g., 3, for example, represented by the structure: whereand X is O or X is S; e.g.,. However, in an embodiment of the disclosure, a co-formulation of the present disclosure further comprises degradation products represented by one or more of the following structures (wavy line represents double stranded RNA structure):wherein 1, 2 or 3 of the terminal N-acetylgalactosamines (GalNAc) are missing.

[0112] iRNAs of the present disclosure can be chemically linked, by the RNA portion of the molecule, to one or more ligands, moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the iRNA. Such moieties include but are not limited to lipid moieties such as a cholesterol moiety (Letsinger et al., Proc. Natl. Acid. Sci. USA, 1989, 86: 6553-6556), cholic acid (Manoharan et al., Biorg. Med. Chem. Let., 1994, 4:1053- 1060), a thioether, e.g., beryl-S-tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660:306-309; Manoharan et al., Biorg. Med. Chem. Let., 1993, 3:2765-2770), a thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20:533-538), an aliphatic chain, e.g., dodecandiol or undecyl residues (Saison-Behmoaras et al., EMBO J, 1991, 10:1111- 1118; Kabanov et al., FEBS Lett., 1990, 259:327-330; Svinarchuk et al., Biochimie, 1993, 75:49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O- hexadecyl-rac-glycero-3-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36:3651- 3654; Shea et al., Nucl. Acids Res., 1990, 18:3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14:969-973), or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654), a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264:229-237), or an octadecylamine or hexylamino-carbonyloxycholesterol moiety (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277:923-937).

[0113] A ligand can be a carbohydrate. A carbohydrate conjugated RNA is advantageous for the in vivo delivery of nucleic acids. As used herein, “carbohydrate”ligand refers to a compound which is either a carbohydrate per se made up of one or more monosaccharide units having at least 6 carbon atoms (which can be linear, branched or cyclic) with an oxygen, nitrogen or sulfur atom bonded to each carbon atom; or a compound having as a part thereof a carbohydrate moiety made up of one or more monosaccharide units each having at least six carbon atoms (which can be linear, branched or cyclic), with an oxygen, nitrogen or sulfur atom bonded to each carbon atom. Representative carbohydrates include the sugars (mono-, di-, tri- and oligosaccharides containing from about 4, 5, 6, 7, 8, or 9 monosaccharide units), and polysaccharides such as starches, glycogen, cellulose and polysaccharide gums. Specific monosaccharides include C5 and above (e.g., C5, C6, C7, or C8) sugars; di- and trisaccharides include sugars having two or three monosaccharide units (e.g., C5, C6, C7, or C8).

[0114] In one embodiment, a carbohydrate conjugate for use in the compositions and methods of the disclosure is a monosaccharide. In one embodiment, the monosaccharide is an N-acetylgalactosamine, such as ;;;; ;;; ; ;;or,when one of X or Υ is an oligonucleotide, the other is a hydrogen.

[0115] In an embodiment of the invention, the iRNA, e.g., Cemdisiran, is in a lipid nanoparticle.

[0116] In some embodiments, the conjugate or ligand described herein can be attached to an iRNA oligonucleotide with various linkers that can be cleavable or non-cleavable. The term “linker” or “linking group” means an organic moiety that connects two parts of a compound, e.g., covalently attaches two parts of a compound. Linkers typically comprise a direct bond or an atom such as oxygen or sulfur, a unit such as NR8, C(O), C(O)NH, SO, SO2, SO2NH or a chain of atoms, such as, but not limited to, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkenyl, alkylhererocyclylalkynyl, alkenylheterocyclylalkyl,alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, alkynylhereroaryl, which one or more methylenes can be interrupted or terminated by O, S, S(O), SO2, N(R8), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic; where R8 is hydrogen, acyl, aliphatic or substituted aliphatic. In one embodiment, the linker is between about 1-24 atoms, 2-24, 3-24, 4-24, 5-24, 6-24, 6-18, 7-18, 8-18 atoms, 7-17, 8-17, 6-16, 7-16, or 8-16 atoms. Linkers may comprise redox cleavable linking groups, phosphate-based cleavable linking groups, acid cleavable linking groups, ester-based linking groups and / or peptide-based cleaving groups., ,hydrogen. In certain embodiments of the compositions and methods of the disclosure, a ligand is one or more GalNAc (N-acetylgalactosamine) derivatives attached through a bivalent or trivalent branched linker. Co-Formulations

[0117] The present disclosure provides pharmaceutical, preferably aqueous, co- formulations and combinations that include a pharmaceutically acceptable carrier and the components: (i) an anti-C5 antibody or antigen-binding fragment thereof (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; Crovalimab; Eculizumab, Tesidolumab, Mubodina or Ravulizumab; preferably, Pozelimab); and(ii) a C5 iRNA, preferably a glycoconjugate, such as Cemdisiran. Methods of treating or preventing a C5-associated disease or disorder, e.g., MG, including the step of administering a therapeutically effective amount of a co-formulation or combination as described herein, e.g., wherein 200 mg of the antibody or fragment and 200 mg of the C5 iRNA are administered on or more times, e.g., about once every 4 weeks.

[0118] A co-formulation may be designated in the form: antibody / iRNA; for example, “Pozelimab / Cemdisiran” or “Cemdisiran / Pozelimab” denotes a co-formulation of the present disclosure including Pozelimab and Cemdisiran.

[0119] A co-formulation or pharmaceutical co-formulation, as used herein, refers to a formulation including an anti-C5 antigen-binding protein (e.g., antibody or antigen-binding fragment thereof), a C5 iRNA and a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier includes, for example, one or more excipients. In an embodiment of the disclosure, a co-formulation of the present disclosure is aqueous, i.e., includes water.

[0120] Pharmaceutical formulations including anti-C5 antigen-binding proteins may be prepared by admixing the antigen-binding protein with one or more excipients (see, 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 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).

[0121] The present invention provides a method for making a co-formulation including combining a C5 iRNA (e.g., Cemdisiran or the Na+salt thereof; e.g., wherein the C5 iRNA is reconstituted with water from a lyophilized composition thereof); an antibody or antigen- binding fragment thereof that binds specifically to C5 (e.g., Pozelimab); a buffer (e.g., Histidine); a viscosity reducer (e.g., L-arginine); a stabilizer (e.g., sucrose); and a non-ionic surfactant (e.g., polysorbate 80), and, optionally, adjusting the co-formulation pH to greater than or less than about 6 (e.g., about 6.5±0.2); and, optionally sterile filtering the co- formulation.

[0122] The present disclosure provides methods for making a co-formulation of the present disclosure including combining an RNAi (e.g., Cemdisiran) and the antibody or antigen-binding fragment thereof (e.g., Pozelimab) (e.g., that includes detectable quantities of beta-hexosaminidase contaminant), and (i) adding GalNAc to the co-formulation and / or (ii) adjusting the pH of the co-formulation to about or below about 6 (e.g., within not less than 0.5). In an embodiment of the disclosure, other excipients are also combined, e.g., buffer, viscosity reducer, stabilizer and / or surfactant. Co-formulations (e.g., Cemdisiran / Pozelimab) produced by such methods are part of the present disclosure. In an embodiment of the disclosure, the antibody or fragment which is combined with the other components is initially in a lot that includes beta-hexosaminidase (also referred to herein as “beta-hex”) contaminant and is diluted by a factor of 0.25, 0.5 or 0.75 when incorporated into the co-formulation.

[0123] Various viscosity reducers are known in the art for use with co-formulations. viscosity reducer are agents that can reduce the viscosity of a formulation. Viscosity reducers may also function as tonicifiers that modulate the osmolality of the formulation. Such viscosity reducer include an adipic acid; an amino acid or salt thereof; (D- or L-) arginine; L-arginine HCl; (D- or L-) alanine; benzenesulfonic acid; caffeine; a dicarboxylic acid; an ester of citric acid; (D- or L-) glutamate; Glycine; (D- or L-) histidine; an inorganic salt; L-Ornithine; (D- or L-) lysine; Proline; (D- or L-) phenylalanine; (D- or L-) serine; NaCl; pyridoxamine; pyridoxine; thiamine phosphoric acid ester chloride dihydrate; triethyl citrate; (D- or L-) valine; and / or a xanthine. In an embodiment of the disclosure, the amino acid is an L-amino acid such as L-arginine. L-arginine acts both as a tonicifier as well as a stabilizer and viscosity reducer. Arginine HCl can decrease Cemdisiran degradation and allow for a near isotonic solution.

[0124] Stabilizers include agents, such as sugars or polyols, that aid in the reduction of degradation, for example, of antibodies or antigen-binding fragments, e.g., aggregation. Polyols are sugar alcohols having multiple hydroxyl groups. Stabilizers include a sugar or polyol, e.g., trehalose, sorbitol, mannitol, taurine, propane sulfonic acid, L-proline, sucrose, glycerol, threitol, maltitol, and / or polyethylene glycol (PEG; such as PEG3350).

[0125] Non-ionic surfactants contain molecules with head groups that are uncharged. Non-ionic surfactants include a non-ionic surfactant including a polyoxyethylene moiety; a sorbitan; a polyoxyethylene glycol alkyl ether, such as octaethylene glycol monododecyl ether; pentaethylene glycol monododecyl ether; polyoxypropylene glycol alkyl ether;glucoside alkyl ether, such as decyl glucoside, lauryl glucoside, octyl glucoside; polyoxyethylene glycol octylphenol ether, such as triton Χ-100; polyoxyethylene glycol alkylphenol ether, such as nonoxynol-9; glycerol alkyl ester, such as glyceryl laurate; polyoxyethylene glycol sorbitan alkyl ester, such as polysorbate; sorbitan alkyl ester, such as spans; cocamide ΜΕΑ, cocamide DEA, dodecyldimethylamine oxide; block copolymer of polyethylene glycol and polypropylene glycol, such as poloxamer; and polyethoxylated tallow amine (ΡΟΕΑ); poloxamer 188, polyethylene glycol 3350, a polyethylene glycol (e.g., PEG3350) or a polysorbate such as polysorbate 80 (PS80) or polysorbate 20 (PS20). In an embodiment of the disclosure, the non-ionic detergent is polysorbate-20 (PS20), polysorbate-80 (PS80).

[0126] A buffer is a mixture of a weak acid and its conjugate base or vice versa which resists changes in its pH and therefore keeps the pH at a nearly constant value. Various buffers may be used in the co-formulations of the present disclosure, for example, histidine- based buffer, phosphate buffer or citrate buffer. A histidine-based buffer is a buffer including histidine. Examples of histidine buffers include histidine chloride, histidine hydrochloride, histidine acetate, histidine phosphate, and histidine sulphate.

[0127] The present disclosure encompasses co-formulations having any of the specifically recited components, e.g., at the specifically recited concentrations, but wherein the pH of the co-formulation is about 6.5.

[0128] In an embodiment of the disclosure, the co-formulation contains the impurity, beta-hexosaminidase, e.g., in a quantity of about 0.04 to about 0.17 micrograms / ml, e.g., when pH of the co-formulation is less than or greater than about 6 (e.g., by at least 0.5), e.g., 6.5.

[0129] In an embodiment of the invention, the anti-C5 antibody or antigen-binding fragment thereof (e.g., Pozelimab) and the C5 iRNA (e.g., Cemdisiran Na+ form or another salt form or free acid form) are formulated in separate aqueous formulations, for example, wherein the Pozelimab is formulated at about 200 mg / mL in about 20 mM histidine (e.g., histidine-based buffer), about 100 mM L-arginine (e.g., L-arginine hydrochloride), about 2% sugar or polyol (e.g., sucrose) (w / v), about 0.15% (w / v) nonionic surfactant (e.g., polysorbate 80), pH about 5.8; and / or wherein the Cemdisiran is formulated at about 189 mg / mL (of the free acid form) in water. In an embodiment of the invention, the antibody or fragment is taken from a vial (e.g., a glass vial or pre-filled syringe or autoinjector) containing about 200 mg (±20 mg) of the antibody or fragment and / or the C5 iRNA is takenfrom a vial containing about 200 mg (±20 mg) or the molar equivalent thereof or about 10- 13 (± 2) micromoles of the C5 iRNA.

[0130] For example, the disclosure includes an aqueous pharmaceutical co-formulation (e.g., Cemdisiran / Pozelimab) including: • One or more C5 iRNAs, for example as set forth herein (e.g., Cemdisiran, preferably the Na+form), for example, at a concentration of about 20-100, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg / ml (or higher, e.g., 110, 115, 120, 130, 140, 150, 155, 160, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 20-50, 20-200, 20-300, 20-400, 100-300, or 100-400 mg / ml mg / ml); wherein the free acid form content can be determined by multiplying the Na+form concentration by 0.9443; • One or more anti-C5 antibodies or antigen-binding fragments thereof (e.g., Pozelimab), for example, at a concentration from about 90 to about 275 mg / ml (e.g., about 90; 91; 92; 93; 94; 95; 96; 97; 98; 99; 100; 101; 102; 103; 104; 105; 106; 107; 108; 109; 110; 111; 112; 113; 114; 115; 116; 117; 118; 119; 120; 121; 122; 123; 124; 125; 126; 127; 128; 129; 130; 131; 132; 133; 134; 135; 136; 137; 138; 139; 140; 141; 142; 143; 144; 145; 146; 147; 148; 149; 150; 151; 152; 153; 154; 155; 156; 157; 158; 159; 160; 161; 162; 163; 164; 165; 166; 167; 168; 169; 170; 171; 172; 173; 174; 175; 176; 177; 178; 179; 180; 181; 182; 183; 184; 185; 186; 187; 188; 189; 190; 191; 192; 193; 194; 195; 196; 197; 198; 199; 200; 211, 220, 242, 274 mg / ml) or at least about 150 mg / ml, at least about 175 mg / ml, at least about 200 mg / ml, at least about 211 mg / ml, at least about 220 mg / ml, at least about 242 mg / ml or at least about 274 mg / ml, 100-275, 100-300, 150-275, or 150-300); • A viscosity reducer such as L-arginine (e.g., L-arginine HCl) (e.g., at a concentration from about 40-140 mM, e.g., about 50 mM or 90 mM) (e.g., 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139 or 140 mM, 30-150, 40-100 or 50-150); • A stabilizer, such as a sugar or polyol (e.g., at a concentration from about 0.8 to about 3.6% (w / v), for example about 1%) (e.g., 0.8, 0.9, 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% (w / v)), 0.5- 4.0, 1-2, 1-3, or 2-4% (w / v)); • A non-ionic surfactant, such as polysorbate 80 (PS80) or polysorbate 20 (PS20) (e.g., at a concentration of about 0.025 to about 0.2% (w / v), e.g., about 0.075% (w / v) (e.g., 0.025, 0.05, 0.075, 0.1, 0.125, 0.15, 0.175, 0.2% (w / v)) or 0.02-0.25, 0.025-0.1, 0.025-0.15, or 0.03-0.2% (w / v); • A buffer such as a histidine-based buffer (e.g., at a concentration from about 10 to about 50 mM, for example about 30 mM e.g., 10; 11; 12; 13; 14; 15; 16; 17; 18; 19; 20; 21; 22; 23; 24; 25; 26; 27; 28; 29; 30; 31; 32; 33; 34; 35; 36; 37; 38; 39; 40; 41; 42; 43; 44; 45; 46; 47; 48; 49; 50 mM; or 10-30, 10-40, 20-40, or 20-50 mM)); and having • A pH of about 5.5 to about 7.0, e.g., about 6.5; or within not less than 0.5 of pH 6.0 or 5.5-6, 5.5-6.5, 6-6.5, 6-7, 0-5.5, or 6.5-14.

[0131] In an embodiment of the disclosure, a co-formulation (e.g., Cemdisiran / Pozelimab) comprises (e.g., for example, with detectable quantities of beta- hexosaminidase as discussed herein): A double stranded C5 iRNA that is conjugated to a triantennary GalNAc moiety; and an anti-C5 antibody or antigen-binding fragment thereof that was expressed and isolated from a mammalian host cell that includes beta-hexosaminidase, a pH above or below (by at least 0.5) 6.0; a C5 iRNA (e.g., that is conjugated to a triantennary GalNAc moiety), an anti-C5 antibody or antigen-binding fragment thereof (e.g., that was expressed and isolated from a mammalian host cell that includes beta-hexosaminidase), a buffer, a viscosity reducer, a stabilizer, and a non-ionic surfactant; a C5 iRNA (e.g., that is conjugated to a triantennary GalNAc moiety), an anti-C5 antibody or antigen-binding fragment thereof (e.g., that was expressed and isolated from a mammalian host cell that includes beta-hexosaminidase),Histidine-based buffer, L-arginine, a stabilizer, and a non-ionic surfactant; a C5 iRNA (e.g., that is conjugated to a triantennary GalNAc moiety), An anti-C5 antibody or antigen-binding fragment thereof (e.g., that was expressed and isolated from a mammalian host cell that includes beta-hexosaminidase), Histidine-based buffer, L-arginine, a sugar or polyol, and a non-ionic surfactant; Cemdisiran, Pozelimab (e.g., that was expressed and isolated from a mammalian host cell that includes beta-hexosaminidase), Histidine-based buffer, L-arginine, a stabilizer, and a non-ionic surfactant, pH about 6.5; Cemdisiran, Pozelimab (e.g., that was expressed and isolated from a mammalian host cell that includes beta-hexosaminidase), Histidine-based buffer, L-arginine, sucrose, and polysorbate 80, pH about 6.5; 100 (±10) mg / mL C5 iRNA such as Cemdisiran (Na+form),100 (±10) mg / mL anti-C5 antibody or antigen-binding fragment thereof such as Pozelimab (e.g., that was expressed and isolated from a mammalian host cell that includes beta- hexosaminidase), 50 (±10) mM viscosity reducer such as L-arginine (e.g., L-arginine HCl), 10 (±2) mM buffer such as histidine-based buffer, 1.0 (±0.2)% stabilizer such as sucrose, 0.075 (±0.00375)% non-ionic surfactant such as PS80, pH 6.5; 75 (±7.5) mg / mL C5 iRNA such as Cemdisiran (Na+form), 150 (±15) mg / mL anti-C5 antibody or antigen-binding fragment thereof such as Pozelimab (e.g., that was expressed and isolated from a mammalian host cell that includes beta- hexosaminidase), 75 (±15) mM viscosity reducer such as L-arginine (e.g., L-arginine HCl), 15 (±3) mM buffer such as histidine-based buffer, 1.5 (±0.3)% stabilizer such as sucrose, 0.1125 (±0.056)% non-ionic surfactant such as PS80, pH 6.5; 50 (±5) mg / mL C5 iRNA such as Cemdisiran (Na+form), 100 (±10) mg / mL anti-C5 antibody or antigen-binding fragment thereof such as Pozelimab (e.g., that was expressed and isolated from a mammalian host cell that includes beta- hexosaminidase), 75 mM (±15) viscosity reducer such as L-arginine (e.g., L-arginine HCl), 15 (±3) mM buffer such as histidine-based buffer, 1.5 (±0.3)% stabilizer such as sucrose, 0.1125 (±0.056)% non-ionic surfactant such as PS80; pH 6.5; 50 (±5) mg / mL C5 iRNA such as Cemdisiran (Na+form), 100 (±10) mg / mL anti-C5 antibody or antigen-binding fragment thereof such as Pozelimab (e.g., that was expressed and isolated from a mammalian host cell that includes beta- hexosaminidase),75 (±15) mM viscosity reducer such as L-arginine (e.g., L-arginine HCl), 35 (±7) mM buffer such as histidine-based buffer, 1.5 (±0.3)% stabilizer such as sucrose, 0.1125 (±0.056)% non-ionic surfactant such as PS80, pH 6.5; 100 (±10) mg / mL C5 iRNA such as Cemdisiran (Na+form), 100 (±10) mg / mL anti-C5 antibody or antigen-binding fragment thereof such as Pozelimab (e.g., that was expressed and isolated from a mammalian host cell that includes beta- hexosaminidase), 50 (±10) mM viscosity reducer such as L-arginine (e.g., L-arginine HCl), 30 (±6) mM buffer such as histidine-based buffer, 1 (±0.2)% stabilizer such as sucrose, 0.075 (±0.00375)% non-ionic surfactant such as PS80, pH 6.5; 50 (±5) mg / mL C5 iRNA such as Cemdisiran (Na+form), 100 (±10) mg / mL anti-C5 antibody or antigen-binding fragment thereof such as Pozelimab (e.g., that was expressed and isolated from a mammalian host cell that includes beta- hexosaminidase), 90 (±18) mM viscosity reducer such as L-arginine (e.g., L-arginine HCl), 30 (±6) mM buffer such as histidine-based buffer, 1 (±0.2)% stabilizer such as sucrose, 0.075 (±0.00375)% non-ionic surfactant such as PS80, pH 6.5; 100 mg / mL Cemdisiran (Na+form), 100 mg / mL Pozelimab, 50 mM L-arginine (e.g., L-arginine HCl), 30 mM histidine-based buffer, 1% (w / v) sucrose, 0.075% (w / v) PS80, pH 6.5;50 mg / mL Cemdisiran (Na+form), 100 mg / mL Pozelimab, 90 mM L-arginine (e.g., L-arginine HCl), 30 mM histidine-based buffer, 1% (w / v) sucrose, 0.075% (w / v) PS80, pH 6.5; 100 mg / mL Cemdisiran (Na+form), 100 mg / mL Pozelimab, 50 mM L-arginine (e.g., L-arginine HCl), 10 mM histidine-based buffer, 1.0% sucrose, 0.075% PS80, pH 6.5; 75 mg / mL Cemdisiran (Na+form), 150 mg / mL Pozelimab, 75 mM L-arginine (e.g., L-arginine HCl), 15 mM histidine-based buffer, 1.5% sucrose, 0.1125% PS80, pH 6.5; 50 mg / mL Cemdisiran (Na+form), 100 mg / mL Pozelimab, 75 mM L-arginine (e.g., L-arginine HCl), 15 mM histidine-based buffer, 1.5% sucrose, 0.1125% PS80; pH 6.5; 50 mg / mL Cemdisiran (Na+form),100 mg / mL Pozelimab, 75 mM L-arginine (e.g., L-arginine HCl), 35 mM histidine-based buffer, 1.5% sucrose, 0.1125% PS80, pH 6.5; 100 mg / mL Cemdisiran (Na+form), 100 mg / mL Pozelimab, 50 mM L-arginine (e.g., L-arginine HCl), 30 mM histidine-based buffer, 1% sucrose, 0.075% PS80, pH 6.5; 47.2 mg / mL Cemdisiran (Free Acid Form (FAF)) molecule, which may be any salt form, such as Na+, 100 mg / mL Pozelimab, 30 mM histidine, 90 mM L-arginine, 1% (w / v) sucrose, 0.075% (w / v) polysorbate 80 (e.g., super refined grade (SR)), pH 6.5 50 mg / mL Cemdisiran (Na+form), 100 mg / mL Pozelimab, 90 mM L-arginine (e.g., L-arginine HCl), 30 mM buffer such as histidine-based buffer, 1% stabilizer such as sucrose, 0.075% PS80, pH 6.5; optionally, any of the co-formulations set forth herein further comprises GalNAc or GlcNAc, e.g., about 5% (w / v). The present invention includes methods for treating or preventing a C5-associated disease or disorder, e.g., MG, including administering 200 mg of theantibody or fragment and 200 mg of the C5 iRNA one or more time, e.g., about once every 4 weeks.

[0132] In an embodiment of the disclosure, a co-formulation of the present disclosure includes the antibody and iRNA and is in association with a further therapeutic agent, such as, for example, an anti-coagulant, warfarin, aspirin, heparin, phenindione, fondaparinux, idraparinux, a thrombin inhibitor, argatroban, lepirudin, bivalirudin, dabigatran, an anti- inflammatory drug, a corticosteroid, a non-steroidal anti-inflammatory drug (NSAID), an antihypertensive, an angiotensin-converting enzyme inhibitor, an immunosuppressive agent, vincristine, cyclosporine A, or methotrexate, a fibrinolytic agent ancrod, E- aminocaproic acid, antiplasmin-a1, prostacyclin, defibrotide, a lipid-lowering agent, an inhibitor of hydroxymethylglutaryl CoA reductase, an anti-CD20 agent, rituximab, an anti- TNFalpha agent, infliximab, an anti-seizure agent, magnesium sulfate, a C3 inhibitor and / or an anti-thrombotic agent.

[0133] The present invention includes method for treating or preventing a C5-associated disease or disorder, e.g., MG, by administering 200 mg of anti-C5 antibody or antigen- binding fragment thereof in association with 200 mg of a C5 iRNA about once every 4 weeks.

[0134] The term "in association with" indicates that multiple components (e.g., Pozelimab and Cemdisiran) can be formulated into a single composition, e.g., for simultaneous delivery, or formulated separately into two or more compositions (e.g., a kit including each component, for example, wherein the further therapeutic agent is in a separate formulation). Components administered in association with each another can be administered to a subject at the same time or at a different time than when the other component is administered or in a given sequence of one component and then the other or the reverse thereof; for example, each administration may be given simultaneously (e.g., together in a single composition or essentially simultaneously during the same administration session) or non-simultaneously at one or more intervals over a given period of time. Moreover, the separate components administered in association with each other may be administered to a subject by the same or by a different route.

[0135] In an embodiment of the invention, the further therapeutic agent that may be administered in association with an anti-C5 antibody or antigen binding fragment and a C5 iRNA may be one or more of: an anticholinesterase agent, an immunosuppressive drug, a C5 complement inhibitor, a neonatal Fc receptor blocker, prednisone, tacrolimus, rituximab,eculizumab, ravulizumab, efgartigimod, rozanolixizumab, pyridostigmine, plasmapheresis (PLEX) and / or intravenous IgG.

[0136] The present disclosure includes co-formulations described herein wherein the concentration of the antibody and / or iRNA is ±10% the value shown; the concentration of surfactant is ±50% the value shown; and / or any of the other excipient concentrations (e.g., viscosity reducer, buffer, stabilizer) or pH are ±20% the value shown.

[0137] In an embodiment of the disclosure, a co-formulation of the present disclosure, • comprises about 0.04 to 0.17 micrograms / ml of beta-hexosaminidase (e.g., about 0.04; 0.05; 0.06; 0.06; 0.0605; 0.061, 0.0605; 0.0605; 0.062, 0.063; 0.07; 0.07; 0.075; 0.0765; 0.078; 0.08; 0.14; 0.141; 0.15; 0.1525; 0.166; or 0.17 micrograms / ml; or 0.02-0.2, 0.05-0.15, or 0.1-0.15 (or no more than such an amount)); • is a clear to slightly opalescent liquid; • is essentially free of visible particulates; • has a colorless to yellow color; • is characterized by a ratio of Cemdisiran concentration:Pozelimab concentration of about 1:1, 1:2, 1:3, 1:4, 1:5 or 2:3, e.g., wherein the viscosity if less than about 20 cP or less than about 30 cP at 20oC; • has a Viscosity < 30 cP (at 20⁰C) (e.g., about 6, 10, 20 or 30 cP, such as 6-30, 6-25, or 6-20 cP)); • has an osmolality of 266-706 (e.g., about 266; 276; 286; 296; 306; 316; 326; 334; 336; 346; 356; 366; 376; 386; 396; 406; 416; 426; 436; 446; 456; 466; 476; 486; 496; 506; 516; 526; 536; 546; 556; 566; 576; 586; 596; 606; 616; 626; 636; 646; 656; 666; 676; 686; 696; or 706; or 270-700, 300-500, 300-600, 400-600, 400-700, or 500-700) mOsm / kg; • has a density of about 1.1 or 1.061 or 1.05-1.1 or 1.075-1.1 g / ml; • has a pH of about 6.5 ± 0.2; • Has a pH higher than 6 which results in a significant reduction in Cemdisiran degradation at 40°C, 25°C, and 2-8°C relative to pH 6; • exhibits a Cemdisiran Purity (%) by dIPRP of about 90.5% at t=0; 91.1% after 1 month storage at 2-8°C; 90.8% after 3 months storage at 2-8°C; 90% after 6 months storage at 2-8°C; 88.8% after 9 months storage at 2-8°C; 88.7% after 12 months storage at 2-8°C; 89% after 18 months storage at 2-8°C; 89.4% after 24 monthsstorage at 2-8°C; and / or 87.4% after 36 months storage at 2-8oC, e.g., wherein the co-formulation was liquid (aqueous) during storage and includes 100 mg / ml Cemdisiran and 100 mg / ml Pozelimab (e.g., at pH 6.0); for example wherein the co- formulation includes about 60.5 ng / ml beta-hex; • exhibits a Cemdisiran Purity (%) by dIPRP of about 90.8% at t=0; 90.6% after 1 month storage at 2-8°C; 90.5% after 3 months storage at 2-8°C; 89.4% after 6 months storage at 2-8°C; 88.3% after 9 months storage at 2-8°C; 87.8% after 12 months storage at 2-8°C; 87.8% after 18 months storage at 2-8°C; and / or 87.4% after 24 months storage at 2-8°C and / or about 85.4% after 36 months storage at 2- 8oC; e.g., wherein the co-formulation was liquid (aqueous) during storage and includes 75 mg / ml Cemdisiran and 150 mg / ml Pozelimab (e.g., at pH 6.0); for example wherein the co-formulation includes about 60.5 ng / ml beta-hex; • exhibits a Cemdisiran Single Strand Purity (%) by dIPRP of about 90.5% at t=0; 90.2% after 1 month storage at 25°C and 60% RH (relative humidity); 87.8% after 3 months storage at 25°C and 60% RH; 85.1% after 6 months storage at 25°C and 60% RH; 90% after 0.5 months storage at 40°C and 75% RH; 88.9% after 1 month storage at 40°C and 75% RH; 85.8% after 3 months storage at 40°C and 75% RH; e.g., wherein the co-formulation was liquid (aqueous) during storage and includes 100 mg / ml Cemdisiran and 100 mg / ml Pozelimab (e.g., at pH 6.0); for example wherein the co-formulation includes about 60.5 ng / ml beta-hex; • exhibits a Cemdisiran Single Strand Purity (%) by dIPRP of about 91.4% after about 48 hours agitation, and / or about 90.7% after about 4 freeze-thaw cycles e.g., wherein the co-formulation was liquid (aqueous) and includes 100 mg / ml Cemdisiran and 100 mg / ml Pozelimab (e.g., at pH 6.0); • exhibits a Cemdisiran Purity (%) by dIPRP of about 90.8% at t=0; 88.8% after 1 month storage at 25°C and 60% RH; 85.9% after 3 months storage at 25°C and 60% RH; 82.3% after 6 months storage at 25°C and 60% RH; 88.9% after 0.5 months storage at 40°C and 75% RH; 87.3% after 1 month storage at 40°C and 75% RH; 82.3% after 3 months storage at 40°C and 75% RH; e.g., wherein the co-formulation was liquid (aqueous) during storage and includes 75 mg / ml Cemdisiran and 150mg / ml Pozelimab (e.g., at pH 6.0); for example wherein the co-formulation includes about 60.5 or 91 ng / ml beta-hex; • exhibits a Cemdisiran Purity (%) by dIPRP of about 90.7% after about 48 hours agitation, and / or about 91.2% after about 4 freeze-thaw cycles e.g., wherein the co- formulation was liquid (aqueous) during storage and includes 75 mg / ml Cemdisiran and 150 mg / ml Pozelimab (e.g., at pH 6.0); • exhibits no more (e.g., within 5%) increase in detectable high molecular weight species (HMW species) after 48 hours of agitation on an orbital shaker at 250 rpm in the presence of 0.025% non-ionic surfactant (e.g., polysorbate 80) than in the presence of 0.050, 0.075, 0.100, 0.125, 0.150, 0.175 or 0.200% (w / v); e.g., wherein the co-formulation includes 50 or 100 mg / mL Cemdisiran and 100 mg / mL Pozelimab, for example, 100 mg / mL Cemdisiran, 100 mg / mL Pozelimab, 50 mM arginine HCl, 30 mM histidine, 1% sucrose, X% PS80, pH 6.5, or 50 mg / mL Cemdisiran, 100 mg / mL Pozelimab, 90 mM arginine HCl, 30 mM histidine, 1% sucrose, X% PS80, pH 6.5 (wherein X is about 0.025% to about 0.2% (w / v), e.g., 0.075%); • exhibits a Cemdisiran purity (%) by dlPRP of about 90.9% at t=0; about 90.1% after 1 month of storage at 25°C, 60% RH; about 90.9% after 3 months of storage at 25°C, 60% RH; about 90.4% after 6 months of storage at 25°C, 60% RH; about 89.9% after 0.5 months of storage at 40°C, 75% RH; about 89.7% after 1 month of storage at 40°C, 75% RH; and / or about 89.5% after 3 months of storage at 40°C, 75% RH; e.g., wherein the co-formulation was liquid (aqueous) during storage and contained 50 mg / ml Cemdisiran and 100 mg / ml Pozelimab, pH6 with 5% GlcNAc; e.g., wherein the co-formulation includes about 78 ng / ml beta-hex; • exhibits a Cemdisiran purity (%) by dlPRP of about 90.8% at t=0; about 90.2% after 1 month of storage at 25°C, 60% RH; about 90.8% after 3 months of storage at 25°C, 60% RH; about 90.3% after 6 months of storage at 25°C, 60% RH; about 89.5% after 0.5 months of storage at 40°C, 75% RH; about 89.6% after 1 month of storage at 40°C, 75% RH; and / or about 89.1% after 3 months of storage at 40°C, 75% RH; e.g., wherein the co-formulation was liquid (aqueous) during storage and contained 50 mg / ml Cemdisiran and 100 mg / ml Pozelimab, pH6 with 5% GalNAc; e.g., wherein the co-formulation includes about 78 ng / ml beta-hex;• exhibits a Cemdisiran purity (%) by dlPRP of about 90.5% at t=0; about 89.9% after 1 month of storage at 25°C, 60% RH; about 90.8% after 3 months of storage at 25°C, 60% RH; about 90.4% after 6 months of storage at 25°C, 60% RH; about 90.1% after 0.5 months of storage at 40°C, 75% RH; about 89.6% after 1 month of storage at 40°C, 75% RH; and / or about 89.9% after 3 months of storage at 40°C, 75% RH; e.g., wherein the co-formulation was liquid (aqueous) during storage and contained 100 mg / ml Cemdisiran and 100 mg / ml Pozelimab, pH6 with 5% GlcNAc; e.g., wherein the co-formulation includes about 78 ng / ml beta-hex; and / or • exhibits a Cemdisiran purity (%) by dlPRP of about 91.1% at t=0; about 90% after 1 month of storage at 25°C, 60% RH; about 91% after 3 months of storage at 25°C, 60% RH; about 90.7% after 6 months of storage at 25°C, 60% RH; about 90% after 0.5 months of storage at 40°C, 75% RH; about 89.7% after 1 month of storage at 40°C, 75% RH; and / or about 89.9% after 3 months of storage at 40°C, 75% RH; e.g., wherein the co-formulation was liquid (aqueous) during storage and contained 100 mg / ml Cemdisiran and 100 mg / ml Pozelimab, pH 6 with 5% GalNAc; e.g., wherein the co-formulation includes about 78 ng / ml beta-hex. Dosing Regimens of Anti-C5 and C5 iRNA

[0138] The present disclosure includes methods that comprise administering, to a subject in need thereof, with a disease or disorder or condition associated with C5 (e.g., MG, for example, wherein the subject is anti-acetylcholine receptor (AChR) and / or anti-low- density lipoprotein receptor-related protein 4 (LRP4) antibody positive): • a C5 iRNA such as Cemdisiran (optionally, wherein an additional C5 inhibitor is not administered); or • an anti-C5 antibody or antigen-binding fragment thereof in combination with a C5 iRNA (e.g., in the form of a co-formulation including both the antibody or fragment and the iRNA, e.g., as set forth herein; or separate injections of the antibody or fragment and iRNA), at a dosing amount and frequency that achieves a safe and effective therapeutic response (combination therapy of the present disclosure).

[0139] The present disclosure encompasses methods for administering a C5 iRNA (but, optionally, not an anti-C5 antibody or antigen-binding fragment thereof or other C5 inhibitor)including introducing the C5 iRNA into the body of a subject, e.g., by injection, such as by subcutaneous injection or intravenous infusion, for example, under a schedule according to any of the dosing regimens discussed herein, e.g., • about 567 mg (±57 mg) of C5 iRNA, 32-35 or 33.8 (±4) micromoles of C5 iRNA or 600 mg (±60 mg) of C5 iRNA which is in salt for such as Na+form (e.g., wherein the C5 iRNA is Cemdisiran Na+form of another salt form or the free form), preferably subcutaneously, about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), about 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), about 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about ¼ year; or • about 200 mg (±20 mg) of the anti-C5 antibody or antigen-binding fragment thereof (e.g., Pozelimab) and about 189 mg (±19 mg) of C5 iRNA, 11-13 (±2) micromoles of C5 iRNA or 200 mg (±20 mg) of C5 iRNA which is in salt for such as Na+form (e.g., wherein the C5 iRNA is Cemdisiran Na+form of another salt form or the free form), which may be administered in a single co-formulation or by two separate administrations of the antibody or fragment and the C5 iRNA, about once every 28, 29 or 30 days (± 1, 2, 3, 4, 5, 6 or 7 days), once a month (± 1, 2, 3, 4, 5, 6 or 7 days) or once every 4 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), preferably subcutaneously. In an embodiment of the invention, the Cemdisiran Na+form is in an aqueous pharmaceutical formulation comprising 200 mg / ml Cemdisiran Na+form. In an embodiment of the invention, the 600 mg of Cemdisiran is in an aqueous pharmaceutical formulation and 3 ml of the formulation is administered to achieve a full dose, e.g., in two doses of 1.5 ml each or 3 injections of 1 ml each or a single injection with a full dose.

[0140] In some embodiments, the present disclosure relates to the administration of one or more doses of an anti-C5 antibody or antigen-binding fragment thereof (e.g., Pozelimab) in combination with one or more doses of a C5 iRNA (e.g., Cemdisiran). In an embodiment of the invention, the administration is in a co-formulation of the present disclosure (as discussed herein), e.g., 100:100 or 50:100 (Cemdisiran mg / ml : Pozelimab mg / ml)), for example in an injection volume of about 2 ml.

[0141] Generally, herein, a co-formulation including Cemdisiran and Pozelimab may be referred to in the following format: 100:100. In such notation, when referring to such a co-formulation, the first number indicates the mg / ml of Cemdisiran and the second number indicates the mg / ml of Pozelimab.

[0142] Thus, the present disclosure provides a method for administering to a subject, e.g., who is in need thereof, e.g., who is suffering from a C5-associated disease or disorder (for example, MG, for example, wherein the subject is anti-acetylcholine receptor (AChR) and / or anti-low-density lipoprotein receptor-related protein 4 (LRP4) antibody positive) including introducing into the body of the subject, e.g., parenterally, a C5 iRNA (e.g., Cemdisiran) and / or a combination of C5 iRNA (e.g., Cemdisiran) and anti-C5 antibody or antigen-binding fragment thereof (e.g., Pozelimab) according to the following: • One or more doses of about 600 mg (±60 mg) C5 iRNA Na+form or a molar equivalent amount of another salt form or the free form; • One or more doses about 32-25 (±4) (e.g., 32, 33, 33.8, 34 or 35) micromoles C5 iRNA, e.g., Na+form or another salt form or the free form; or • One or more doses about 567 mg (±57 mg) of C5 iRNA free form which is in Na+salt form or another salt form; • One or more doses of about 600 mg (±60 mg) Cemdisiran Na+form or a molar equivalent amount of another salt form or the free form; • One or more doses of about 32-25 (±4) (e.g., 32, 33, 33.8, 34 or 35) micromoles Cemdisiran, e.g., Na+form or another salt form or the free form; • One or more doses of about 567 mg (±57 mg) of Cemdisiran free form which is in Na+salt form or another salt form; • about 600 mg (±60 mg) Cemdisiran Na+form or a molar equivalent amount of another salt form or the free form about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about every ¼ year; • about 32-25 (±4) (e.g., 32, 33, 33.8, 34 or 35) micromoles Cemdisiran, e.g., Na+form or another salt form or the free form, about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about every ¼ year; or • about 567 mg (±57 mg) of Cemdisiran free form which is in Na+salt form or another salt form about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 12 weeks(± 1, 2, 3, 4, 5, 6 or 7 days), or about every 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about every ¼ year; • one or more doses of about 200 mg (±20 mg) of the anti-C5 antibody or antigen- binding fragment thereof (e.g., Pozelimab) subcutaneously, in combination with about 200 mg (±20 mg) C5 iRNA which is in Na+salt form or the molar equivalent of another salt form or the free form, subcutaneously, e.g., once every 28, 29 or 30 days (± 1, 2, 3, 4, 5, 6 or 7 days), once a month (± 1, 2, 3, 4, 5, 6 or 7 days) or once every 4 weeks (± 1, 2, 3, 4, 5, 6 or 7 days); • one or more does of about 200 mg (±20 mg) of the anti-C5 antibody or antigen- binding fragment thereof (e.g., Pozelimab), in combination with about 10-13 (± 2) micromoles of the C5 iRNA (e.g., Cemdisiran Na+form of another salt form or the free form), subcutaneously, e.g., once every 28, 29 or 30 days (± 1, 2, 3, 4, 5, 6 or 7 days), once a month (± 1, 2, 3, 4, 5, 6 or 7 days) or once every 4 weeks (± 1, 2, 3, 4, 5, 6 or 7 days); and / or • one or more doses of about 200 mg (±20 mg) of the anti-C5 antibody or antigen- binding fragment thereof (e.g., Pozelimab) in combination with about 189 mg of the C5 iRNA free form which is in a salt form, e.g., Cemdisiran free form which is in Na+salt form or another salt form, subcutaneously, e.g., once every 28, 29 or 30 days (± 1, 2, 3, 4, 5, 6 or 7 days), once a month (± 1, 2, 3, 4, 5, 6 or 7 days) or once every 4 weeks (± 1, 2, 3, 4, 5, 6 or 7 days); for example, wherein a combination including the antibody or fragment and the C5 iRNA is administered in a co-formulation that includes the antibody or fragment and the C5 iRNA; or in two separate formulations, one including the antibody or fragment and the other including the C5 iRNA.

[0143] Thus, the present disclosure provides a method for treating or preventing a C5- associated disease or disorder (for example, MG, for example, wherein the subject is anti- acetylcholine receptor (AChR) and / or anti-low-density lipoprotein receptor-related protein 4 (LRP4) antibody positive) in a subject in need thereof including administering to the subject a C5 iRNA according to the following: • One or more doses of about 600 mg (±60 mg) C5 iRNA Na+form or a molar equivalent amount of another salt form or the free form;• One or more doses about 32-35 (±4) (e.g., 32, 33, 33.8, 34 or 35) micromoles C5 iRNA, e.g., Na+form or another salt form or the free form; or • One or more doses about 567 mg (±57 mg) of the C5 iRNA free form which is in Na+salt form or another salt form, for example, wherein the doses are administered once every about 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), about 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), about 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about ¼ year. In an embodiment of the invention, the C5 iRNA is in an aqueous formulation comprising 200 mg / ml C5 iRNA and 3 ml of the formulation is administered to achieve a full dose.

[0144] Thus, the present disclosure provides a method for treating or preventing a C5- associated disease or disorder (for example, MG, for example, wherein the subject is anti- acetylcholine receptor (AChR) and / or anti-low-density lipoprotein receptor-related protein 4 (LRP4) antibody positive) in a subject in need thereof including administering to the subject Cemdisiran according to the following: • One or more doses of about 600 mg (±60 mg) Cemdisiran Na+form or a molar equivalent amount of another salt form or the free form; • One or more doses about 32-35 (±4) (e.g., 32, 33, 33.8, 34 or 35) micromoles Cemdisiran, e.g., Na+form or a molar equivalent amount of another salt form or the free form; or • One or more doses about 567 mg (±57 mg) of the Cemdisiran free form which is in Na+salt form or another salt form. In an embodiment of the invention, no further C5 inhibitor, such as an anti-C5 antibody or antigen-binding fragment thereof, is administered. In an embodiment of the invention, the Cemdisiran Na+form is in an aqueous formulation comprising about 200 mg / ml Cemdisiran Na+form, about 10-13 micromoles / ml of Cemdisiran (Na+ form or other salt form or free form); or about 189 mg / ml Cemdisiran free form which is in Na+form or other salt form; and about 3 ml of the formulation is administered to achieve a full dose. Such a dosing regimen may be referred to herein as Cemdisiran monotherapy.

[0145] Thus, the present disclosure provides a method for treating or preventing a C5- associated disease or disorder (for example, MG, for example, wherein the subject is anti- acetylcholine receptor (AChR) and / or anti-low-density lipoprotein receptor-related protein 4(LRP4) antibody positive) in a subject in need thereof including administering to the subject Cemdisiran according to the following: • about 600 mg (±60 mg) Cemdisiran Na+form or a molar equivalent amount of another salt form or the free form about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about every ¼ year; • about 32-25 (±4) (e.g., 32, 33, 33.8, 34 or 35) micromoles Cemdisiran, e.g., Na+form or a molar equivalent amount of another salt form or the free form about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about every ¼ year; or • about 567 mg (±57 mg) of Cemdisiran free form which is in Na+salt form or another salt form about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about every ¼ year. In an embodiment of the invention, no further C5 inhibitor, such as an anti-C5 antibody or antigen-binding fragment thereof, is administered. In an embodiment of the invention, the subject receives at least two doses of the C5 iRNA. In an embodiment of the invention, the Cemdisiran Na+form is in an aqueous formulation comprising about 200 mg / ml Cemdisiran Na+form, about 10-13 micromoles / ml of Cemdisiran (Na+form or other salt form or free form); or about 189 mg / ml Cemdisiran free form which is in Na+form or other salt form; and about 3 ml of the formulation is administered to achieve a full dose.

[0146] In an embodiment of the invention, a full dose of C5 iRNA is delivered in three doses of 1 / 3 of a dose each or two doses of half a dose each.

[0147] Thus, the present disclosure provides a method for treating or preventing a C5- associated disease or disorder (for example, MG, for example, wherein the subject is anti- acetylcholine receptor (AChR) and / or anti-low-density lipoprotein receptor-related protein 4 (LRP4) antibody positive) in a subject in need thereof including administering to the subject an anti-C5 antibody or antigen-binding fragment thereof (“the anti-C5 Ab”) and a C5 iRNA according to the following: (i) one or more doses of about 200 mg (±20 mg) of the anti-C5 antibody or antigen-binding fragment thereof (e.g., Pozelimab) subcutaneously, in combination withabout 200 mg (±20 mg) or 10-13 (± 2) micromoles of the C5 iRNA (e.g., Cemdisiran Na+form or a molar equivalent amount of another salt form or the free form) subcutaneously; (ii) one or more does of about 200 mg (±20 mg) of the anti-C5 antibody or antigen-binding fragment thereof (e.g., Pozelimab), in combination with about 200 mg (±20 mg) or 10-13 (± 2) micromoles of the C5 iRNA (e.g., Cemdisiran Na+form or a molar equivalent amount of another salt form or the free form); or (iii) one or more doses of about 200 mg (±20 mg) of the anti-C5 antibody or antigen-binding fragment thereof (e.g., Pozelimab) in combination with about 189 mg of C5 iRNA, e.g., Cemdisiran free form which is in Na+salt form or another salt form; administered subcutaneously, for example, about every 4 weeks (±7 days), preferably in a single injection of a co-formulation that includes both the anti-C5 Ab and the C5 iRNA, or in two separate injections of the antibody or fragment and the C5 iRNA.

[0148] In an embodiment of the disclosure, the subject is administered, concurrently, • about 200 mg (±20 mg) of the anti-C5 antibody or antigen-binding fragment thereof (e.g., Pozelimab) subcutaneously about once every 28, 29 or 30 days (± 1, 2, 3, 4, 5, 6 or 7 days), once a month (± 1, 2, 3, 4, 5, 6 or 7 days) or once every 4 weeks (± 1, 2, 3, 4, 5, 6 or 7 days); and • about 200 mg (±20 mg) C5 iRNA, e.g., Cemdisiran Na+form or a molar equivalent amount of another salt form or the free form) or 10-13 (± 2) micromoles of the C5 iRNA, e.g., Cemdisiran Na+form or another salt form or free form, subcutaneously about once every 28, 29 or 30 days (± 1, 2, 3, 4, 5, 6 or 7 days), once a month (± 1, 2, 3, 4, 5, 6 or 7 days) or once every 4 weeks (± 1, 2, 3, 4, 5, 6 or 7 days). This dosing regimen may be referred to herein as “Pozelimab Q4W and Cemdisiran”, “Pozelimab and Cemdisiran Q4W”, or “Pozelimab 200 mg (±20 mg) SC Q4W + Cemdisiran 200 mg (±20 mg) SC Q4W”).

[0149] Generally, an initial dose or doses that are non-recurring may be referred to as “loading” doses and subsequent doses that are recurring may be referred to as “maintenance” doses.

[0150] In an embodiment of the disclosed technology, a loading dose is administered.

[0151] In an embodiment of the disclosed technology, no loading dose is administered.

[0152] In an embodiment of the disclosed technology, the anti-C5 antibody or antigen- binding fragment thereof (e.g., Pozelimab) and / or the C5 iRNA (e.g., Cemdisiran) is administered intravenously.

[0153] In an embodiment of the disclosed technology, the anti-C5 antibody or antigen- binding fragment thereof (e.g., Pozelimab) and / or the C5 iRNA (e.g., Cemdisiran) is not administered intravenously.

[0154] A dosing regimen including monthly doses of both anti-C5 antibody or antigen- binding fragment thereof (e.g., Pozelimab) and C5 iRNA (e.g., Cemdisiran), may be referred to as the q4w or Q4W combination regimen.

[0155] A dosing regimen including monthly doses of anti-C5 antibody or antigen-binding fragment thereof (e.g., Pozelimab) may be referred to as the q4w or Q4W anti-C5 regimen.

[0156] A dosing regimen including doses every 3 months of C5 iRNA (e.g., Cemdisiran) may be referred to as the q12w or Q12W C5 iRNA regimen.

[0157] In an embodiment of the invention, q4w refers to doses about every 4 weeks, about every month, about every 30 days, about 3 times per quarter or about 12 times per year.

[0158] The term “4 weeks”, in an embodiment of the disclosed technology, refers to about 28, 29 or 30 days (± 1, 2, 3, 4, 5, 6 or 7 days) or about 4 calendar weeks (± 1, 2, 3, 4, 5, 6 or 7 days).

[0159] The term “2 weeks”, in an embodiment of the disclosed technology, refers to about 14 days (± 1, 2, 3, 4, 5, 6 or 7 days) or about 2 calendar weeks (± 1, 2, 3, 4, 5, 6 or 7 days).

[0160] The term “one month”, in an embodiment of the disclosed technology, refers to approximately a calendar month (± 1, 2, 3, 4, 5, 6 or 7 days); 28, 29 or 30 days (± 1, 2, 3, 4, 5, 6 or 7 days) or 4 weeks (± 1, 2, 3, 4, 5, 6 or 7 days).

[0161] The term “3 months”, in an embodiment of the disclosed technology, refers to a period of approximately 3 calendar months (± 1, 2, 3, 4, 5, 6 or 7 days), e.g., a period of from January 1 to March 31 or April 1; about 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days); or about 84 days (± 1, 2, 3, 4, 5, 6 or 7 days).

[0162] The term “12 weeks”, in an embodiment of the disclosed technology, refers to approximately 12 calendar weeks (± 1, 2, 3, 4, 5, 6 or 7 days); or about 84 days (± 1, 2, 3, 4, 5, 6 or 7 days) which may include 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90 or 91 days.

[0163] The term “1 / 4 year”, in an embodiment of the disclosed technology, refers to a period of approximately 4 times per year (e.g., 365 days or a calendar year) or about 3 months (± 1, 2, 3, 4, 5, 6 or 7 days).

[0164] The term 600 mg (±60 mg) includes about 600 mg (±50 mg), 600 mg (±40 mg), 600 mg (±30 mg), 600 mg (±20 mg), 600 mg (±10 mg), 600 mg (±10 mg), 600 mg (±1 mg) 540 mg, 541 mg, 542 mg, 543 mg, 544 mg, 545 mg, 546 mg, 547 mg, 548 mg, 549 mg, 550 mg, 551 mg, 552 mg, 553 mg, 554 mg, 555 mg, 556 mg, 557 mg, 558 mg, 559 mg, 560 mg, 561 mg, 562 mg, 563 mg, 564 mg, 565 mg, 566 mg, 567 mg, 568 mg, 569 mg, 570 mg, 571 mg, 572 mg, 573 mg, 574 mg, 575 mg, 576 mg, 577 mg, 578 mg, 579 mg, 580 mg, 581 mg, 582 mg, 583 mg, 584 mg, 585 mg, 586 mg, 587 mg, 588 mg, 589 mg, 590 mg, 591 mg, 592 mg, 593 mg, 594 mg, 595 mg, 596 mg, 597 mg, 598 mg, 599 mg, 600 mg, 601 mg, 602 mg, 603 mg, 604 mg, 605 mg, 606 mg, 607 mg, 608 mg, 609 mg, 610 mg, 611 mg, 612 mg, 613 mg, 614 mg, 615 mg, 616 mg, 617 mg, 618 mg, 619 mg, 620 mg, 621 mg, 622 mg, 623 mg, 624 mg, 625 mg, 626 mg, 627 mg, 628 mg, 629 mg, 630 mg, 631 mg, 632 mg, 633 mg, 634 mg, 635 mg, 636 mg, 637 mg, 638 mg, 639 mg, 640 mg, 641 mg, 642 mg, 643 mg, 644 mg, 645 mg, 646 mg, 647 mg, 648 mg, 649 mg, 650 mg, 651 mg, 652 mg, 653 mg, 654 mg, 655 mg, 656 mg, 657 mg, 658 mg, 659 mg or 660 mg.

[0165] Anti-C5 antibody or antigen-binding fragment thereof 200 mg (±20 mg) SC Q4W refers to administration of about 200 mg (±20 mg) of the antibody or fragment (e.g., Pozelimab) subcutaneously about every 4 weeks (e.g., 28 days (± 1, 2, 3, 4, 5, 6 or 7 days)).

[0166] C5 iRNA 200 mg (±20 mg) SC Q4W refers to administration of about 200 mg (±20 mg) of the iRNA (e.g., Cemdisiran Na+form or a molar equivalent amount of another salt form or the free form) subcutaneously about every 4 weeks (e.g., 28 days (± 1, 2, 3, 4, 5, 6 or 7 days)).

[0167] C5 iRNA about 600 mg (±60 mg) or about 32-35 or 33.8 (±4) micromoles SC Q12W refers to administration of about 600 mg (±60 mg) or about 32-35 or 33.8 (±4) micromoles of the iRNA (e.g., Cemdisiran Na+form or a molar equivalent amount of another salt form or the free form) subcutaneously about every 3 months, 12 weeks or 84 days (± 1, 2, 3, 4, 5, 6 or 7 days) or about 4 times per year.

[0168] As set forth herein, any dosing episode (e.g., which involves multiple doses of drugs), may be followed by a 30 minute to 2-hour observation period after the last administration or for however long, in the judgment of the treating physician, no adverseevents are likely to occur acutely. Typically, on a given day when a subject receives an intravenous dose and one or more subcutaneous doses, the intravenous dose is given first; however, the scope of the present disclosure includes embodiments wherein the doses are given in any order, e.g., SC then IV then SC.

[0169] In an embodiment of the invention, Cemdisiran is provided as three separate vials containing about 1 ml of solution including Cemdisiran. Administration can include one or more of the steps: • removing the vials from refrigeration and allowing the vials to sit for at least 15 minutes at room temperature 20ºC to 25ºC (68ºF to 77ºF) before use. • inspecting the solution visually for particulate matter and discoloration prior to administration and discarding if the solution is cloudy, discolored or contains particulate matter. Cemdisiran should be a clear, colorless to yellow solution that is free from visible particulates. • gently swirling the vials in an upright position. Shaking should be avoided since this may result in foaming. • using a withdrawal needle (21 gauge (G) needle with Luer-Lok) to withdraw 3 mL of the Cemdisiran solution. • dividing the dose equally into two syringes (each containing 1.5 mL) or 3 syringes (each containing 1 ml) or a single syringe with a full dose. • changing the needle on each syringe to an injection needle fulfilling the following criteria: 25G to 27G and 1 / 2 or 5 / 8-inch stainless steel needle with Luer-Lok. • administering the subcutaneous injections consecutively, each at a different injection site, into the thigh, back of the upper arm, or abdomen, on opposite sides or at least 2 cm apart. Injections should not be performed into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact. • observing the subject for 30 minutes following completion of the first visit. • administering the subcutaneous injection within 4 hours of preparation.

[0170] In an embodiment of the disclosure, a subject receiving the combination therapy of anti-C5 Ab and C5 iRNA achieves or achieves and maintains while receiving the therapy one or more of the following:• Improvement in Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score from baseline to week 24; • Improvement in Quantitative Myasthenia Gravis (QMG) score from baseline to week 24; • ≥3-point improvement from baseline to week 24 on the MG-ADL; • ≥5-point improvement from baseline to week 24 on the QMG; • At least a 2-point MG-ADL improvement on 2 or more consecutive assessments on the MG-ADL spanning 4 or more weeks during the double-blind treatment period (DBTP); • Minimal symptom expression (MSE), defined by a score of 0 to 1 on the MG-ADL at week 24; • Improvement in the Myasthenia Gravis Composite (MGC) total score from baseline to week 24; • Improvement in Myasthenia Gravis Quality of Life (MG-QOL15r) total score from baseline to week 24; • Improvement point threshold of ≥2, 4, 5, 6, 7, 8, 9, or 10 on MG-ADL at week 24; • Improvement point threshold of ≥3, 4, 6, 7, 8, 9, or 10 on QMG at week 24; • Reduced incidence and severity of treatment-related adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) in comparison to placebo through week 24; • Improvement from baseline in MG-ADL total score by visit; • Improvement from baseline in QMG total score by visit; • Reduced time to achievement of a 3-point improvement from baseline on the MG- ADL in comparison to placebo; • Reduced time to achievement of a 5-point improvement from baseline on the QMG in comparison to placebo; • Improvement from baseline in the physical performance measures of hand grip strength, supine leg lift, supine head lift, onset of dysarthria, and all timed items of the QMG; • Improvement from baseline in individual domains (ocular, bulbar, respiratory, and gross motor / limb impairment) of the MG-ADL;• Improvement from baseline in sentinel domains (ocular, facial, bulbar, gross motor, axial, and respiratory) of the QMG; • Improvement from baseline in continuous variable measures from the MGC; • Improvement from baseline in timed step count, cadence, and other exploratory measures using a wearable device; • Increased total MG-ADL score and secondary efficacy endpoints in comparison to placebo through week 48 and through week 120; • Improvement in patient-reported fatigue as measured by the Neuro-QoL-Fatigue from baseline to week 24; • Improvement from baseline in patient-reported health status as measured by the EuroQol-5 Dimensions-5 Levels (EQ-5D-5L); • Reduced number of myasthenic crises (including impending crises), days of hospitalization due to MG, and / or procedures related to MG from time periods prior to randomization; • Improvement from baseline and percent change from baseline in alternative pathway hemolytic activity assay (AH50) and total C5 over time; • Reduced use of rescue therapy from baseline to week 24; • Increase in corticosteroid dosage from baseline to week 24; • Decrease in corticosteroid dosage from baseline to week 24; • Reduced incidence and severity of adverse events through the end of study in comparison to placebo; • Improvement from baseline in Modified MGFA Post-Intervention Status (MG-PIS) at week 24, week 48, and week 120; • A percent change in serum CH50 by week 1, week 2, week 4, week 12 or week 24, after treatment initiation with Pozelimab monotherapy (200 mg, q4w) of about -18.49, -9.19, -7.06, -6 or -7.31, U / ml, respectively; • A percent change in serum CH50 by week 1, week 2, week 4, week 12 or week 24 after treatment initiation with Pozelimab (PZ) and Cemdisiran (CMD) combination (200 mg PZ + 200 CMD, q4w) of about -63.31, -83.53, -84.62, -98.91 or -99.57, U / ml, respectively; • A percent change in serum CH50 by week 1, week 2, week 4, week 12 or week 24 after treatment initiation with Cemdisiran monotherapy (about 600 mg, q12w;preferably, about 600 mg Cemdisiran Na+form; or the molar equivalent of Cemdisiran free form or of another salt form thereof) of about -32.62, -55.75, -76.77, -73.53 or -76.61, U / ml, respectively; • A change in MG-ADL total score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab monotherapy (200 mg, q4w) of about -1.31, -1.98, -2.59, - 2.66, -2.80, -2.59 or -2.77, respectively; • A change in MG-ADL total score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab (PZ) + Cemdisiran (CMD) combination (200 mg PZ + 200 mg CMD, q4w) of about -2.56, -3.08, -3.38, -3.76, -3.75, -3.91 or -3.96, respectively; • A change in MG-ADL total score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Cemdisiran monotherapy (about 600 mg, q12w; ; preferably, about 600 mg Cemdisiran Na+form; or the molar equivalent of Cemdisiran free form or of another salt form thereof) of about -2.50, -3.22, -3.96, -4.31, -4.14, -4.59 or -4.52, respectively; • An absolute MD-ADL score, by week, 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab (200 mg, q4w), of about 8.50, 7.87, 7.08, 7.13, 6.94, 7.15 or 6.92, respectively; • An absolute MD-ADL score, by week, 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab (PZ) + Cemdisiran (CMD) (200 mg PZ + 200 mg CMD, q4w), of about 6.91, 6.25, 5.84, 5.45, 5.33, 5.22 or 5.08, respectively; • An absolute MD-ADL score, by week, 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Cemdisiran (about 600 mg, q12w; preferably, about 600 mg Cemdisiran Na+form; or the molar equivalent of Cemdisiran free form or of another salt form thereof), of about 6.52, 5.81, 5.08, 4.70, 4.81, 4.44 or 4.53, respectively; • A change in QMG total score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab monotherapy (200 mg, q4w) of about -0.83, -0.73, -1.58, - 1.78, -1.44, -1.77 or -1.55, respectively; • A change in QMG total score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab (PZ) and Cemdisiran (CMD) combination (200 mg PZ + 200 CMD, q4w) of about -2.11, -2.77, -2.56, -3.07, -3.27, -3.18 or -3.32, respectively; • A change in QMG total score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Cemdisiran monotherapy (about 600 mg, q12w; preferably, about 600mg Cemdisiran Na+form; or the molar equivalent of Cemdisiran free form or of another salt form thereof) of about -1.95, -2.60, -3.91, -3.94, -4.11, -3.92 or -4.24, respectively; • An absolute MD-ADL score, by week, 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab monotherapy (200 mg, q4w), of about 15.33, 15.54, 14.38, 14.41, 14.47, 14.19 or 14.31, respectively; • An absolute MD-ADL score, by week, 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab (PZ) + Cemdisiran (CMD) (200 mg PZ + 200 mg CMD, q4w) (200 mg, q4w), of about 13.84, 12.85, 12.94, 12.33, 11.97, 11.98 or 11.94, respectively; • An absolute MD-ADL score, by week, 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Cemdisiran monotherapy (about 600 mg, q12w; preferably, about 600 mg Cemdisiran Na+form; or the molar equivalent of Cemdisiran free form or of another salt form thereof), of about 13.64, 12.98, 11.69, 11.64, 11.45, 11.76 or 11.44, respectively; • A change in MGC score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab (PZ) + Cemdisiran (CMD) combination (200 mg PZ + 200 mg CMD, q4w) of about -4.31, -4.77, -5.49, -5.89, -5.85, -6.01 or -6.04, respectively; • A change in MGC score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Cemdisiran monotherapy (about 600 mg, q12w; preferably, about 600 mg Cemdisiran Na+form; or the molar equivalent of Cemdisiran free form or of another salt form thereof) of about -4.49, -5.22, -6.55, -7.55, -7.57, -7.69 or -7.78, respectively; • A change in MGC score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab (PZ) monotherapy (200 mg, q4w) of about -1.64, -2.13, -3.34, -3.47, -3.30, -3.57 or -3.19, respectively; • A change in MG-QoL15r score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab (PZ) + Cemdisiran (CMD) combination (200 mg PZ + 200 mg CMD, q4w) of about -2.44, -2.86, -4.00, -3.79, -3.86, -3.91 or -4.25, respectively; • A change in MG-QoL15r score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Cemdisiran monotherapy (about 600 mg, q12w; preferably, about 600 mg Cemdisiran Na+form; or the molar equivalent of Cemdisiran free form or ofanother salt form thereof) of about -1.43, -2.67, -4.08, -4.31, -4.52, -4.65 or -4.68, respectively; and / or • A change in MG-QoL15r score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Pozelimab (PZ) monotherapy (200 mg, q4w) of about -1.65, -1.26, - 0.92, -1.76, -1.49, -0.70 or -1.58, respectively.

[0171] Achieving a given score or score improvement (e.g., in MG-ADL score; QMG score, MGC score, MG-QOL15r score, Neuro-QoL-Fatigue score, or EQ-5D-5L score) includes embodiments wherein the subject’s conditions are measured, for example, according to the relevant questionnaire or scale; and embodiments wherein, though not measured with the questionnaire or scale, the subject’s condition would achieve such a score or improvement if measured with the questionnaire or scale.

[0172] The present invention includes a method for achieving or maintaining any one or more of 1. Improvement in Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score e.g., from baseline to week 24; 2. Improvement in Quantitative Myasthenia Gravis (QMG) score, e.g., from baseline to week 24; 3. ≥3-point improvement, e.g., from baseline to week 24, on the MG-ADL; 4. ≥5-point improvement, e.g., from baseline to week 24, on the QMG; 5. At least a 2-point MG-ADL improvement on 2 or more consecutive assessments on the MG-ADL spanning 4 or more weeks during the double-blind treatment period (DBTP); 6. Minimal symptom expression (MSE), defined by a score of 0 to 1 on the MG-ADL, e.g., at week 24; 7. Improvement in the Myasthenia Gravis Composite (MGC) total score, e.g., from baseline to week 24; 8. Improvement in Myasthenia Gravis Quality of Life (MG-QOL15r) total score, e.g., from baseline to week 24; 9. Improvement point threshold of ≥2, 4, 5, 6, 7, 8, 9, or 10 on MG-ADL, e.g., at week 24; 10. Improvement point threshold of ≥3, 4, 6, 7, 8, 9, or 10 on QMG, e.g., at week 24;11. Improvement from baseline in MG-ADL total score by visit; 12. Improvement from baseline in QMG total score by visit; 13. Improvement from baseline in the physical performance measures of hand grip strength, supine leg lift, supine head lift, onset of dysarthria, and all timed items of the QMG; 14. Improvement from baseline in individual domains (ocular, bulbar, respiratory, and gross motor / limb impairment) of the MG-ADL; 15. Improvement from baseline in sentinel domains (ocular, facial, bulbar, gross motor, axial, and respiratory) of the QMG; 16. Improvement from baseline in continuous variable measures from the MGC; 17. Improvement from baseline in timed step count, cadence, and other exploratory measures using a wearable device; 18. Improvement in patient-reported fatigue as measured by the Neuro-QoL-Fatigue, e.g., from baseline to week 24; 19. Improvement from baseline in patient-reported health status as measured by the EuroQol-5 Dimensions-5 Levels (EQ-5D-5L); 20. Reduced number of myasthenic crises (including impending crises), days of hospitalization due to MG, and / or procedures related to MG from time periods prior to treatment initiation; 21. Improvement from baseline and percent change from baseline in alternative pathway hemolytic activity assay (AH50) and total C5 over time; 22. Reduced use of rescue therapy, e.g., from baseline to week 24; 23. Increase in corticosteroid dosage, e.g., from baseline to week 24; 24. Decrease in corticosteroid dosage, e.g., from baseline to week 24; 25. Improvement from baseline in Modified MGFA Post-Intervention Status (MG-PIS) , e.g., at week 24, week 48, and week 120; 26. A percent change in serum CH50 by week 1, week 2, week 4, week 12 or week 24, after treatment initiation of about -18.49, -9.19, -7.06, -6 or -7.31 U / ml; 27. A percent change in serum CH50 by week 1, week 2, week 4, week 12 or week 24 after treatment initiation of about -63.31, -83.53, -84.62, -98.91 or -99.57 U / ml; 28. A percent change in serum CH50 by week 1, week 2, week 4, week 12 or week 24 after treatment initiation of about -32.62, -55.75, -76.77, -73.53 or -76.61 U / ml;29. A change in MG-ADL total score by week 2, 4, 8, 12, 16, 20 or 24 of about -1.31, - 1.98, -2.59, -2.66, -2.80, -2.59 or -2.77; 30. A change in MG-ADL total score by week 2, 4, 8, 12, 16, 20 or 24 of about -2.56, - 3.08, -3.38, -3.76, -3.75, -3.91 or -3.96; 31. A change in MG-ADL total score by week 2, 4, 8, 12, 16, 20 or 24 of about -2.50, - 3.22, -3.96, -4.31, -4.14, -4.59 or -4.52; 32. An absolute MD-ADL score, by week, 2, 4, 8, 12, 16, 20 or 24 of about 8.50, 7.87, 7.08, 7.13, 6.94, 7.15 or 6.92; 33. An absolute MD-ADL score, by week, 2, 4, 8, 12, 16, 20 or 24 of about 6.91, 6.25, 5.84, 5.45, 5.33, 5.22 or 5.08; 34. An absolute MD-ADL score, by week, 2, 4, 8, 12, 16, 20 or 24 of about 6.52, 5.81, 5.08, 4.70, 4.81, 4.44 or 4.53; 35. A change in QMG total score by week 2, 4, 8, 12, 16, 20 or 24 of about -0.83, -0.73, -1.58, -1.78, -1.44, -1.77 or -1.55; 36. A change in QMG total score by week 2, 4, 8, 12, 16, 20 or 24 of about -2.11, -2.77, -2.56, -3.07, -3.27, -3.18 or -3.32; 37. A change in QMG total score by week 2, 4, 8, 12, 16, 20 or 24 of about -1.95, -2.60, -3.91, -3.94, -4.11, -3.92 or -4.24; 38. An absolute MD-ADL score, by week, 2, 4, 8, 12, 16, 20 or 24 of about 15.33, 15.54, 14.38, 14.41, 14.47, 14.19 or 14.31; 39. An absolute MD-ADL score, by week, 2, 4, 8, 12, 16, 20 or 24 of about 13.84, 12.85, 12.94, 12.33, 11.97, 11.98 or 11.94; 40. An absolute MD-ADL score, by week, 2, 4, 8, 12, 16, 20 or 24 of about 13.64, 12.98, 11.69, 11.64, 11.45, 11.76 or 11.44; 41. A change in MGC score by week 2, 4, 8, 12, 16, 20 or 24 of about -4.31, -4.77, - 5.49, -5.89, -5.85, -6.01 or -6.04; 42. A change in MGC score by week 2, 4, 8, 12, 16, 20 or 24 of about -4.49, -5.22, - 6.55, -7.55, -7.57, -7.69 or -7.78; 43. A change in MGC score by week 2, 4, 8, 12, 16, 20 or 24 of about -1.64, -2.13, - 3.34, -3.47, -3.30, -3.57 or -3.19; 44. A change in MG-QoL15r score by week 2, 4, 8, 12, 16, 20 or 24 of about -2.44, - 2.86, -4.00, -3.79, -3.86, -3.91 or -4.25;45. A change in MG-QoL15r score by week 2, 4, 8, 12, 16, 20 or 24 of about -1.43, - 2.67, -4.08, -4.31, -4.52, -4.65 or -4.68; and / or 46. A change in MG-QoL15r score by week 2, 4, 8, 12, 16, 20 or 24 of about -1.65, - 1.26, -0.92, -1.76, -1.49, -0.70 or -1.58; in a subject in need thereof having MG (for example, wherein the subject is anti- acetylcholine receptor (AChR) and / or anti-low-density lipoprotein receptor-related protein 4 (LRP4) antibody positive) including administering, to the subject, • one or more 200 mg (±20 mg) doses of the anti-C5 antibody or antigen-binding fragment, e.g., about every 4 weeks (±7 days); and one or more 200 mg (±20 mg) doses of the C5 iRNA, e.g., about every 4 weeks (±7 days); preferably, wherein the antibody or fragment is Pozelimab and the C5 iRNA is Cemdisiran Na+form or another salt form or the free form; • about 600 mg (±60 mg) Cemdisiran Na+form or a molar equivalent amount of another salt form or the free form every about 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), about 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), about 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about ¼ year; • about 32-25 (±4) (e.g., 32, 33, 33.8, 34 or 35) micromoles Cemdisiran, e.g., Na+form or another salt form or the free form, every about 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), about 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), about 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about ¼ year; or • about 567 mg of Cemdisiran free form which is in Na+salt form or another salt form every about 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), about 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), about 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about ¼ year; preferably, wherein each administration is by SC injection.

[0173] As used herein, the expression “in combination with” means that the anti-C5 antibody or antigen-binding fragment thereof is administered before, after, or concurrently with the C5 iRNA. This expression includes sequential or concurrent administration of the anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA. Thus, a method of treatment as set forth herein including administering an anti-C5 antibody or antigen-binding fragment thereof (e.g., 200 mg Pozelimab) in combination with a C5 iRNA (e.g., 200 mg Cemdisiran), to a subject in need thereof, may be referred to as a combination therapy of the present invention.

[0174] In some embodiments, when the anti-C5 antibody or antigen-binding fragment thereof is administered “before” the C5 iRNA, the anti-C5 antibody or antigen-binding fragment thereof may be administered about 4 weeks (±7 days), about 3 weeks (±7 days), about 2 weeks (±7 days), about 1 week (±7 days), about 150 hours, about 100 hours, about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours prior to the administration of the C5 iRNA.

[0175] In some embodiments, when the anti-C5 antibody or antigen-binding fragment thereof is administered “after” the C5 iRNA, the anti-C5 antibody or antigen-binding fragment thereof may be administered about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 1 week (±7 days), about 2 weeks (±7 days), about 3 weeks (±7 days), about 4 weeks (±7 days) after the administration of the C5 iRNA.

[0176] As used herein, "concurrent" administration means that the anti-C5 antibody or antigen-binding fragment thereof (e.g., Pozelimab) and a C5 iRNA (e.g., Cemdisiran) are administered to the subject in a single dosage form (e.g., co-formulated) or in separate dosage forms administered to the subject during the same treatment episode, preferably within about 1 or 2 hours or 30 minutes or less of each other (i.e., before, after, or at the same time), such as about 15 minutes or less, or about 5 minutes or less. If administered in separate dosage forms, each dosage form may be administered via the same route (e.g., both administered intravenously, subcutaneously, etc.); or, alternatively, each dosage form may be administered via a different route. In any event, administering the components in a single dosage from, in separate dosage forms by the same route, or in separate dosage forms by different routes are all considered "concurrent” administration" for purposes of the present disclosure. In an embodiment of the disclosure, concurrent subcutaneous doses of anti-C5 antibody or antigen-binding fragment thereof and C5 iRNA are administered by injection into separate body areas, e.g., separate arms.

[0177] The co-formulations and / or combination therapy of the present disclosure (e.g., Cemdisiran / Pozelimab) are useful for treating or preventing a disease or disorder or condition associated with C5 that includes the step of administering a therapeutically effective amount of anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA, preferably in a co-formulation, e.g., by parenteral route, e.g., intramuscular (IM), subcutaneous (SC), or intravenous (IV) injection / infusion. Preferably, about 200 mg (±20 mg) of the antibody, preferably Pozelimab, is administered about every 4 weeks (±7 days) and about 200 mg (±20 mg) iRNA, preferably Cemdisiran Na+form or a molar equivalentamount of another salt form or the free form, is administered about every 4 weeks (±7 days). Preferably, the antibody or fragment and the iRNA is administered by subcutaneous injection (SC).

[0178] In an embodiment of the invention, any dose mentioned herein (e.g., of Pozelimab or Cemdisiran) is administered ± 1, ± 2, ± 3, ± 4, ± 5, ± 6 or ± 7 days, for example, q4w (± 7 days).

[0179] In an embodiment of the invention, a subject receiving a dosing regimen as set forth herein, may receive one or more doses of anti-C5 antibody or antigen-binding fragment and / or C5 iRNA that are in addition to the regular doses required by the regimen.

[0180] In an embodiment of the invention, a subject receiving a dosing regimen as set forth herein, may skip one or more of the regular doses of anti-C5 antibody or antigen- binding fragment and / or C5 iRNA required by the regimen.

[0181] In an embodiment of the invention, the subject receives a dosing regimen of the present invention for at least one dose, at least 2 doses, 1 year, 2 years, 5 years or 10 years; or more.

[0182] The present invention includes methods for treating or preventing atypical hemolytic uremic syndrome (aHUS) in a subject in need thereof comprising administering, to the subject (a) one or more about 200 mg (±20 mg) doses of the anti-C5 antibody or antigen-binding fragment (e.g., Pozelimab) (e.g., about every 4 weeks (±7 days)); and one or more about 200 mg (±20 mg) doses of the C5 iRNA (e.g., Cemdisiran Na+form or a molar equivalent amount of another salt form or the free form) (e.g., about every 4 weeks (±7 days)); or (b) about 600 mg (±60 mg) Cemdisiran Na+form or a molar equivalent amount of another salt form or the free form about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about every ¼ year; about 32-25 (±4) (e.g., 32, 33, 33.8, 34 or 35) micromoles Cemdisiran, e.g., Na+form or a molar equivalent amount of another salt form or the free form about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about every ¼ year; or about 567 mg (±57 mg) of Cemdisiran free form which is in Na+salt form or another salt form about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about every ¼ year.In an embodiment of the invention, the antibody or fragment and the iRNA are administered in a single co-formulation; in another embodiment, the antibody and iRNA are in separate formulations. Signs and symptoms of aHUS include, but are not limited to, platelet activation, hemolysis, systemic thrombotic microangiopathy (formation of blood clots in small blood vessels throughout the body) leading to stroke, heart attack, kidney failure and / or death, end-stage renal disease, permanent renal damage, abdominal pain, confusion, edema, fatigue, nausea / vomiting, diarrhea, and microangiopathic anemia. Thus, the present disclosure includes methods for treating or preventing aHUS, in a subject in need thereof, including the steps of administering a therapeutically effective amount of co- formulation of the present disclosure to the subject (e.g., by SC, IM or IV injection).

[0183] The present invention includes methods for treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) in a subject in need thereof comprising administering, to the subject (a) one or more about 200 mg (±20 mg) doses of the anti-C5 antibody or antigen-binding fragment (e.g., Pozelimab) (e.g., about every 4 weeks (±7 days)); and one or more about 200 mg (±20 mg) doses of the C5 iRNA (e.g., Cemdisiran Na+form or a molar equivalent amount of another salt form or the free form) (e.g., about every 4 weeks (±7 days)); or (b) about 600 mg (±60 mg) Cemdisiran Na+form or a molar equivalent amount of another salt form or the free form about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about every ¼ year; about 32-25 (±4) (e.g., 32, 33, 33.8, 34 or 35) micromoles Cemdisiran, e.g., Na+form or a molar equivalent amount of another salt form or the free form about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about every ¼ year; or about 567 mg (±57 mg) of Cemdisiran free form which is in Na+salt form or another salt form about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about every ¼ year. In an embodiment of the invention, the antibody or fragment and the iRNA are administered in a single co-formulation; in another embodiment, the antibody and iRNA are in separate formulations. Signs and symptoms of PNH include, but are not limited to, destruction of red blood cells, thrombosis (including deep vein thrombosis, pulmonary embolism), intravascular hemolytic anemia, red discoloration of urine, symptoms of anemia such astiredness, shortness of breath, and palpitations, abdominal pain and difficulty swallowing. Thus, the present disclosure includes methods for treating or preventing PNH, in a subject in need thereof, including the steps of administering a therapeutically effective amount of co-formulation of the present disclosure to the subject (e.g., by SC, IM or IV injection).

[0184] The present invention includes methods for treating or preventing CHAPLE disease (CD55 deficiency with hyperactivation of complement, angiopathic thrombosis and protein-losing enteropathy) in a subject in need thereof comprising administering, to the subject (a) one or more about 200 mg (±20 mg) doses of the anti-C5 antibody or antigen-binding fragment (e.g., Pozelimab) (e.g., about every 4 weeks (±7 days)); and one or more about 200 mg (±20 mg) doses of the C5 iRNA (e.g., Cemdisiran Na+form or a molar equivalent amount of another salt form or the free form) (e.g., about every 4 weeks (±7 days)); or (b) about 600 mg (±60 mg) Cemdisiran Na+form or a molar equivalent amount of another salt form or the free form about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about every ¼ year; about 32-25 (±4) (e.g., 32, 33, 33.8, 34 or 35) micromoles Cemdisiran, e.g., Na+form or a molar equivalent amount of another salt form or the free form about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about every ¼ year; or about 567 mg (±57 mg) of Cemdisiran free form which is in Na+salt form or another salt form about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about every ¼ year. In an embodiment of the invention, the antibody or fragment and the iRNA are administered in a single co-formulation; in another embodiment, the antibody and iRNA are in separate formulations. CHAPLE disease is characterized by symptoms such as inflammatory bowel disease, protein losing enteropathy (which can be associated with hypoalbuminemia), hypogammaglobulinemia, intestinal lymphangiectasia, and / or thrombotic events. Thus, the present disclosure includes methods for treating or preventing CHAPLE, in a subject in need thereof, including the steps of administering a therapeutically effective amount of co- formulation of the present disclosure to the subject (e.g., by SC, IM or IV injection).

[0185] The present invention includes methods for treating or preventing (including reducing or eliminating signs or symptoms thereof, or reducing complement activationassociated therewith) a disease or disorder or condition associated with C5 (e.g., MG) in a subject in need thereof comprising administering, to the subject, (a) one or more about 200 mg (±20 mg) doses of the anti-C5 antibody or antigen-binding fragment (e.g., Pozelimab) (e.g., about every 4 weeks (±7 days)); and one or more about 200 mg (±20 mg) doses of the C5 iRNA (e.g., Cemdisiran Na+form or a molar equivalent amount of another salt form or the free form) (e.g., about every 4 weeks (±7 days)); or (b) about 600 mg (±60 mg) Cemdisiran Na+form or a molar equivalent amount of another salt form or the free form about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about every ¼ year; about 32-25 (±4) (e.g., 32, 33, 33.8, 34 or 35) micromoles Cemdisiran, e.g., Na+form or a molar equivalent amount of another salt form or the free form about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about every ¼ year; or about 567 mg (±57 mg) of Cemdisiran free form which is in Na+salt form or another salt form about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about every ¼ year. In an embodiment of the invention, the antibody or fragment and the iRNA are administered in a single co-formulation; in another embodiment, the antibody and iRNA are in separate formulations. Thus, the present disclosure includes methods for treating or preventing any of such disorders, in a subject in need thereof, including the steps of administering a therapeutically effective amount of co-formulation of the present disclosure to the subject (e.g., by SC, IM or IV injection).

[0186] The diseases or disorders or conditions associated with C5 which may be treated or for which signs and symptoms may be reduced or eliminated or for which complement activation may be reduced by administering (a) one or more about 200 mg (±20 mg) doses of the anti-C5 antibody or antigen-binding fragment (e.g., Pozelimab) (e.g., about every 4 weeks (±7 days)); and one or more about 200 mg (±20 mg) doses of the C5 iRNA (e.g., Cemdisiran Na+form or a molar equivalent amount of another salt form or the free form) (e.g., about every 4 weeks (±7 days)); or (b) about 600 mg (±60 mg) Cemdisiran Na+form or a molar equivalent amount of another salt form or the free form about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), or about every12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about every ¼ year; about 32-25 (±4) (e.g., 32, 33, 33.8, 34 or 35) micromoles Cemdisiran, e.g., Na+form or a molar equivalent amount of another salt form or the free form about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about every ¼ year; or about 567 mg (±57 mg) of Cemdisiran free form which is in Na+salt form or another salt form about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), or about every 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about every ¼ year; include, for example, adult respiratory distress syndrome; Alport's syndrome; Alzheimer's disease; atherosclerosis; bullous pemphigoid; C3 glomerulopathy; capillary leak syndrome; CHAPLE disease / syndrome (CD55 deficiency with hyperactivation of complement, angiopathic thrombosis and PLE); complement activation due to a burn; complement activation due to obesity; complement activation due to frostbite; complement activation due to sepsis; Crohn's disease; diabetes; diabetic nephropathy; epilepsy; glomerulopathy; Guillain-Barre Syndrome; hemolytic anemia; hyperacute allograft rejection; an infectious disease; inherited CD59 deficiency; interleukin-2 induced toxicity during IL-2 therapy; lupus nephritis; membranoproliferative glomerulonephritis; membranoproliferative nephritis; mesenteric artery reperfusion after aortic reconstruction; multiple sclerosis; myasthenia gravis; myocardial infarction; neuromyelitis optica; Parkinson's disease; progressive kidney failure; psoriasis; a post-ischemic reperfusion condition; a renal ischemia; a renal ischemia- reperfusion injury; rheumatoid arthritis; schizophrenia; SLE nephritis; stroke; systemic lupus erythematosus (SLE); traumatic brain injury; vasculitis; xenograft rejection, a lung disease or disorder such as dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, a fibrogenic dust disease, injury due to inert dusts and minerals (e.g., silicon, coal dust, beryllium, and asbestos), pulmonary fibrosis, an organic dust disease, a chemical injury (due to irritant gasses and chemicals, e.g., chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, and hydrochloric acid), a smoke injury, a thermal injury (e.g., burn or freeze), allergy, bronchoconstriction, hypersensitivity pneumonitis, a parasitic disease, Goodpasture's Syndrome, pulmonary vasculitis, hereditary angioedema, immune complex- associated inflammation, an ocular disease such as age-related macular degeneration (AMD), diabetic macular edema (DME), diabetic retinopathy, ocular angiogenesis (ocularneovascularization affecting choroidal, corneal, or retinal tissue), geographic atrophy (GA), uveitis and / or neuromyelitis optica.

[0187] In an embodiment of the invention, the subject was receiving crovalimab, ronzanolixizumab, efgartigimod, belimumab, avacincaptad pegol and / or zilucoplan for treatment of MG prior to initiation of treatment with a method according to the present invention.

[0188] In an embodiment of the invention, the subject was receiving Eculizumab for treatment of MG, e.g., (a) 900 mg Eculizumab (e.g., intravenously (IV)) weekly for the first 4 weeks, followed by (b) 1200 mg Eculizumab (e.g., intravenously (IV)) for the fifth dose 1 week later, then (c) 1200 mg Eculizumab (e.g., intravenously (IV)) every 2 weeks thereafter (q2w); and then switches to a treatment regimen according to the present invention.

[0189] In an embodiment of the invention, the subject was receiving Ravulizumab for treatment of MG, e.g., (a) For 40 to less than 60 kg bodyweight (BW), 2,400 mg loading dose and 3,000 mg doses every 8 weeks (e.g., intravenously (IV) or subcutaneously (SC)); (b) For 60 to less than 100 mg BW, 2,700 mg loading dose and 3,300 mg doses every 8 weeks (e.g., intravenously (IV) or subcutaneously (SC)); or (c) For 100 mg or greater BW, 3,000 mg loading dose and 3,600 every 8 weeks (e.g., intravenously (IV) or subcutaneously (SC)).

[0190] "Treat" or "treating" refers to reducing or eliminating one or more signs or symptoms thereof in a subject e.g., reducing complement activation associated therewith.

[0191] A therapeutically effective dose or amount of C5 iRNA is about 567 mg (±57 mg) of C5 iRNA, 32-35 or 33.8 (±4) micromoles of C5 iRNA or 600 mg (±60 mg) of C5 iRNA which is in salt for such as Na+form (e.g., wherein the C5 iRNA is Cemdisiran Na+form of another salt form or the free form, preferably subcutaneously, about every 84 days (± 1, 2, 3, 4, 5, 6 or 7 days), about 12 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), about 3 months (± 1, 2, 3, 4, 5, 6 or 7 days) or about ¼ year; or of anti-C5 antibody or antigen-binding fragment thereof and C5 iRNA is about 200 mg (±20 mg) of the anti-C5 antibody or antigen-binding fragment thereof (e.g., Pozelimab) and about 189 mg (±19 mg) of C5 iRNA, 11-13 (±2) micromoles of C5 iRNA or 200 mg (±20 mg) of C5 iRNA which is in salt for such as Na+form (e.g., wherein the C5 iRNA is Cemdisiran Na+form of another salt form or the free form), which may be administered in a single co-formulation or by two separateadministrations of the antibody or fragment and the C5 iRNA, about once every 28, 29 or 30 days (± 1, 2, 3, 4, 5, 6 or 7 days), once a month (± 1, 2, 3, 4, 5, 6 or 7 days) or once every 4 weeks (± 1, 2, 3, 4, 5, 6 or 7 days), preferably subcutaneously.

[0192] A subject or patient – used interchangeably herein - refers to a mammal, preferably, a human. In an embodiment of the disclosure, the subject suffers from a disease or disorder or condition associated with C5, such as MG. In an embodiment of the present disclosure, a subject has a confirmed diagnosis (e.g., seropositive for anti-AChR or anti-LRP4 antibodies) of MG and / or has signs and / or symptoms of MG (as defined by MG- ADL score ≥6 and MGFA Class II to IVa at screening). In an embodiment of the present disclosure, the subject or patient does not have any one or more of the following characteristics: • An antibody profile that is only positive for MuSK (MuSK positivity is based on a documented prior history of positive serologic test for antibodies to MuSK or a positive result during screening); • History of thymectomy within 12 months prior to screening or planned during the study; • History of malignant thymoma, or history of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer; • Myasthenic crisis or MGFA Class V within past 1 month; • Any systemic bacterial or other infection that was clinically significant in the opinion of a physician and had not been treated with appropriate therapy within the past 2 weeks; • Unresolved meningococcal infection; • Meningococcal vaccination within past 5 years; • Known contraindication to meningococcal vaccines (group ACWY conjugate and group B vaccines); • Requirement for antibiotics for meningococcal prophylaxis and have a contraindication, warning, or precaution precluding the use of penicillin class and penicillin-alternative antibiotics planned to be used for prophylaxis, or a history of intolerance leading to the discontinuation of these antibiotics; • Positive hepatitis B surface antigen or hepatitis C virus RNA during screening;• History of HIV infection or a positive test at screening per local requirements; • An estimated glomerular filtration rate (eGFR) <30 mL / min / 1.73 m2(according to the Chronic Kidney Disease Epidemiology Collaboration creatinine equation, with one re-test allowed; • Documented history of liver cirrhosis or known liver disease with current evidence of ongoing impaired liver function (e.g., screening international normalized ratio [INR] >1.5 × ULN that is considered hepatic in origin); • Screening serum ALT levels >3 × ULN and / or total bilirubin >2 × ULN (unless bilirubin elevation is due to suspected Gilbert’s syndrome), with one re-test allowed; • Receiving azathioprine; • Receiving other intratympanic steroid therapy (ISTs) (e.g., systemic corticosteroids, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, or cyclophosphamide); • Receiving cholinesterase inhibitors; • Undergoing ongoing treatment with IVIG or PLEX / other comparable therapeutic apheresis (TA) procedure or treatment within past 4 weeks; • Use of rituximab within past 6 months; • Use of complement inhibitor therapy within past 6 months or neonatal Fc receptor (FcRn) inhibitors within past 4 months or 5 half-lives, whichever is longer; • Muscular weakness predominantly due to conditions other than MG, such as myopathies, concurrent infections, medications, or hospitalization / bedrest immobilization; • Hypersensitivity to Pozelimab or Cemdisiran or to one of its excipients; • Functional or anatomic asplenia; and / or • Any life-time suicidal actions. In an embodiment of the present disclosure, the subject or patient has any one or more of the following characteristics: • Male or female patients ≥18 years of age; • Diagnosis of MG based on medical history and supported by previous evaluations. Examples of supportive evaluations include any one of the following: − History of abnormal neuromuscular transmission by repetitive nerve stimulation / single-fiber electromyography− History of positive anticholinesterase test − Positive response (improvement in signs) with anticholinesterase treatment, as assessed by the treating physician; • History of positive serologic test or a positive result of anti-AChR antibodies or anti- LRP4 antibodies; • MGFA Clinical Classification Class II to IVa; • MG-ADL score ≥6; • Currently receiving an acetylcholinesterase inhibitor; and / or • Currently receiving an IST for MG (ISTs include, but are not limited to, systemic corticosteroids, azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, or cyclophosphamide).

[0193] In an embodiment of the invention, the subject is monitored for: Meningococcal infection; Serious infection; Sepsis; Embryofetal toxicity; Immunogenicity; Anti-drug antibody formation; Any clinical Consequences of large Drug-Target-Drug immune complexes in subjects who switch from Eculizumab or Ravulizumab to Pozelimab; Liver transaminase elevations; and / or Injection site reaction. In an embodiment of the invention, treatment is terminated or suspended of any one of the foregoing is observed. Myasthenia Gravis (MG)

[0194] In some embodiments, the disclosed co-formulations and / or combination therapy of the present disclosure (e.g., Cemdisiran / Pozelimab) are useful in treating or preventing myasthenia gravis (MG) of any type or class (e.g., generalized and / or ocular). Two types of myasthenia gravis are generalized myasthenia gravis and ocular myasthenia gravis. Generalized MG causes weakness in many muscle groups. Ocular myasthenia gravis affects the muscles that move the eyes and eyelids.

[0195] Myasthenia gravis is an autoimmune disorder affecting the neuromuscular junction. It manifests as a generalized muscle weakness which can involve the respiratory muscles and can lead to a myasthenic crisis, which is a medical emergency. A classic presentation of MG is fluctuating weakness that is more prominent in the afternoon. It usually involves muscles of the eyes, throat, and extremities. The reduced transmission of electrical impulses across the neuromuscular junction due to the formation of autoantibodies against the specific postsynaptic membrane proteins consequently causesmuscle weakness. A wide variety of conditions can precipitate MG, such as infections, immunization, surgeries, and drugs. Myasthenia gravis causes a significant number of complications. These include myasthenic crisis, an acute respiratory paralysis that requires intensive care, as well as adverse events due to long term medication treatment like opportunistic infections and lymphoproliferative malignancies. In an embodiment of the invention, a subject has MG and one or more of such characteristics, e.g., generalized muscle weakness.

[0196] The presence of autoantibodies directed against the muscle nicotinic acetylcholine receptor (AChR) is a common cause of myasthenia gravis (MG). These antibodies damage the postsynaptic membrane of the neuromuscular junction and cause muscle weakness by depleting AChRs and thus impairing synaptic transmission.

[0197] Antibodies (Abs) specific for the low‑density lipoprotein receptor-related protein 4 (LRP4) occur in some patients with myasthenia gravis (MG). LRP4 forms a multiprotein complex with MuSK and facilitates AChR clustering through the agrin / LRP4 / MuSK / Dok7 / rapsyn pathway.

[0198] Commonly implicated proteins in the NMJ against which autoantibodies are produced include • the nicotinic acetylcholine receptors (n-AChRs), • muscle-specific kinase (MuSK), and • lipoprotein-related protein 4 (LPR4).

[0199] The Agrin–LRP4–MuSK protein complex is essential for the formation and maintenance of NMJ, including the distribution and clustering of the AChR.

[0200] Classes of MG include, depending on the type of clinical features and the type of antibodies involved, include (i) Early-onset MG characterized by an age at onset of less than 50 years with thymic hyperplasia; (ii) Late-onset MG characterized by an age at onset of greater than 50 years with thymic atrophy; (iii) Thymoma-associated MG; (iv) MG with anti-MuSK antibodies; (v) Ocular MG characterized by symptoms from periocular muscles; and (vi) MG with no detectable AChR and MuSK antibodies.Gilhus et al., Myasthenia gravis: a review of available treatment approaches. Autoimmune Dis.2011;2011:847393.

[0201] Clinical classification divides MG into 5 main classes based on the clinical features and the disease severity. Each class carries different prognoses or responses to therapy: • Class I: Involves any ocular muscle weakness, including weakness of eye closure. All other muscle groups are normal; • Class II: Involves mild weakness of muscles other than ocular muscles. Ocular muscle weakness of any severity may be present; • Class IIa: Involves predominant weakness of the limb, axial muscles, or both. It may also involve the oropharyngeal muscles to a lesser extent; • Class IIb: Involves mostly oropharyngeal, respiratory muscles, or both. It can have the involvement of limb, axial muscles, or both to a lesser extent; • Class III: Involves muscles other than ocular muscles moderately. Ocular muscle weakness of any severity can be present; • Class IIIa: involves the limb, axial muscles, or both predominantly. Oropharyngeal muscles can be involved to a lesser degree; • Class IIIb: Involves oropharyngeal, respiratory muscles, or both predominantly. The limb, axial muscles, or both can have lesser or equal involvement; • Class IV: Involves severe weakness of affected muscles. Ocular muscle weakness of any severity can be present; • Class IVa: Involves limb, axial muscles, or both predominantly. Oropharyngeal muscles can be involved to a lesser degree; • Class IVb: Involves oropharyngeal, respiratory muscles, or both predominantly. The limb, axial muscles, or both can have lesser or equal involvement. It also includes patients requiring feeding tubes without intubation; and • Class V: Involves intubation with or without mechanical ventilation, except when employed during routine postoperative management. (Beloor Suresh A, Asuncion RMD. Myasthenia Gravis. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https: / / www.ncbi.nlm.nih.gov / books / NBK559331 / )

[0202] Diagnosis of MG can be done on the basis of laboratory investigations and procedures. Serologic Tests for anti-AChR Abs is very specific, and confirms the diagnosis in patients with classical clinical findings. It is present in four-fifths of patients with generalized MG and only in half of the patients with pure ocular MG (Bindu et al., Ann Indian Acad Neurol.2008 Oct;11(4):242-4). Other patients will demonstrate anti-MuSK antibodies, both anti-AChR and anti-MuSK; anti-LRP4 antibodies; or anti-striated muscle antibodies. The present invention includes treating MG in patients having any one or more of these antibodies.

[0203] Electrophysiologic tests (e.g., RNS or SFEMG) can be performed on patients who are seronegative for antibody testing. Tests for MG are the repetitive nerve stimulation (RNS) test and single-fiber electromyography (SFEMG). Both the tests assess for conduction delays in the NMJ. Routine nerve conduction studies are usually performed to determine the functioning of the nerves and muscles before undertaking these tests. The repeated nerve stimulation (RNS) test is done by stimulating the nerve at 2-3Hz. RNS depletes the ACh in the NMJ, and produces a low excitatory postsynaptic potential (EPSP). A 10% or more decrease in the EPSP between the first and fifth stimulus is diagnostic of MG. Single-fiber electromyography (SFEMG) records action potential (AP) from individual muscle fibers, and thus allows to record the AP simultaneously from two muscle fibers innervated by a single motor neuron. The difference between the time of onset of these two action potentials is called the "jitter." In MG, the "jitter" will increase because of the reduced NMJ transmission.

[0204] The Edrophonium (Tensilon) test is a short-acting acetylcholinesterase inhibitor that increases the availability of ACh in the NMJ. This is particularly useful for ocular MG, where electrophysiologic testing cannot be performed. It is administered intravenously, and the patient is observed for improvement in the symptoms of ptosis or diplopia.

[0205] The Ice-pack test, may be used when edrophonium testing is contraindicated. This test requires an ice-pack placed over the eye for 2-5 minutes. Then, an assessment for any improvement in ptosis is done. This test cannot be used for the evaluation of extraocular muscles.

[0206] Imaging such as Chest computed tomography (CT) or Magnetic resonance imaging (MRI) should be performed in patients diagnosed with MG to assess for thymoma. In cases presenting with pure ocular MG, MRI of orbits and the brain can be performed to evaluate for any localized mass lesions.

[0207] Myasthenia gravis commonly coexists with other autoimmune disorders, and testing for anti-nuclear (ANA) antibodies, rheumatoid factor (RF), and baseline thyroid functions can be indicative of MG.

[0208] The present invention includes methods of treatment that include a step of diagnosing MG in the subject before or during such treatment, e.g., wherein diagnosis is performed using RNS, SFEMG, Tensilon, Ice-pack, imaging tests. For example, the present invention includes a method for treating or preventing a MG in a subject in need thereof comprising administering, to the subject one or more 200 mg (±20 mg) doses of anti-C5 antibody or antigen-binding fragment; and one or more 200 mg (±20 mg) doses of C5 iRNA; wherein prior to or during said treatment, MG was diagnosed in the subject by repeated nerve stimulation (RNS) test comprising the step of stimulating a nerve at 2-3Hz, thereby producing a low excitatory postsynaptic potential (EPSP), wherein a 10% or more decrease in the EPSP between the first and fifth stimulus is diagnostic of MG and wherein, if the subject was diagnosed as having MG, then initiating or continuing said treatment. Devices

[0209] The present disclosure also provides an injection device including the co- formulations of the present disclosure (e.g., Cemdisiran / Pozelimab) or C5 iRNA monotherapy formulations of the present invention, e.g., including Cemdisiran (e.g., but not including Pozelimab). An injection device is a device that introduces a substance into the body of a patient via a parenteral route, e.g., intramuscular, subcutaneous, or intravenous. For example, an injection device may be a syringe (e.g., pre-filled or auto-injector) which, for example, includes a cylinder or barrel for holding fluid to be injected (e.g., the formulation or co-formulation), a needle for piecing skin and / or blood vessels for injection of the fluid; and a plunger for pushing the fluid out of the cylinder and through the needle bore. In an embodiment of the disclosure, an injection device that comprises a formulation or co- formulation is suitable for subcutaneous, or intravenous (IV) injection. Such a device includes a formulation or co-formulation in a cannula or trocar / needle which may be attached to a tube which may be attached to a bag or reservoir for holding fluid (e.g., saline; or lactated ringer solution including NaCl, sodium lactate, KCl, CaCl2and optionally including glucose) introduced into the body of the patient through the cannula or trocar / needle.

[0210] A prefilled syringe is a single-use device that is provided containing a quantity of a drug product, e.g., Cemdisiran, where the user is not required to fill the device with the drug product.

[0211] The formulation or co-formulation can, in an embodiment of the disclosure, be introduced into the device once the trocar and cannula are inserted into the vein of a subject and the trocar is removed from the inserted cannula. The IV device may, for example, be inserted into a peripheral vein (e.g., in the hand or arm); the superior vena cava or inferior vena cava, or within the right atrium of the heart (e.g., a central IV); or into a subclavian, internal jugular, or a femoral vein and, for example, advanced toward the heart until it reaches the superior vena cava or right atrium (e.g., a central venous line).

[0212] In an embodiment of the disclosure, an injection device is an autoinjector; a jet injector, an on-body subcutaneous injection device or an external infusion pump.

[0213] Autoinjectors are medical devices convenient for the self-administration of injections by patients and for easy administration by healthcare professionals in emergency situations. Although they vary in design and application, autoinjectors are typically built around a spring-loaded pre-filled syringe containing a pre-determined amount of pharmaceutical formulation. Autoinjectors are usually single-use and disposable.

[0214] A jet injector uses a high-pressure narrow jet of liquid which penetrate the epidermis to introduce a co-formulation to a patient's body. External infusion pumps are medical devices that deliver the co-formulation into a patient's body in controlled amounts. External infusion pumps may be powered electrically or mechanically. Different pumps operate in different ways, for example, a syringe pump holds fluid in the reservoir of a syringe, and a moveable piston controls fluid delivery, an elastomeric pump holds fluid in a stretchable balloon reservoir, and pressure from the elastic walls of the balloon drives fluid delivery. In a peristaltic pump, a set of rollers pinches down on a length of flexible tubing, pushing fluid forward. In a multi-channel pump, fluids can be delivered from multiple reservoirs at multiple rates. *****

[0215] All references cited herein are incorporated by reference to the same extent as if each individual publication, database entry (e.g., Genbank sequences or GeneID entries), patent application, or patent, was specifically and individually indicated to be incorporated by reference. This statement of incorporation by reference is intended by Applicants torelate to each and every individual publication, database entry (e.g., Genbank sequences or GeneID entries), patent application, or patent, each of which is clearly identified in even if such citation is not immediately adjacent to a dedicated statement of incorporation by reference. The inclusion of dedicated statements of incorporation by reference, if any, within the specification does not in any way weaken this general statement of incorporation by reference. Citation of the references herein is not intended as an admission that the reference is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents.

[0216] The present invention includes embodiments herein wherein any quantities (e.g., mg) or concentrations (e.g., mg / ml or mM) that are specifically mentioned include such quantities or concentrations ± about 10%. Intervals between doses and other time periods specifically mentioned herein also includes such intervals ±1, 2, 3, 4, 5, 6 or 7 days. EXAMPLES

[0217] These examples are intended to exemplify the present disclosure are not a limitation thereof. Compositions and methods, including dosing re...

Claims

AMENDED CLAIMSreceived by the International Bureau on 08 May 2026 ( 08.05.2026) 1. A method fortreating a C5 -associated disease or disorder;treating myasthenia gravis; ortreating generalized myasthenia gravis (gMG) in adult subjects who are anti-acetylcholine receptor (AChR) or anti-low-density lipoprotein receptor-related protein 4 (LRP4) antibody positive; in a subject in need thereof comprising administering to the subject:(i) about 200 mg (±20 mg) of antibody or antigen-binding fragment thereof that binds specifically to C5, wherein the antibody comprises:a HCVR that comprises a HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 98, anda LCVR that comprises a LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106 about every 4 weeks (±7 days),and(ii) about 189 mg of C5 iRNA, wherein the C5 iRNA is Cemdisiran free form which is in a salt form;about 10-13 (± 2) micromoles of C5 iRNA, wherein the C5 iRNA is Cemdisiran salt form; orabout 200 mg of C5 iRNA, wherein the C5 iRNA is Cemdisiran Na+form;wherein the C5 iRNA is administered about once every 28, 29, or 30 days (±1, 2, 3, 4, 5, 6, or 7 days), once a month (± 1, 2, 3, 4, 5, 6 or 7 days), or once every 4 weeks (± 1, 2, 3, 4, 5, 6, or 7 days).

2. A method for treating myasthenia gravis in a subject in need thereof comprising administering, to the subject, one or more of:(a) approximately 567 or 600 mg (±60 mg) doses of C5 iRNA or a molar equivalent amount thereof or about 32-35 or 33.8 (±4) micromoles of C5 iRNA;(b) approximately 600 mg (±60 mg) doses of C5 iRNA or a molar equivalent amount thereof about every 12 weeks (±7 days) or 84 days (±7 days) or 3 months (±7 days) or about every % year;(c) approximately 32-35 or 33.8 (± 4) micromole doses of C5 iRNA about every 12 weeks (±7 days) or 84 days (±7 days) or 3 months (±7 days) or about every % year; or294(d) approximately 567 mg of the free form of a C5 iRNA which is in a salt form; wherein the C5 iRNA is a double-stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand;wherein the antisense strand comprises a region of complementarity including at least 17 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of 5’UAUUAUAAAAAUAUCUUGCUUUU3’ (SEQ ID NO: 364); and wherein the dsRNA agent comprises at least one modified nucleotide.

3. The method of claim 2, comprising administering one or more doses of approximately 32-35 or 33.8 (± 4) micromoles of the C5 iRNA, wherein the C5 iRNA is Cemdisiran salt form.

4. The method of claim 2, comprising administering one or more doses of approximately 32-35 or 33.8 (± 4) micromoles of the C5 iRNA, wherein the C5 iRNA is Cemdisiran salt form, once every 12 weeks (±7 days).

5. The method of claim 2, comprising administering one or more doses of approximately 32-35 or 33.8 micromoles (± 4) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran salt form, once every 84 days (±7 days).

6. The method of claim 2, comprising administering one or more doses of approximately 32-35 or 33.8 micromoles (± 4) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran salt form, once every 3 months (±7 days).

7. The method of claim 2, comprising administering one or more doses of approximately 600 mg (±60 mg) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran salt form.

8. The method of claim 2, comprising administering one or more doses of approximately 600 mg (±60 mg) of C5 iRNA, wherein the C5 iRNA is Cemdisiran salt form, once every 12 weeks (±7 days).

9. The method of claim 2, comprising administering one or more doses of approximately 600 mg (±60 mg) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran salt form once every 84 days (±7 days).

10. The method of claim 2, comprising administering one or more doses of approximately 600 mg (±60 mg) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran salt form once every 3 months (±7 days).

11. The method of claim 2, comprising administering one or more doses of approximately 567 mg (±57 mg) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran free form which is in a salt form.

12. The method of claim 2, comprising administering one or more doses of approximately 567 mg (±57 mg) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran free form which is in a salt form once every 12 weeks (±7 days).

13. The method of claim 2, comprising administering one or more doses of approximately 567 mg (±57 mg) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran free form which is in a salt form once every 84 days (±7 days).

14. The method of claim 2, comprising administering one or more doses of approximately 567 mg (±57 mg) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran free form which is in a salt form once every 3 months (±7 days).

15. The method of claim 2, comprising administering one or more doses of approximately 32-35 or 33.8 (± 4) micromoles of the C5 iRNA, wherein the C5 iRNA is Cemdisiran Na± salt form.

16. The method of claim 2, comprising administering one or more doses of approximately 32-35 or 33.8 (± 4) micromoles of the C5 iRNA, wherein the C5 iRNA is Cemdisiran Na± salt form once every 12 weeks (±7 days).

17. The method of claim 2, comprising administering one or more doses of approximately 32-35 or 33.8 micromoles (± 4) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran Na± salt form once every 84 days (±7 days).

18. The method of claim 2, comprising administering one or more doses of approximately 32-35 or 33.8 micromoles (± 4) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran Na± salt form once every 3 months (±7 days).

19. The method of claim 2, comprising administering one or more doses of approximately 600 mg (±60 mg) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran Na± salt form.

20. The method of claim 2, comprising administering one or more doses of approximately 600 mg (±60 mg) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran Na± salt form once every 12 weeks (±7 days).

21. The method of claim 2, comprising administering one or more doses of approximately 600 mg (±60 mg) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran Na± salt form once every 84 days (±7 days).

22. The method of claim 2, comprising administering one or more doses of approximately 600 mg (±60 mg) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran Na± salt form once every 3 months (±7 days).

23. The method of claim 2, comprising administering one or more doses of approximately 567 mg (±57 mg) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran free form which is in a Na± salt form.

24. The method of claim 2, comprising administering one or more doses of approximately 567 mg (±57 mg) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran free form which is in a Na± salt form once every 12 weeks (±7 days).

25. The method of claim 2, comprising administering one or more doses of approximately 567 mg (±57 mg) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran free form which is in a Na± salt form once every 84 days (±7 days).

26. The method of claim 2, comprising administering one or more doses of approximately 567 mg (±57 mg) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran free form which is in a Na± salt form once every 3 months (±7 days).

27. The method of claim 2, comprising administering one or more doses of an amount of Cemdisiran salt form that is the molar equivalent of 600 mg (±60 mg) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran Na± salt form.

28. The method of claim 2, comprising administering one or more doses of an amount of Cemdisiran salt form that is the molar equivalent of 600 mg (±60 mg) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran Na± salt form once every 12 weeks (±7 days).

29. The method of claim 2, comprising administering one or more doses of an amount of Cemdisiran salt form that is the molar equivalent of 600 mg (±60 mg) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran Na± salt form once every 84 days (±7 days).

30. The method of claim 2, comprising administering one or more doses of an amount of Cemdisiran salt form that is the molar equivalent of 600 mg (±60 mg) of the C5 iRNA, wherein the C5 iRNA is Cemdisiran Na± salt form once every 3 months (±7 days).

31. The method of any one of the preceding claims, wherein the C5 iRNA is Cemdisiran which is administered by subcutaneous injection.

32. The method of any one of the preceding claims, wherein the C5 iRNA is Cemdisiran which is in a pharmaceutical formulation comprising water or saline.

33. The method of any one of the preceding claims, wherein the C5 iRNA is Cemdisiran which is administered from an on-body injection device, a pre-filled syringe or an autoinjector.

34. The method of claim 1, wherein the disease or disorder is myasthenia gravis.

35. The method of any one of claims 2-34, wherein the disease or disorder is generalized myasthenia gravis.

36. The method of any one of the preceding claims, comprising after receiving two or more doses of the C5 iRNA separated by a 12-week interval, administering one or more doses of the C5 iRNA separated by an interval of greater than 12 weeks or less than 12 weeks.

37. The method of any one of the preceding claims, wherein the C5 iRNA is Cemdisiran which is chemically synthesized.

38. The method of any one of the preceding claims, further comprising administering to the subject Pozelimab.

39. The method of any one of the preceding claims, wherein the C5 iRNA is a double-stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand;wherein the sense strand comprises the nucleotide sequence of5'-AAGCAAGAUAUUUUUAUAAUA-3' (SEQ ID NO: 406),and the antisense strand comprises the nucleotide sequence of5'-UAUUAUAAAAAUAUCUUGCUUUU-3' (SEQ ID NO: 369).

40. The method of any one of the preceding claims, wherein the C5 iRNA is a double-stranded ribonucleic acid (dsRNA) agent including a sense strand and an antisense strand;wherein the antisense strand comprises 5'-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3', and the antisense strand comprises 5'-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3'; whereina, g, c and u are 2'-0-methyl (2'-0Me) A, G, C, and U, respectively;Af, Gf, Cf and Uf are 2'-fluoro A, G, C and U, respectively;dT is a deoxy-thymine nucleotide;298s is a phosphorothioate linkage; andwherein the sense strand is conjugated at the 3 '-terminus to the ligand<IMG file=null he=null id=imgf000006_0001 img-content=null img-format=null inline=null orientation=null wi=null>

41. The method of any one of the preceding claims wherein the C5 iRNA is a duplex comprising [(2S,4R)- 1 - { 1 - [(2-acetamido-2-deoxy- P-Dgalactopyranosyl) oxy] - 16, 16-bis( {3 - [(3 -{5-[(2-acetamido-2- deoxy-P-D-galactopyranosyl)oxy]pentanamido}propyl)amino]-3-oxopropoxy } methyl)-5, 11,18-trioxo- 14-oxa-6, 10, 17- triazanonacosan-29-oyl} -4-hydroxypyrrolidin-2-yl]methyl hydrogen all-P-ambo-2'-O-methyl-P-thioadenylyl-(3'— >5')-2'-Omethyl- P-thioadenylyl-(3'^5')-2'-deoxy-2'-fluoroguanylyl- (3'^5')-2'-O-methylcytidylyl-(3'^5')-2'-deoxy-2'-fluoroadenylyl- (3'^5')-2'-O-methyladenylyl-(3'^5')-2'-deoxy-2'-fluoroguanylyl- (3'^5')-2'-O-methyladenylyl-(3'^5')-2'-deoxy-2'-fluorouridylyl- (3'— >5')-2'-deoxy-2'-fluoroadenylyl-(3'^5')-2'-deoxy-2'- fhrorouridylyl-(3'^5')-2'-O-methyluridylyl-(3'— >5')-2'-deoxy-2'- fluorouridylyl-(3'— >5')-2'-O-methyluridylyl-(3'— >5')-2'-Omethyluridylyl-( 3'^5')-2'-deoxy-2'-fluoroadenylyl-(3'^5')-2'-Omethyluridylyl-( 3'^5')-2'-deoxy-2'-fluoroadenylyl-(3'— >5')-2'-Omethyladenylyl-( 3'— >5')-2'-O-methyluridylyl-(3'— >5')-2'-Omethyl-3'-adenylate and all-P-ambo-thymidylyl-(5'^3')- thymidylyl-(5'^3')-2'-O-methyl-P-thiouridylyl-(5'— >3')-2'-Omethyl- P-thiouridylyl-(5'— >3')-2'-O-methyluridylyl-(5'— >3')-2'-Omethyluridylyl-( 5'— >3')-2'-O-methylcytidylyl-(5'— >3')-2'-deoxy-2'- fhroroguanylyl-(5'^3')-2'-O-methyluridylyl-(5'— >3')-2'-deoxy-2'- fluorouridylyl-(5'^3')-2'-O-methylcytidylyl-(5'^3')-2'-deoxy-2'-fluorouridylyl-(5'— >3')-2'-O-methyladenylyl-(5'— >3')-2'-Omethyluridylyl-( 5'— >3')-2'-O-methyladenylyl-(5'— >3')-2'-deoxy-2'- fluoroadenylyl-(5'— >3')-2'-O-methyladenylyl-(5'— >3')-2'-deoxy-2'- fluoroadenylyl-(5'— >3')-2'-O-methyladenylyl-(5'— >3')-2'-Omethyluridylyl-( 5'— >3')-2'-299deoxy-2'-fluoroadenylyl-(5'— >3')-2'-Omethyluridylyl-( 5'^3')-2'-deoxy-2'-fluoro-P-thiouridylyl-(5'— >3')- 2'-deoxy-2'-fluoro-P-thioadenylyl-(5'— >3')-2'-O-methyluridine.

42. The method of any one of the preceding claims, wherein the C5 iRNA is Cemdisiran.

43. The method of claim 42, wherein the Cemdisiran is the Na+ salt form, another salt form or free form.

44. The method of claim 2, wherein the myasthenia gravis is generalized myasthenia gravis, ocular myasthenia gravis, Class I myasthenia gravis, Class II myasthenia gravis, Class Ila myasthenia gravis, Class lib myasthenia gravis, Class III myasthenia gravis, Class Illa myasthenia gravis, Class Illb myasthenia gravis, Class IV myasthenia gravis, Class IVa myasthenia gravis, Class IVb myasthenia gravis, Class V myasthenia gravis, Early-onset myasthenia gravis, Late-onset myasthenia gravis, Thymoma-associated myasthenia gravis, myasthenia gravis with anti-MuSK antibodies, Ocular myasthenia gravis characterized by symptoms from periocular muscles, and / or myasthenia gravis with no detectable AChR and MuSK antibodies.

45. The method of any one of the preceding claims, further comprising diagnosing the subject with myasthenia gravis.

46. The method of any one of the preceding claims, wherein• one week after said administering of the C5 iRNA, the subject serum CH50 decreases by about 33%,• two weeks after said administering of the C5 iRNA, the subject serum CH50 decreases by about 56%,• four weeks after said administering of the C5 iRNA, the subject serum CH50 decreases by about 77%;relative to before the administration.

47. A method for treating myasthenia gravis in a subject in need thereof comprising administering, to the subject, a dose of C5 iRNA wherein the subject serum CH50 decreases by at least about 33, 56, 74, 75 or 77% relative to before treatment initiation.

48. A method for treating myasthenia gravis in a subject in need thereof comprising administering, to the subject, a dose of C5 iRNA wherein the subject serum CH50 decreases by no more than about 70, 71, 72, 73, 74, 75, 76, 77, 78, 79 or 80% relative to before treatment initiation.30049. The method of any one of claims 47-48, wherein the CH50 decreases by 1, 2, 4, 8, 16, 20 or 24 weeks after treatment initiation.

50. The method of any one of the preceding claims, wherein the subject has been diagnosed with myasthenia gravis by a method comprising an electrophysiologic test, a repetitive nerve stimulation (RNS) test, a single-fiber electromyography (SFEMG) test, an Edrophonium (Tensilon) test, an Ice-pack test, Chest computed tomography (CT), and / or Magnetic resonance imaging (MRI).

51. The method of any one of the preceding claims, further comprising diagnosing the subject with myasthenia gravis by a method comprising an electrophysiologic test, a repetitive nerve stimulation (RNS) test, a single-fiber electromyography (SFEMG) test, an Edrophonium (Tensilon) test, an Ice-pack test, Chest computed tomography (CT) and / or Magnetic resonance imaging (MRI).

52. The method of any one of the preceding claims, wherein the subject has myasthenia gravis and one or more criteria selected from: (a) a history of abnormal neuromuscular transmission by repetitive nerve stimulation; (b) a history of abnormal neuromuscular transmission by single-fiber electromyography; (c) a history of a positive anticholinesterase test; and (d) improvement in symptoms with anticholinesterase treatment.

53. The method of any one of the preceding claims, wherein the subject has myasthenia gravis and is positive for anti-acetylcholinesterase (anti-AChR) antibodies or anti-Lipoprotein receptor-related protein 4 (anti-LRP4) antibodies.

54. The method of any one of the preceding claims, further comprising administering to the subject one or more further therapeutic agents.

55. The method of claim 54, wherein the one or more further therapeutic agents is selected from a chemotherapeutic agent, an anti- coagulant, warfarin, aspirin, heparin, phenindione, fondaparinux, idraparinux, a thrombin inhibitor, argatroban, lepirudin, bivalirudin, dabigatran, an anti-inflammatory drug, a corticosteroid, a non-steroidal anti-inflammatory drug (NS AID), an antihypertensive, an angiotensin-converting enzyme inhibitor, an immunosuppressive agent, vincristine, cyclosporine A, methotrexate, a fibrinolytic agent ancrod, E-aminocaproic acid, antiplasmin-al, prostacyclin, defibrotide, a lipid-lowering agent, an inhibitor of301hydroxymethylglutaryl CoA reductase, an anti-CD20 agent, rituximab, an anti-TNFalpha agent, infliximab, an anti-seizure agent, magnesium sulfate, a C3 inhibitor and an anti-thrombotic agent.

56. The method of any one of claims 54-55, wherein the further therapeutic agent is not an anti-CD20 antibody,an anti-FcRN antibody,and / oran androgen deprivation therapy.

57. The method of any one of the preceding claims, which is continued up until or terminated when:• the subject becomes pregnant;• the subject contracts a serious meningococcal infection;• the subject suffers a liver impairment as confirmed by a repeat test on 1 or more of the following criteria and no other reason can be found to explain the following lab abnormalities:- ALT (Alanine aminotransferase) or AST (Aspartate aminotransferase) level >8 ULN (upper limit of normal), or- ALT or AST level >5* ULN for >2 weeks, or- ALT or AST level >3* ULN and total bilirubin >2* ULN (or INR (international normalized ratio) >1.5);and / or• the subject makes a suicide attempt.

58. The method of any one of the preceding claims, where the subject has received one or more of: an anticholinesterase agent, an immunosuppressive drug, a C5 complement inhibitor, a neonatal Fc receptor blocker, prednisone, tacrolimus, rituximab, eculizumab, ravulizumab, efgartigimod, rozanolixizumab, pyridostigmine, plasmapheresis (PLEX) and / or intravenous IgG.

59. The method of any one of the preceding claims, wherein, during said treatment, the subject is monitored for:meningococcal infection;serious infection;sepsis;302embryofetal toxicity;immunogenicity;anti- drug antibody formation;any clinical consequences of large Drug-Target-Drug immune complexes in subjects who switch from Eculizumab or Ravulizumab to Pozelimab;liver transaminase elevations; and / orinjection site reaction;and, optionally, terminating treatment if one or more monitored conditions are observed.

60. The method of any one of the preceding claims, wherein the subject achieves one or more of:• improvement in Myasthenia Gravis- Activities of Daily Living (MG-ADL) total score from baseline to week 24;• improvement in Quantitative Myasthenia Gravis (QMG) score from baseline to week 24;• >3 -point improvement from baseline to week 24 on the MG-ADL;• >5 -point improvement from baseline to week 24 on the QMG;• at least a 2-point MG-ADL improvement on 2 or more consecutive assessments on the MG-ADL spanning 4 or more weeks during the double-blind treatment period (DBTP);• minimal symptom expression (MSE), defined by a score of 0 to 1 on the MG-ADL at week 24;• improvement in the Myasthenia Gravis Composite (MGC) total score from baseline to week 24;• improvement in Myasthenia Gravis Quality of Life (MG-QOL15r) total score from baseline to week 24;• improvement point threshold of >2, 4, 5, 6, 7, 8, 9, or 10 on MG-ADL at week 24;• improvement point threshold of >3, 4, 6, 7, 8, 9, or 10 on QMG at week 24;• reduced incidence and severity of treatment-related adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) in comparison to placebo through week 24;• improvement from baseline in MG-ADL total score by visit;• improvement from baseline in QMG total score by visit;303• reduced time to achievement of a 3 -point improvement from baseline on the MG-ADL in comparison to placebo;• reduced time to achievement of a 5-point improvement from baseline on the QMG in comparison to placebo;• improvement from baseline in the physical performance measures of hand grip strength, supine leg lift, supine head lift, onset of dysarthria, and all timed items of the QMG; • improvement from baseline in individual domains (ocular, bulbar, respiratory, and gross motor / limb impairment) of the MG-ADL;• improvement from baseline in sentinel domains (ocular, facial, bulbar, gross motor, axial, and respiratory) of the QMG;• improvement from baseline in continuous variable measures from the MGC;• improvement from baseline in timed step count, cadence, and other exploratory measures using a wearable device;• increased total MG-ADL score and secondary efficacy endpoints in comparison to placebo through week 48 and through week 120;• improvement in patient-reported fatigue as measured by the Neuro-QoL-Fatigue from baseline to week 24;• improvement from baseline in patient-reported health status as measured by the EuroQol- 5 Dimensions-5 Levels (EQ-5D-5L);• reduced number of myasthenic crises (including impending crises), days of hospitalization due to MG, and / or procedures related to MG from time periods prior to randomization;• improvement from baseline and percent change from baseline in alternative pathway hemolytic activity assay (AH50) and total C5 over time;• reduced use of rescue therapy from baseline to week 24;• increase in corticosteroid dosage from baseline to week 24;• decrease in corticosteroid dosage from baseline to week 24;• reduced incidence and severity of adverse events through the end of study in comparison to placebo;• improvement from baseline in Modified MGFA Post-Intervention Status (MG-PIS) at week 24, week 48, and week 120;304• percent change in serum CH50 by week 1, week 2, week 4, week 12 or week 24 after treatment initiation with Cemdisiran monotherapy (600 mg, q12w) of about -32.62, -55.75, -76.77, -73.53 or -76.61, U / ml, respectively;• a change in MG-ADL total score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Cemdisiran monotherapy (600 mg, q12w) of about -2.50, -3.22, -3.96, -4.31, -4.14, - 4.59 or -4.52, respectively;• an absolute MD-ADL score, by week, 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Cemdisiran (600 mg, q12w), of about 6.52, 5.81, 5.08, 4.70, 4.81, 4.44 or 4.53, respectively;• a change in QMG total score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Cemdisiran monotherapy (600 mg, q12w) of about -1.95, -2.60, -3.91, -3.94, -4.11, - 3.92 or -4.24, respectively;• an absolute MD-ADL score, by week, 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Cemdisiran monotherapy (600 mg, q12w), of about 13.64, 12.98, 11.69, 11.64, 11.45, 11.76 or 11.44, respectively;• a change in MGC score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Cemdisiran monotherapy (600 mg, q12w) of about -4.49, -5.22, -6.55, -7.55, -7.57, -7.69 or -7.78, respectively; and / or• a change in MG-QoL15r score by week 2, 4, 8, 12, 16, 20 or 24 after treatment initiation with Cemdisiran monotherapy (600 mg, q12w) of about -1.43, -2.67, -4.08, -4.31, -4.52, - 4.65 or -4.68, respectively.

61. A method for treating generalized myasthenia gravis (gMG) in an adult patient who is antiacetylcholine receptor (AChR) antibody positive comprising administering 600 mg Cemdisiran sodium form by subcutaneous injection every 12 weeks or 3 months wherein the Cemdisiran Na+ form is represented by the chemical structure:3052? fcja* r S' »' o* »' sr Q- q* <y «* »' s???' <y <r «- or ' [ < S: S [ § s' f> [ § [ § f § I §; »;'?> [ $:’ § [< J | S [ § [ £ s $: § [§ [■§ \ & A-126W Aw A*» At *”» 8* & H** & &w #*» £ws At ^** A*” A t 2584?;;;;;;:: s 5;;8T rfT Uw Um Um Um 5*» V”* M* A*** V® At« At Am At Am Um At Um Uf At UmAt, < St, Uf « g‘«F fiborjsssssfoskiss ALH-&2S43 Am, Cm, Um ® z-SA&s mmmxwrn&m rfT s-;<IMG file=null he=null id=imgf000013_0001 img-content=null img-format=null inline=null orientation=null wi=null>wherein the Cemdisiran Na+ form is in an aqueous pharmaceutical formulation in one or more vials.

62. The method of claim 61, wherein the aqueous pharmaceutical formulation comprises the Cemdisiran Na+ form, Water for Injection, USP and sodium hydroxide and / or phosphoric acid, pH~7.0.

63. The method of claim 62, wherein the aqueous pharmaceutical formulation comprising the Cemdisiran Na+ form is in a sterile, preservative-free, clear, colorless-to-yellow solution supplied in glass vials, free from visible particulates.

64. The method of any one of claim 63, wherein each vial contains 200 mg Cemdisiran Na+ form in 1 mL with Water for Injection, USP and sodium hydroxide and / or phosphoric acid, pH ~7.0.

65. The method of any one of claims 61-64, wherein the Cemdisiran Na+ form is administered in 2 subcutaneous injections with a volume of 1.5 ml each or 3 subcutaneous injections with 1 ml each.

66. The method of any one of claims 61-65, wherein the full 600 mg Cemdisiran Na+ form dose is in three separate vials.30667. The method of any one of claims 61-66, wherein the vials are refrigerated, comprising remove the vials from refrigeration and allowing the vials to sit for at least 15 minutes at 20°C to 25°C (68°F to 77°F) before use.

68. The method of any one of claims 61-67, comprising inspecting the aqueous composition, visually, for particulate matter and discoloration prior to administration.

69. The method of any one of claims 61-68, comprising discarding the aqueous pharmaceutical formulation if it is cloudy, discolored or contains particulate matter.

70. The method of any one of claims 61-69, comprising gently swirling the vials comprising the aqueous pharmaceutical formulation in an upright position but not shaking the vials.

71. The method of any one of claims 61-70, comprising subcutaneously administering the Cemdisiran Na+ form with a 25 gauge to 27 gauge, % inch or 5 / 8-inch stainless steel needle with Luer-Lok.

72. The method of any one of claims 61-71, comprising withdrawing 3 ml of the aqueous pharmaceutical formulation, comprising the Cemdisiran Na+ form, with a 21 gauge withdrawal needle with Luer-Lok, equally into two syringes each containing 1.5 mL.

73. The method of claim 72, comprising changing the withdrawal needle on each syringe to an injection needle fulfilling the following criteria: 25 gauge to 27 gauge and 1 / 2 or 5 / 8-inch stainless steel needle with Luer-Lok.

74. The method of any one of claims 61-73, comprising administering 2 subcutaneous injections consecutively, each at a different injection site, into the thigh, back of the upper arm, or abdomen, on opposite sides or at least 2 cm apart, but not injecting into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.

75. The method of any one of claims 61-74, comprising observing the subject for 30 minutes following completion of the first 600 mg Cemdisiran Na+ form dose.

76. The method of any one of claims 61-75, comprising administering the subcutaneous injection within 4 hours of preparation.

77. The method of any one of claims 61-76, for treating generalized myasthenia gravis (gMG) in an adult patient who is anti-acetylcholine receptor (AChR) antibody positive comprising:• inspecting three vials, each containing an aqueous pharmaceutical formulation comprising 200 mg Cemdisiran Na+ form in 1 mL with Water for Injection, USP and sodium307hydroxide and / or phosphoric acid, pH to ~7.0, visually for particulate matter and discoloration (other than colorless-to-yellow solution) prior to administration and discarding any vial if the formulation is cloudy, discolored or contains particulate matter;• gently swirling the vials in an upright position;• withdrawing the required injection volume of formulation from the vials into an appropriately sized syringe using a 21 gauge withdrawal needle, with Luer-Lok;• changing the syringe needle to an injection needle fulfilling the following criteria: 25 gauge to 27 gauge and 1 / 2 or 5 / 8-inch stainless steel needle with Luer-Lok; and• within 4 hours, administering 600 mg Cemdisiran Na+ form in one or more subcutaneous injections, each at a different injection site, into the thigh, back of the upper arm, or abdomen, on opposite sides or at least 2 cm apart, but not inject into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact; every 3 months;wherein the Cemdisiran Na+ form is represented by the chemical structure:0* A': U: 6 C3 A-1251^7 Am Am Gf Cm At Am Gf Am Ut At Um Ut Um Um At Um AS Am Um AmUm Um Um Um Cm Uf Um Uf Cm Uf Am W Am At Am At Am Um At Um Ut At UmAt, U? » Z'? ALM4®«43 Am j Cm j Um »<IMG file=null he=null id=imgf000015_0001 img-content=null img-format=null inline=null orientation=null wi=null>308

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