Anti-C5 antibody / C5 iRNA combination drug and combination therapy

Abstract

The present disclosure provides a combination comprising an antibody that specifically binds to C5 and a C5 iRNA, which is a glycoconjugate containing a ligand with a terminal N-acetylgalactosamine (GalNAc) residue and / or N-acetylglucosamine (GlcNAc) residue. A method for reducing degradation of glycoconjugate RNA by the beta-hexosaminidase enzyme is also provided. The present disclosure also includes a method for treating or preventing a C5-related disease or disorder by administering one or more doses of an anti-C5 antibody or antigen-binding fragment thereof in combination with one or more doses of a C5 iRNA; preferably, the anti-C5 antibody or fragment and the C5 iRNA are in a combination. The present disclosure also includes a dosing regimen for treating a C5-related disease or disorder with a combination of an anti-C5 antibody and a C5 iRNA in either a treatment-naive subject or a subject switching from a previous C5 inhibitor therapy.

Description

[Technical Field]

[0001] This application is a continuation of U.S. Provisional Patent Application No. 63 / 381,450, filed October 28, 2022, U.S. Provisional Patent Application No. 63 / 382,087, filed November 2, 2022, U.S. Provisional Patent Application No. 63 / 382,264, filed November 3, 2022, U.S. Provisional Patent Application No. 63 / 383,442, filed November 11, 2022, U.S. Provisional Patent Application No. 63 / 385,909, filed December 2, 2022, U.S. Provisional Patent Application No. 63 / 385,909, filed December 9, 2022, and U.S. Provisional Patent Application No. 63 / 385,909, filed December 11, 2022. This application claims the benefit of U.S. Patent Application No. 63 / 386,787, U.S. Provisional Patent Application No. 63 / 495,767, filed April 12, 2023, U.S. Provisional Patent Application No. 63 / 498,112, filed April 25, 2023, U.S. Provisional Patent Application No. 63 / 505,011, filed May 30, 2023, and Taiwanese Patent Application No. 112141079, filed October 26, 2023, each of which is incorporated by reference herein in its entirety.

[0002] The Sequence Listing of the present application is submitted electronically as an ASCII sequence listing with the file name "11282seqlist", a creation date of October 28, 2022, and a size of 112 Kb. This submitted Sequence Listing is a part of the present specification and is incorporated herein by reference in its entirety.

[0003] Field The field of the disclosure relates to methods for stabilizing RNA in compositions comprising beta-hexosaminidase, as well as pharmaceutical combinations and therapies comprising RNA and antibodies or antigen-binding fragments thereof. [Background technology]

[0004] Complement component C5 is a target in several rare diseases, including paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome, neuromyelitis optica, and generalized myasthenia gravis. For example, uncontrolled complement activation in patients with PNH leads to the primary clinical manifestation of chronic hemolysis as well as an increased risk of thromboembolism, ultimately leading to target organ damage and death.

[0005] Complement 5 is a validated target in the treatment of complement-mediated diseases such as generalized myasthenia gravis (gMG), as evidenced by the approval of eculizumab (Ecu) for the treatment of patients with gMG. Monotherapy with the anti-C5 antibody, pozelimab, has been shown to be effective in blocking C5 activity in another disease (paroxysmal nocturnal hemoglobinuria [PNH]) that is highly sensitive to complement-mediated effects.

[0006] A significant degree of complement inhibition is required to achieve complete and uninterrupted inhibition of C5 throughout the C5 inhibitor dosing interval, resulting in rapid and significant disease suppression. Current C5 inhibitor monotherapy does not achieve sufficient levels of inhibition.

[0007] C5-targeting therapies for PNH, such as eculizumab and ravulizumab (Soliris and Ultomiris, Alexion Pharmaceuticals), have demonstrated efficacy. However, in rare cases, eculizumab and ravulizumab are ineffective due to polymorphic variations in the gene encoding C5, which prevent eculizumab or ravulizumab from binding to the C5 protein (Non-Patent Document 1). In addition, treatment is laborious because the drugs are generally administered chronically via IV infusion Q2W or Q8W, respectively, to maintain efficacy. Furthermore, it has been reported that as many as 20% of PNH patients receiving eculizumab treatment at the labeled maintenance dose (900 mg Q2W IV) require a significant increase in dose or dosing frequency due to breakthrough hemolysis secondary to incomplete C5 inhibition (Non-Patent Document 2) (Non-Patent Document 3). Regulatory approval of ravulizumab specifies a Q8W IV dosing frequency for the drug, but patients still experience some degree of hemolytic breakthrough (Non-Patent Document 4).

[0008] A regimen of 30 mg / kg IV loading dose followed by 800 mg SC once weekly was effective in reducing serum LDH to <1.5 × ULN in all patients and <1.0 ULN in the majority of patients in a phase 2 study (R3918-PNH-1852) in complement-naive PNH patients. However, this regimen represents a relatively high dose for the biologic agent.

[0009] The requirement for such high anti-C5 mAb doses is driven by the need for 100% inhibition achieved by complete target engagement (Non-Patent Document 2), and C5 levels are high; to achieve 100% inhibition on a population basis, inter- and intra-patient variability in C5 concentrations and instances of enhanced complement activation (which may occur with concomitant illnesses) must be taken into account.

[0010] Semdisiran is a synthetic small interfering ribonucleic acid (siRNA) that targets C5 messenger ribonucleic acid (mRNA) covalently linked to a triantennary N-acetylgalactosamine (GalNAc) ligand. Semdisiran is designed to suppress hepatic production of C5 protein when administered by SC injection. C5 is encoded by a single gene and is primarily expressed and secreted by hepatocytes. Through the ribonucleic acid (RNA) interference pathway, semdisiran induces degradation of C5 mRNA by RNase, thereby reducing C5 protein production and ultimately resulting in reduced circulating C5 protein levels. Semdisiran monotherapy has proven ineffective as a monotherapy treatment for PNH. (Non-Patent Document 5).

[0011] Combining semdisiran with recombinant antibodies as a combined drug that can be conveniently administered by common injection increases the risk of contaminants from the antibody degrading the semdisiran molecule.

[0012] Furthermore, treating patients suffering from conditions such as PNH increases the likelihood that a significant proportion of such patients are either currently receiving or have recently received another anti-C5 antibody and therefore have detectable blood levels of such an antibody. Experiments suggest that antibodies with the sequences of eculizumab and pozeliimab can, together, form high molecular weight heteromeric complexes with C5, and therefore pose a risk of such complex formation in vivo when both antibodies are present in the circulation. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] U.S. Patent Application Publication No. 2009 / 0220508 [Non-patent literature]

[0014] [Non-Patent Document 1] Nishimuraら, Genetic variants in C5 and poor response to Eculizumab.N Engl J Med 2014;370(7):632~639 pages [Non-licensed Document 2] Peffault de Latour, Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving Eculizumab. Blood 2015;125(5):775~783 pages [Non-licensed Document 3] Hillmen, Long-term safety and efficacy of sustained Eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 2013;162(1):62~73 [Non-licensed Document 4] Lee, Ravulizumab (ALXN1210) vs Eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood 2019;133(6): pages 530~539 [Non-licensed Document 5] Badri, Clin Pharmacokinet.2021;60(3):365-78-Epub October 14, 2020 [Non-licensed Document 6] Roth, The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria. Blood 2020;135(12):912~920 pages [Non-licensed Document 7] Roth et al., The SMART Anti-hC5 Antibody (SKY59 / RO7112689) Shows Good Safety and Efficacy in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). Blood 2018a;132(Supplementary Appendix 1):535 [Non-patent document 8] van der Laken et al., Imaging and serum analysis of immune complex formation of radiolabelled infliximab and anti-infliximab in responders and non-responders to therapy for rheumatoid arthritis. Ann Rheum Dis 2007;66(2):253-256 [Non-Patent Document 9] Wener et al., Immune Complexes in Systemic Lupus Erythematosus (Chapter 19). Systemic Lupus Erythematosus. Academic Press; 2010 [Non-Patent Document 10] Scheinberg et al., Phase III Randomized, Multicenter, Open-Label Commodore 1 Trial: Comparison of Crovalimab vs Eculizumab in Complement Inhibitor-Experienced Patients With Paroxysmal Nocturnal Hemoglobinuria, European Hematology Association, Frankfurt, Germany; Virtual (Hybrid) June 9, 2023 Summary of the Invention [Problem to be solved by the invention]

[0015] Previous clinical studies have reported adverse reactions (e.g., serum sickness-like reactions, skin rash) when switching from one C5 mAb to another, specifically, when switching from eculizumab to clovalimab (SKY59 / RO7112689 / RG6107), a therapeutic C5 antibody that binds to a different epitope than eculizumab. These reactions were thought to be due to the formation of DTD immune complexes containing C5 and two C5 antibodies (Non-Patent Document 6; Non-Patent Document 7; Patent Document 1). The size of such immune complexes has been linked to the occurrence of adverse events. For example, in a study in which anti-drug antibody (ADA)-positive patients were injected with infliximab, an antibody with specificity for a target unrelated to the complement system, severe infusion reactions were observed in one patient when immune complexes larger than 1000 kDa (antibodies >6) were detected, but not in two patients when only smaller immune complexes (<1000 kDa) were detected (Non-Patent Document 8). This suggests that larger DTD immune complexes are more likely to be associated with adverse events. Furthermore, based on extrapolation from other autoimmune disease states such as systemic lupus erythematosus, where small immune complexes are inefficient in terms of complement activation and interaction with Fc gamma receptors and are not deposited in tissues (9), small DTD immune complexes are not expected to be clinically significant.

[0016] Reducing the likelihood of such adverse events is difficult. The COMMODORE-1 clinical trial had two arms in which patients were treated with the anti-C5 antibody crovalimab or eculizumab during the 24-week main treatment period. After the main treatment period, patients on eculizumab had the option to switch to crovalimab treatment. Sixteen percent of patients switching from eculizumab to crovalimab experienced type 3 hypersensitivity (T3H) reactions. T3H reactions and infusion-related reactions were related to large DTD complex formation and subcutaneous administration, respectively, which were exclusive to the crovalimab arm and therefore not to the eculizumab arm. (Non-Patent Document 10) [Means for solving the problem]

[0017] The present invention includes a combination comprising a C5 iRNA conjugated to a ligand comprising one or more terminal amino sugars, e.g., N-acetylgalactosamine (GalNAc) and / or N-acetylglucosamine (GlcNAc) residues; an antibody (anti-C5) or antigen-binding fragment thereof that specifically binds to C5 isolated from a mammalian host cell; a pH greater than or less than about 6 (e.g., about 6.5); and a pharmaceutically acceptable carrier.For example, in an embodiment of the present invention, the combination comprises C5 iRNA; an antibody or antigen-binding fragment thereof that specifically binds to C5; a buffer (e.g., a histidine-based buffer, a citrate-based buffer, a phosphate-based buffer, and / or an acetate-based buffer, e.g., at a concentration of about 10 to 35, 35 to 45, 20 to 50, 20, 25, 30, 35, 40, 45, or 50 mM); a stabilizer (e.g., a polyol, sugar, trehalose, sorbitol, mannitol, taurine, propanesulfonic acid, L-proline, sucrose, glycerin, threitol, maltitol, polyethylene glycol, PEG-14 ... glycol (PEG), and / or PEG 3350; e.g., at a concentration of about 0.8 to 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); viscosity-reducing agents; and nonionic surfactants (e.g., polyoxyethylene glycol alkyl ethers; glucoside alkyl ethers; polyoxyethylene glycol octylphenol ethers; polyoxyethylene glycol alkyl ethers; Alkylphenol ether; Glycerin alkyl ester; Polyoxyethylene glycol sorbitan alkyl ester; Sorbitan alkyl ester; Polypropylene glycol block copolymer; Polyethylene glycol block copolymer; Polysorbate, octaethylene glycol monododecyl ether; Pentaethylene glycol monododecyl ether; Polyoxypropylene glycol alkyl ether; Decyl glucoside, lauryl glucoside, octyl glucoside; Triton X- 100; nonoxynol-9; glyceryl laurate; cocamide MEA, cocamide DEA, dodecyldimethylamine oxide; poloxamer; polyethoxylated tallowamine (POEA); polysorbate-20 (PS20) and / or polysorbate-80 (PS80); e.g., at a concentration of about 0.025, 0.05, 0.075, 0.1, 0.125, 0.15, 0.175% (w / v)), and a pH greater than or less than about 6 (e.g., in the range of 6.0 to 0.5 or greater) (e.g., about 6.5).

[0018] In embodiments of the present invention, viscosity-lowering agents (e.g., dicarboxylic acids, inorganic salts, esters of citric acid, xanthines, adipic acid; NaCl; caffeine; triethyl citrate, amino acids, (D- or L-) arginine, L-arginine HCl, (D- or L-) alanine, (D- or L-) histidine, proline, (D- or L-) valine, glycine, (D- or L-) serine, (D- or L-) phenylalanine, (D- or L-) lysine, and (D- or L-) glutamic acid) may be used. The viscosity-lowering agent may be present in a concentration of about 5 mM to about 100 mM (e.g., 50-75 mM), such as about 20-140 mM (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). The viscosity-lowering agent, when an amino acid, may be the L-enantiomer or D-enantiomer thereof. The viscosity-lowering agent may also be the conjugate base of an acid specified herein, or a salt thereof. In embodiments of the invention, the combination is characterized by an anti-C5 antibody or antigen-binding fragment purity of about 96% or greater as assessed by size exclusion chromatography after about one month at 2-8°C; and / or a C5 iRNA purity of about 94% or greater as assessed by anion exchange chromatography after about one month at 2-8°C. In an embodiment of the invention, the combination has a 1:1 milligram per milliliter concentration ratio of C5 iRNA and anti-C5 antibody or antigen-binding fragment; and optionally a viscosity-lowering agent that is arginine, adipate, NaCl, lysine, aspartic acid, proline, histidine, caffeine, phenylalanine, and / or triethyl citrate, e.g., at a concentration of about 75 mM arginine, 75 mM adipate, 75 mM NaCl, 75 mM lysine, 75 mM aspartic acid, 75 mM proline, 50 mM histidine (if the buffer is histidine-based, the total histidine concentration of the combination is 50 mM), 50 mM caffeine, 50 mM phenylalanine, and / or 75 mM triethyl citrate.In an embodiment of the invention, the combination has a 1:2 milliliter per milligram concentration ratio of C5 iRNA and anti-C5 antibody or antigen-binding fragment; and optionally a viscosity-lowering agent, such as arginine, adipate, NaCl, lysine, and / or aspartic acid, at a concentration of, for example, about 75 mM arginine, 75 mM adipate, 75 mM NaCl, 75 mM lysine, and / or 75 mM aspartic acid.

[0019] In an embodiment of the present invention, the combination comprises an antibody (anti-C5) or an antigen-binding fragment thereof that specifically binds to C5, comprising: a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 18, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 26; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 34, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 42; a light chain variable region (LCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 50, a heavy chain variable region (HCVR) comprising CDR2 and HCDR3, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of said LCVR comprising the amino acid sequence set forth in SEQ ID NO: 58; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of said HCVR comprising the amino acid sequence set forth in SEQ ID NO: 66, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of said LCVR comprising the amino acid sequence set forth in SEQ ID NO: 74; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of said HCVR comprising the amino acid sequence set forth in SEQ ID NO: 82, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of said LCVR comprising the amino acid sequence set forth in SEQ ID NO: 90; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of said HCVR comprising the amino acid sequence set forth in SEQ ID NO: 98, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of said LCVR comprising the amino acid sequence set forth in SEQ ID NO: 106;a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 98, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 114; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 122, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 106; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 98, and a light chain variable region (LCVR) comprising LCDR1, LCDR2 and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 130; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 138, and a light chain variable region (LCVR) comprising LCDR1, LCDR2 and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 106; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 146, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 106; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 122, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 130; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2 and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 146, and a light chain variable region (LCVR) comprising LCDR1, LCDR2 and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 114; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2 and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 146, and a light chain variable region (LCVR) comprising LCDR1, LCDR2 and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 130;a heavy chain variable region (HCVR) comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 138, and a light chain variable region (LCVR) comprising LCDR1, LCDR2 and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 130; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 154, and a light chain variable region (LCVR) comprising LCDR1, LCDR2 and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 162; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 170; a light chain variable region (LCVR) comprising LCDR1, LCDR2 and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 178; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2 and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 186, and a light chain variable region (LCVR) comprising LCDR1, LCDR2 and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 194; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2 and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 202, and a light chain variable region (LCVR) comprising LCDR1, LCDR2 and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 210; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 218, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 226; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 234, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 242; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 250, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 258; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 266, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 258; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 274, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 282; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 290, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 298; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 306, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 314; a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 322, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 330;and / or a heavy chain variable region (HCVR) comprising HCDR1, HCDR2 and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 338, and a light chain variable region (LCVR) comprising LCDR1, LCDR2 and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 346. For example, in an embodiment of the present invention, an antibody (anti-C5) or an antigen-binding fragment thereof that specifically binds to C5 comprises a heavy chain variable region comprising HCDR1 having the amino acid sequence set forth in SEQ ID NO: 4, HCDR2 having the amino acid sequence set forth in SEQ ID NO: 6, and HCDR3 having the amino acid sequence set forth in SEQ ID NO: 8, and a light chain variable region comprising LCDR1 having the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 having the amino acid sequence set forth in SEQ ID NO: 14, and LCDR3 having the amino acid sequence set forth in SEQ ID NO: 16; a heavy chain variable region comprising HCDR1 having the amino acid sequence set forth in SEQ ID NO: 20, HCDR2 having the amino acid sequence set forth in SEQ ID NO: 22, and HCDR3 having the amino acid sequence set forth in SEQ ID NO: 24, and an LCDR1 having the amino acid sequence set forth in SEQ ID NO: 28, HCDR2 having the amino acid sequence set forth in SEQ ID NO: 30, and an HCDR3 having the amino acid sequence set forth in SEQ ID NO: 32. a light chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 36, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 46, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48; a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 52, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 54, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 62, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64;a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 68, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 70, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 76, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 78, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 80; a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 84, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 86, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 88, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 92, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 94, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 100, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 102, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 104, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 108, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 110, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112; a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 100, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 102, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 104, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 118, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 120; a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 126, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 128, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 108, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 110, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112; a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 100, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 102, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 104, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 132, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 134, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136; a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 140, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 142, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 144, and a light chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 108, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 110, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112; a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 148, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 108, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 110, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112; a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 126, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 128, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 132, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 134, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136;a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 148, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 118, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 120; a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 148, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 132, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 134, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136; a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 140, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 142, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 144, and a light chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 132, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 134, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136; a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 156, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 158, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 160, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 164, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 166, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 168; a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 172, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 174, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 176, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 180, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 182, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 184;a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 188, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 190, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 192, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 196, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 198, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 200; a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 204, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 206, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 208, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 212, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 214, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 216; a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 220, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 222, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 224, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 228, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 230, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 232; a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 236, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 238, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 240, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 244, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 246, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 248; a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 252, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 254, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 256; and a light chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 260, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 262, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 264; a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 268, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 270, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 272, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 260, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 262, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 264; a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 276, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 278, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 280, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 284, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 286, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 288;a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 292, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 294, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 296, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 300, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 302, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 304; a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 308, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 310, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 312, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 316, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 318, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 320; a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 324, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 326, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 328, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 332, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 334, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 336; or a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 340, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 342, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 344, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 348, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 350, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 352. In an embodiment of the present invention, an antibody (anti-C5) or antigen-binding fragment thereof that specifically binds to C5 comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 2, a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 10; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 18, a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 26; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 34, a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 42;a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 50, a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 58; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 66, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 74; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:82, a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:90; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:98, a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:106; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:98, a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:114; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:122, a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:106; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:98, a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:130; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:138, a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:106; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:146, a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:106; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:122, a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:130; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:146, a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:146 a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 114; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 146, a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 130; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 138, a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 130; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 154, a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 162; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 170, a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 178; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 186, a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 194; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 202, a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 210; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 218, a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 226; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 234, a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 242;a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 250, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 258; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 266, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 258; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 274, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 282; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 290, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 298; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 306, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 314; a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 322, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 330; or a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 338, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 346. For example, in embodiments of the invention, the combination specifically binds to C5 and is about 90 to about 275 mg / ml; or 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;17 5;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, or 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 of the antibody (anti-C5) or antigen-binding fragment;

[0020] In an embodiment of the invention, the combination agent includes a C5 iRNA, a double-stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises a region of complementarity comprising at least 17 contiguous nucleotides that differ by at most 3 nucleotides from the nucleotide sequence 5'-UAUUAUAAAAAUAUCUUGCUUUU-3' (SEQ ID NO: 364), and the dsRNA agent comprises at least one modified nucleotide. In an embodiment of the invention, the combination agent comprises a C5 iRNA, which is a double-stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3' (SEQ ID NO: 406) and the antisense strand comprises 5'-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3' (SEQ ID NO: 369), wherein a, g, c, and u are 2'-O-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 the sense strand has a ligand at the 3' end.

[0021] [ka] In embodiments of the invention, the combination comprises a C5 iRNA that is a semdisilane and one or more of semdisilane impurity 1, semdisilane impurity 2, and semdisilane impurity 3 discussed herein. In embodiments of the invention, the C5 iRNA is conjugated to about 20-100, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 130, 140, 150, 155, 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, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490 and / or 400 mg / ml.

[0022] In an embodiment of the invention, the combination is characterized by a viscosity of <30 cP at 20°C; and / or an osmolality of 240-450 mOsm / kg; for example, a viscosity of ≦20 cP at 20°C.

[0023] The present invention includes a combination comprising any of the following: double-stranded C5 iRNA; and an anti-C5 antibody or an antigen-binding fragment thereof; a pH above (at least 0.5) or below 6.0 (e.g., about 6.5); C5 iRNA, an anti-C5 antibody or an antigen-binding fragment thereof; buffering agents, viscosity reducers, stabilizers, and nonionic surfactants; C5 iRNA, an anti-C5 antibody or an antigen-binding fragment thereof; histidine-based buffers, L-arginine, stabilizers, and nonionic surfactants; C5 iRNA, an anti-C5 antibody or an antigen-binding fragment thereof; histidine-based buffers, L-arginine, a sugar or polyol, and nonionic surfactants; Semudisilane, Pozelimab, histidine-based buffers, L-arginine, stabilizers, and nonionic surfactants, pH about 6.5; Semudisilane, Pozelimab, histidine-based buffers, L-arginine, sucrose, and Polysorbate 80, pH about 6.5; 100(±10)mg / mL C5 iRNA, 100 (±10) mg / mL anti-C5 antibody or its antigen-binding fragment, 50(±5)mM viscosity-reducing agent, 10(±1)mM buffer, 1.0(±0.1)% stabilizer, 0.075 (±0.0075)% nonionic surfactant, pH about 6.5; 75(±7.5)mg / mL C5 iRNA, 150 (± 15) mg / mL anti-C5 antibody or its antigen-binding fragment, 75 (±7.5) mM viscosity-reducing agent, 15(±1.5)mM buffer, 1.5(±0.15)% stabilizer, 0.1125 (±0.01125)% nonionic surfactant, pH about 6.5; 50(±5)mg / mL C5 iRNA, 100 (±10) mg / mL anti-C5 antibody or its antigen-binding fragment, 75mM (±7.5) viscosity reducing agent, 15(±1.5)mM buffer, 1.5(±0.15)% stabilizer, 0.1125(±0.01125)% nonionic surfactant; pH about 6.5; 50(±5)mg / mL C5 iRNA, 100 (±10) mg / mL anti-C5 antibody or its antigen-binding fragment, 75 (±7.5) mM viscosity-reducing agent, 35(±3.5)mM buffer, 1.5(±0.15)% stabilizer, 0.1125 (±0.01125)% nonionic surfactant, pH about 6.5; 100(±10)mg / mL C5 iRNA, 100 (±10) mg / mL anti-C5 antibody or its antigen-binding fragment, 50(±5)mM viscosity-reducing agent, 30(±3)mM buffer, 1(±0.1)% stabilizer, 0.075 (±0.0075)% nonionic surfactant, pH about 6.5; 50(±5)mg / mL C5 iRNA, 100 (±10) mg / mL anti-C5 antibody or its antigen-binding fragment, 90(±9)mM viscosity-reducing agent, 30(±3)mM buffer, 1(±0.1)% stabilizer, 0.075 (±0.0075)% nonionic surfactant, pH about 6.5; Approximately 100 mg / mL semdisilane, Approximately 100 mg / mL pozelimab, Approximately 50 mM L-arginine, Approximately 30 mM histidine-based buffer, Approximately 1% (w / v) sucrose, Approximately 0.075% (w / v) PS80, pH about 6.5; Approximately 50 mg / mL semdisilane, Approximately 100 mg / mL pozelimab, Approximately 90mM L-arginine, Approximately 30 mM histidine-based buffer, Approximately 1% (w / v) sucrose, Approximately 0.075% (w / v) PS80, pH about 6.5; Approximately 100 mg / mL semdisilane, Approximately 100 mg / mL pozelimab, Approximately 50 mM L-arginine, Approximately 10 mM histidine-based buffer, Approximately 1.0% sucrose, Approximately 0.075%PS80, pH about 6.5; Approximately 75 mg / mL semdisilane, Approximately 150 mg / mL pozelimab, approximately 75mM L-arginine, Approximately 15mM histidine-based buffer, Approximately 1.5% sucrose, Approximately 0.1125%PS80, pH about 6.5; Approximately 50 mg / mL semdisilane, Approximately 100 mg / mL pozelimab, approximately 75mM L-arginine, Approximately 15mM histidine-based buffer, Approximately 1.5% sucrose, Approximately 0.1125%PS80; pH about 6.5; Approximately 50 mg / mL semdisilane, Approximately 100 mg / mL pozelimab, approximately 75mM L-arginine, Approximately 35 mM histidine-based buffer, Approximately 1.5% sucrose, Approximately 0.1125%PS80, pH about 6.5; Approximately 100 mg / mL semdisilane, Approximately 100 mg / mL pozelimab, Approximately 50 mM L-arginine, Approximately 30 mM histidine-based buffer, Approximately 1% sucrose, Approximately 0.075%PS80, pH about 6.5; Approximately 50 mg / mL semdisilane, Approximately 100 mg / mL pozelimab, Approximately 90mM L-arginine, Approximately 30 mM histidine-based buffer, Approximately 1% sucrose, Approximately 0.075%PS80, pH about 6.5; optionally further comprising GalNAc and / or GlcNAc; Approximately 120mg / mL C5 iRNA, about 120 mg / mL anti-C5 antibody or antigen-binding fragment thereof; Viscosity reducers; Approximately 15 mM histidine, pH about 6.2; Approximately 75mg / mL C5 iRNA, about 150 mg / mL anti-C5 antibody or antigen-binding fragment thereof; Viscosity reducers; Approximately 15 mM histidine, pH about 6.2; Approximately 120mg / mL C5 iRNA, about 120 mg / mL anti-C5 antibody or antigen-binding fragment thereof; Approximately 15 mM histidine, pH about 6.2; Approximately 75mg / mL C5 iRNA, about 150 mg / mL anti-C5 antibody or antigen-binding fragment thereof; Approximately 15 mM histidine, pH about 6.2; Approximately 120 mg / mL semdisilane, Approximately 120 mg / mL pozelimab, Approximately 15 mM histidine, pH about 6.2; Approximately 120 mg / mL semdisilane, Approximately 120 mg / mL pozelimab, Approximately 75 mM arginine, Approximately 15 mM histidine, pH about 6.2; Approximately 120 mg / mL semdisilane, Approximately 120 mg / mL pozelimab, approximately 75 mM adipate, Approximately 15 mM histidine, pH about 6.2; Approximately 120 mg / mL semdisilane, Approximately 120 mg / mL pozelimab, Approximately 75 mM NaCl, Approximately 15 mM histidine, pH about 6.2; Approximately 120 mg / mL semdisilane, Approximately 120 mg / mL pozelimab, Approximately 75 mM lysine, Approximately 15 mM histidine, pH about 6.2; Approximately 120 mg / mL semdisilane, Approximately 120 mg / mL pozelimab, approximately 75 mM aspartic acid, Approximately 15 mM histidine, pH about 6.2; Approximately 120 mg / mL semdisilane, Approximately 120 mg / mL pozelimab, Approximately 75 mM proline, Approximately 15 mM histidine, pH about 6.2; Approximately 120 mg / mL semdisilane, Approximately 120 mg / mL pozelimab, Approximately 50 mM histidine, pH about 6.2; Approximately 120 mg / mL semdisilane, Approximately 120 mg / mL pozelimab, Approximately 50mM caffeine, Approximately 15 mM histidine, pH about 6.2; Approximately 120 mg / mL semdisilane, Approximately 120 mg / mL pozelimab, Approximately 50 mM phenylalanine, Approximately 15 mM histidine, pH approx. 6.2 Approximately 120 mg / mL semdisilane, Approximately 120 mg / mL pozelimab, Approximately 50 mM triethyl citrate, Approximately 15 mM histidine, pH about 6.2; Approximately 75 mg / mL semdisilane, Approximately 150 mg / mL pozelimab, Approximately 15 mM histidine, pH about 6.2; Approximately 75 mg / mL semdisilane, Approximately 150 mg / mL pozelimab, Approximately 75 mM arginine, Approximately 15 mM histidine, pH about 6.2; Approximately 75 mg / mL semdisilane, Approximately 150 mg / mL pozelimab, approximately 75 mM adipate, Approximately 15 mM histidine, pH about 6.2; Approximately 75 mg / mL semdisilane, Approximately 150 mg / mL pozelimab, Approximately 75 mM NaCl, Approximately 15 mM histidine, pH about 6.2; Approximately 75 mg / mL semdisilane, Approximately 150 mg / mL pozelimab, Approximately 75 mM lysine, Approximately 15 mM histidine, pH about 6.2; or Approximately 75 mg / mL semdisilane, Approximately 150 mg / mL pozelimab, approximately 75 mM aspartic acid, Approximately 15 mM histidine, pH approx. 6.2.

[0024] The present invention includes a combination comprising a C5 iRNA that is semdisilane; an antibody or antigen-binding fragment that is pozelimab; a viscosity-lowering agent that is L-arginine; a buffer that is a histidine-based buffer; a stabilizer that is sucrose; a non-ionic surfactant that is polysorbate 80; and a pH of about 6.5.

[0025] In an embodiment of the invention, the combination comprises a C5 iRNA conjugated to a ligand comprising one or more terminal N-acetylgalactosamine (GalNAc) or N-acetylglucosamine (GlcNAc) residues; a pH within the range of about 6 to about 0.5 or greater; and / or a pH of about 6.5.

[0026] In embodiments of the invention, the combination is characterized by one or more of the following: comprising beta-hexosaminidase; comprising an antibody of an antigen-binding fragment thereof expressed and isolated from a mammalian host cell containing beta-hexosaminidase; comprising an antibody of an antigen-binding fragment thereof expressed and isolated from a Chinese hamster ovary cell; containing at most about 1% semdisilane impurity 1 relative to total semdisilane; containing at least about 80% semdisilane relative to total semdisilane after 2 years of storage at 2-8°C; containing at least about 91% semdisilane prior to storage (at t=0). have greater than about 80% semdisilane after 1 year, 1.5 years, 2 years, 2.5 years, or 3 years of storage at 2-8°C; have about 80% to about 91% semdisilane; have a semdisilane purity (%) of about 90.5% at t=0 by dIPRP; 91.1% after 1 month of storage at 2-8°C; 90.8% after 3 months of storage at 2-8°C; 90% after 6 months of storage at 2-8°C; 88.8% after 9 months of storage at 2-8°C; 88.7% after 12 months of storage at 2-8°C; 89% after 18 months of storage at 2-8°C; and / or 89.4% after 24 months of storage at 2-8°C. The dIPRP shows semdisilane purity (%) of approximately 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 89.4% after 24 months storage at 2-8°C. The dIPRP shows approximately 90.5% at t=0, 90.2% after 1 month storage at 25°C and 60% RH, and 89.4% after 3 months storage at 25°C and 60% RH. The purity (%) of the semdisilane single chain is 7.8%; 85.1% after 6 months of storage at 25°C and 60% RH; 90% after 0.5 months of storage at 40°C and 75% RH; 88.9% after 1 month of storage at 40°C and 75% RH; and 85.8% after 3 months of storage at 40°C and 75% RH. dIPRP shows approximately 90.8% at t=0; 88.8% after 1 month of storage at 25°C and 60% RH; 85.9% after 3 months of storage at 25°C and 60% RH; 82.3% after 6 months of storage at 25°C and 60% RH; and 88% after 0.5 months of storage at 40°C and 75% RH.The purity (%) of the semdisilane is approximately 90.9% at t=0 by dIPRP; 87.3% after 1 month storage at 40°C and 75% RH; 82.3% after 3 months storage at 40°C and 75% RH; approximately 90.9% after 1 month storage at 25°C and 60% RH; approximately 90.1% after 3 months storage at 25°C and 60% RH; approximately 90.9% after 6 months storage at 25°C and 60% RH; approximately 89.9% after 0.5 months storage at 40°C and 75% RH; and approximately 89% after 1 month storage at 40°C and 75% RH. 0.7%; and / or approximately 89.5% purity (%) of semdisilane after 3 months storage at 40°C, 75% RH; approximately 90.8% at t=0 by dIPRP; approximately 90.2% after 1 month storage at 25°C, 60% RH; approximately 90.8% after 3 months storage at 25°C, 60% RH; approximately 90.3% after 6 months storage at 25°C, 60% RH; approximately 89.5% after 0.5 months storage at 40°C, 75% RH; approximately 89.6% after 1 month storage at 40°C, 75% RH; and / or approximately 90.8% after 6 months storage at 25°C, 60% RH by dIPRP. The purity (%) of the semdisilane is approximately 89.1% after 3 months of storage at 60% RH; approximately 90.5% by dIPRP at t=0; approximately 89.9% after 1 month of storage at 25°C and 60% RH; approximately 90.8% after 3 months of storage at 25°C and 60% RH; approximately 90.4% after 6 months of storage at 25°C and 60% RH; approximately 90.1% after 0.5 months of storage at 40°C and 75% RH; approximately 89.6% after 1 month of storage at 40°C and 75% RH; and / or approximately 89.9% after 3 months of storage at 40°C and 75% RH. and / or exhibits a semdisilane purity (%) of about 91.1% at t=0; about 90% after 1 month of storage at 25°C and 60% RH; about 91% after 3 months of storage at 25°C and 60% RH; about 90.7% after 6 months of storage at 25°C and 60% RH; about 90% after 0.5 months of storage at 40°C and 75% RH; about 89.7% after 1 month of storage at 40°C and 75% RH; and / or exhibits a semdisilane purity (%) of about 89.9% after 3 months of storage at 40°C and 75% RH by dIPRP. In embodiments of the invention, the combination is characterized by one or more of the following: a molar ratio of at most about 2.1 parts per million (ppm) beta-hexosaminidase to antibody or antigen-binding fragment; containing at most about 0.170 micrograms / ml beta-hexosaminidase;0.04 micrograms / ml of beta-hexosaminidase; and / or about 0.04; 0.05; 0.06; 0.06; 0.0605; 0.0605; 0.0605; 0.063; 0.07; 0.07; 0.0765; 0.078; 0.08; 0.14; 0.141; 0.15; 0.1525; 0.166; or 0.17 micrograms / ml of beta-hexosaminidase; or at most any of such concentrations.

[0027] The present invention also includes methods for administering the combinations provided herein to a subject, comprising introducing the combination into the subject's body, for example, by injecting the combination into the subject's body; for example, by intramuscular, subcutaneous, intravenous, intraocular, and / or intravitreal injection.

[0028] The present invention relates to the treatment of a C5-related disease or disorder in a subject in need thereof (e.g., disorders of inappropriate or undesired complement activation; hemodialysis complications; pulmonary diseases or disorders; neurological disorders; parasitic diseases; post-ischemic reperfusion states; proteinuric kidney disease; renal disorders; adult respiratory distress syndrome; adult respiratory distress syndrome (ARDS); age-related macular degeneration (AMD); allergies; Alport syndrome; Alzheimer's disease; autoimmune diseases or disorders; immune complex disorders; inflammatory disorders; eye diseases; organic pneumoconiosis; blood disorder thrombosis and protein-losing enteropathy); asthma; asthma; atheroma. atherosclerosis; bronchoconstriction; bullous pemphigoid; C3 glomerulopathy; capillary leak syndrome; CHAPLE disease (CD55 deficiency with complement hyperactivation); chemical injury due to irritant gases and / or chemicals; chronic obstructive pulmonary disease (COPD); complement activation due to burns; 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; dry AMD; dyspnea; emphysema; epilepsy; fibrosing pneumoconiosis; geographic atrophy (GA); glomerulopathy; Goodpasture's syndrome; Guillain-Barré syndrome; hemolytic anemia; hemoptysis; hereditary angioedema; hyperacute allograft rejection; hypersensitivity pneumonitis; immune complex-associated inflammation; inflammatory diseases; autoimmune inflammation; hereditary CD59 deficiency; injury due to inert dust and / or minerals; 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; ocular neovascularization; Parkinson's disease; pneumonia; progressive renal failure; psoriasis; lung Also included are methods for treating or preventing embolism and infarction; pulmonary fibrosis; pulmonary vasculitis; renal ischemia; renal ischemia-reperfusion injury; rheumatoid arthritis; schizophrenia; SLE nephritis; smoke poisoning; stroke; systemic inflammatory response in post-pump syndrome due to cardiopulmonary or renal bypass surgery; systemic lupus erythematosus (SLE); burns; traumatic brain injury; uveitis; vasculitis; wet AMD; paroxysmal nocturnal hemoglobinuria (PNH); and / or xenograft rejection, comprising administering to a subject a therapeutically effective amount of a combination drug described herein.In embodiments of the invention, the subject is administered one or more additional therapeutic agents, such as androgens, anticoagulants, anti-inflammatory agents, antihypertensive agents, immunosuppressants, fibrinolytic agents, lipid-lowering agents, anti-CD20 agents, anti-TNF alpha agents, C3 inhibitors, antithrombotic agents, corticosteroids, nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, inhibitors of hydroxymethylglutaryl CoA reductase, anticonvulsants, warfarin, aspirin, heparin, phenindione, fondaparinux, idraparinux; and thrombin inhibitors, such as argatroban, lepirudin, bivalirudin, dabigatran; vincristine, cyclosporine A, methotrexate, ancrod, epsilon-aminocaproic acid, antiplasmin-a1, prostacyclin, defibrotide, rituximab, infliximab, and / or magnesium sulfate.

[0029] The present invention provides a method for increasing RNA stability or reducing beta-hexosaminidase activity in a composition comprising RNA conjugated to a ligand containing one or more terminal N-acetylgalactosamine (GalNAc) and / or N-acetylglucosamine (GlcNAc) residues; and beta-hexosaminidase, the method comprising (i) adding GalNAc and / or GlcNAc to the composition and / or (ii) raising or lowering the pH of the composition from about 6; for example, the composition comprises RNA that is a C5 iRNA; an antibody or antigen-binding fragment thereof expressed and isolated from a mammalian host cell (e.g., a Chinese hamster ovary (CHO) cell) containing beta-hexosaminidase; and optionally, a buffer; a viscosity-reducing agent; a stabilizer; and a non-ionic surfactant. In an embodiment of the present invention, the RNA is double-stranded RNA, optionally containing one or two nucleotide overhangs on one or both ends; for example, the RNA is chemically synthesized.

[0030] The invention includes a method for making a combination comprising combining an RNAi and an antibody or antigen-binding fragment, and (i) adding GalNAc to the combination and / or (ii) adjusting the pH of the combination to about 6 or less. The product of the method, the combination, forms part of the invention.

[0031] The present invention provides a method for administering to a subject an antibody that specifically binds to C5 (anti-C5) or its antigen-binding fragment in combination with a C5 iRNA, the method comprising introducing the antibody or fragment and the iRNA into the body of the subject. In an embodiment of the present invention, the antibody or fragment and the iRNA are introduced by subcutaneous injection or intravenous infusion of a combination containing both the antibody or fragment and the iRNA; or by subcutaneous injection or intravenous infusion of separate formulations each containing either the antibody or fragment or the iRNA.

[0032] The present invention provides methods for treating or preventing a C5-related disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds C5, in combination with a C5 iRNA, either in a single combination or in separate formulations. In embodiments of the invention, the method further comprises administering to the subject one or more initial intravenous or subcutaneous loading doses of the antibody or antigen-binding fragment and / or iRNA. For example, in embodiments of the invention, the method comprises administering one or more doses of both: (1) about 400 mg of an anti-C5 antibody or antigen-binding fragment; and (2) about 200 mg of a C5 iRNA; e.g., about 400 mg of the anti-C5 antibody or antigen-binding fragment is administered about every 2, 3, or 4 weeks (± 3 days); and about 200 mg of the C5 iRNA is administered about every 4 weeks (± 3 days). In an embodiment of the invention, the method comprises: (i) about 400 mg of anti-C5 antibody or antigen-binding fragment subcutaneously about every 2 weeks (± 3, 4, 5, 6, or 7 days) and about 200 mg of C5 iRNA subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days); (ii) about 400 mg of anti-C5 antibody or antigen-binding fragment subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days) and about 200 mg of C5 iRNA subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days); (iii) an intravenous loading dose of anti-C5 antibody or antigen-binding fragment, about 400 mg of anti-C5 antibody or antigen-binding fragment subcutaneously, and about 200 mg of C5 iRNA subcutaneously; then, about every 4 weeks (± 3, 4, 5, 6, or 7 days) thereafter, about 400 mg of anti-C5 antibody or antigen-binding fragment subcutaneously and about 200 mg of C5 iRNA subcutaneously. (iv) an intravenous loading dose of about 30 or 60 mg / kg of anti-C5 antibody or antigen-binding fragment, about 400 mg of anti-C5 antibody or antigen-binding fragment subcutaneously, and about 200 mg of C5 iRNA subcutaneously; then, about every 4 weeks (± 3, 4, 5, 6, or 7 days) thereafter, about 400 mg of anti-C5 antibody or antigen-binding fragment subcutaneously and about 200 mg of C5 iRNA subcutaneously;(v) an intravenous loading dose of about 30 or 60 mg / kg of an anti-C5 antibody or antigen-binding fragment, followed by one or more weekly subcutaneous doses of about 800 mg of an anti-C5 antibody or antigen-binding fragment, then, after an optional one-week period, about 400 mg of an anti-C5 antibody or antigen-binding fragment subcutaneously and about 200 mg of C5 iRNA subcutaneously; then about every four weeks (± 3, 4, 5, 6, or 7 days) thereafter, about 400 mg of an anti-C5 antibody or antigen-binding fragment subcutaneously and about 200 mg of C5 iRNA subcutaneously; (vi)(a) a dose of eculizumab intravenously and C5 (b) a dose of eculizumab by about 14 days (± 3, 4, 5, 6, or 7 days) later; and (c) about 14 or 15 days later, an anti-C5 antibody or antigen-binding fragment dose of 30 or 60 mg / kg body weight intravenously, about 400 mg of the anti-C5 antibody or antigen-binding fragment subcutaneously, and about 200 mg of C5 iRNA subcutaneously, and (d) about every 4 weeks (± 3, 4, 5, 6, or 7 days) thereafter, doses of about 400 mg of the anti-C5 antibody or antigen-binding fragment subcutaneously and about 200 mg of C5 iRNA subcutaneously; or (vii) (a) an about 200 mg SC dose of C5 iRNA; (b) about 28 days (± 3, 4, 5, 6, or 7 days) later, 30 or 60 mg / kg of the anti-C5 antibody or antigen-binding fragment an IV loading dose, a 400 mg SC dose of the anti-C5 antibody or antigen-binding fragment, and a 200 mg SC dose of the C5 iRNA; and (c) about 29 days (± 3, 4, 5, 6, or 7 days) later and about every 4 weeks (± 3, 4, 5, 6, or 7 days) thereafter, an about 400 mg SC dose of the anti-C5 antibody or antigen-binding fragment, and about 200 mg SC dose of the C5 iRNA; or (viii) (a) about 4 weeks (± 3, 4, 5, 6, or 7 days) after administration of ravulizumab, an about 200 mg SC dose of the C5 iRNA; (b) about 28 days (± 3, 4, 5, 6, or 7 days) later, an IV loading dose of 30 or 60 mg / kg of the anti-C5 antibody or antigen-binding fragment, a 400 mg SC dose of the anti-C5 antibody or antigen-binding fragment, and a 200 mg SC dose of the C5 iRNA;and (c) administering a 400 mg SC dose of an anti-C5 antibody or antigen-binding fragment and a 200 mg SC dose of C5 iRNA about 29 days (± 3, 4, 5, 6, or 7 days) later and about every 4 weeks (± 3, 4, 5, 6, or 7 days) thereafter. In embodiments of the invention, the anti-C5 antibody or antigen-binding fragment and the C5 iRNA are administered subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days) as a single injection of a combination comprising the anti-C5 antibody or antigen-binding fragment and the C5 iRNA; about every 4 weeks (± 3, 4, 5, 6, or 7 days), an additional injection of the anti-C5 antibody or antigen-binding fragment is administered subcutaneously; about every 4 weeks (± 3, 4, 5, 6, or 7 days), the anti-C5 antibody or antigen-binding fragment and the C5 iRNA are administered subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days) as separate injections of separate formulations, one comprising the anti-C5 antibody or antigen-binding fragment and the other comprising the C5 iRNA; about every 4 weeks (± 3, 4, 5, 6, or 7 days), an additional injection of the anti-C5 antibody or antigen-binding fragment is administered subcutaneously; a single injection of a combination comprising an anti-C5 antibody or antigen-binding fragment and an iRNA is administered subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days); an additional injection of an anti-C5 antibody or antigen-binding fragment is administered subcutaneously about every 2 weeks (± 3, 4, 5, 6, or 7 days); and / or the anti-C5 antibody or antigen-binding fragment and the C5 iRNA are administered subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days) in separate injections of separate formulations, one comprising the anti-C5 antibody or antigen-binding fragment and the other comprising the C5 iRNA; an additional injection of an anti-C5 antibody or antigen-binding fragment is administered subcutaneously about every 2 weeks (± 3, 4, 5, 6, or 7 days);

[0033] In an embodiment of the invention, the subject has previously received ravulizumab (e.g., administered intravenously or subcutaneously) and / or eculizumab (e.g., administered intravenously, e.g., 900 mg intravenously) therapy; and / or pozelimuab monotherapy. In an embodiment of the invention, the subject is complement inhibitor naive.

[0034] The present invention provides a method for treating or preventing a C5-related disease or disorder in a subject in need thereof, comprising administering to the subject therapeutically effective amounts of an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA, wherein the subject has previously received eculizumab, and administering to the subject (i) a dose of eculizumab intravenously and 200 mg of C5 iRNA subcutaneously; (ii) a dose of eculizumab by about 14 days (± 3, 4, 5, 6, or 7 days) later (about day 15); (iii) about 14 or 15 days (± 3, 4, 5, 6, or 7 days) later (about day 29), an anti-C5 antibody or antigen-binding fragment at a dose of about 60 mg / kg body weight intravenously, about 400 mg of the anti-C5 antibody or antigen-binding fragment subcutaneously, and C5 iRNA. and (iv) starting about 28 days (± 3, 4, 5, 6, or 7 days) later (about day 57), and about every 28 days (± 3, 4, 5, 6, or 7 days) thereafter, about 400 mg of an anti-C5 antibody or antigen-binding fragment and about 200 mg of C5 iRNA are administered subcutaneously.

[0035] The present invention provides a method for treating or preventing a C5-related disease or disorder in a subject in need thereof, comprising administering to the subject therapeutically effective amounts of an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA, wherein the subject has previously received ravulizumab, and administering to the subject: (i) about 28 days (± 3, 4, 5, 6, or 7 days) after the last administration of ravulizumab, an about 200 mg SC dose of C5 iRNA; (ii) about 28 days (± 3, 4, 5, 6, or 7 days) after the last administration of ravulizumab (about day 29), an about 60 mg / kg IV dose of the anti-C5 antibody or antigen-binding fragment, an about 400 mg SC dose of the anti-C5 antibody or antigen-binding fragment, and about 200 mg SC dose of C5 iRNA. (iii) starting about 28 days (± 3, 4, 5, 6, or 7 days) later (about day 57), about a 400 mg SC dose of anti-C5 antibody or antigen-binding fragment and about a 200 mg SC dose of C5 iRNA are administered about every 28 days (± 3, 4, 5, 6, or 7 days) thereafter.

[0036] The present invention provides methods for treating or preventing a C5-related disease or disorder in a subject in need thereof, comprising administering to the subject therapeutically effective amounts of an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA, wherein the subject has not previously received or has not recently received complement inhibitor treatment, and the subject is administered: (i) on about day 1, an intravenous dose of about 30 mg / kg of the anti-C5 antibody or antigen-binding fragment, an about 400 mg subcutaneous (SC) dose of the antibody or fragment, and about 200 mg SC dose of the C5 iRNA; and (ii) starting about 28 days later (± 3, 4, 5, 6, or 7 days), about every 4 weeks (± 3, 4, 5, 6, or 7 days) thereafter, about 400 mg SC of the anti-C5 antibody or antigen-binding fragment, and about 200 mg SC of the C5 iRNA.

[0037] The present invention provides a method for treating or preventing a C5-related disease or disorder in a subject in need thereof, wherein the subject has previously received anti-C5 antibody or antigen-binding fragment monotherapy, and the method comprises administering to the subject therapeutically effective amounts of: (i) about a 400 mg SC dose of the anti-C5 antibody or antigen-binding fragment, and about a 200 mg SC dose of the C5 iRNA, starting about 7-8 (±3 days) days after the final dose of the anti-C5 antibody or antigen-binding fragment monotherapy or when the next dose of the monotherapy is scheduled, and about every 4 weeks (±3, 4, 5, 6, or 7 days) thereafter; or (ii) about a 400 mg SC dose of the anti-C5 antibody or antigen-binding fragment, starting about 7-8 (±3 days) days after the final dose of the anti-C5 antibody or antigen-binding fragment monotherapy or when the next dose of the monotherapy is scheduled, followed by another dose about every 2 weeks (±3, 4, 5, 6, or 7 days); and C5 The method includes administering about a 200 mg SC dose of iRNA, followed by another dose about every 4 weeks (± 3, 4, 5, 6, or 7 days).

[0038] The present invention provides a method for treating or preventing a C5-related disease or disorder in a subject in need thereof, the subject having received one or more doses of a non-competitive anti-C5 antibody or antigen-binding fragment (N / C Ab), comprising administering to the subject (e.g., the subject has detectable blood levels of the N / C Ab when treatment is initiated) a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment thereof in combination with a C5 iRNA: (1) a dose of C5 iRNA and a non-competitive antibody or fragment on the day a dose of the N / C Ab is scheduled; (2) a subsequent dose of the non-competitive anti-C5 antibody or antigen-binding fragment on the day such dose is scheduled; (3) approximately 1-2 half-lives of the N / C Ab, followed by a 60 mg / kg IV loading dose of pozeliman 400 mg SC and semdisiran 200 mg SC; or (4) starting 4 weeks thereafter, pozeliman 400 mg SC Q4W and semdisiran 200 mg SC. or (1) a dose of C5 iRNA one to two half-lives after the last dose of the non-competing anti-C5 antibody or antigen-binding fragment; (2) about one to two half-lives after the last dose of N / C Ab, a 60 mg / kg IV loading dose of pozelimuab, 400 mg SC pozelimuab, and 200 mg SC semdisiran; or (3) starting four weeks later, administering pozelimuab 400 mg SC Q4W and 200 mg SC semdisiran. In an embodiment of the invention, the C5 iRNA is semdisiran; the anti-C5 antibody or antigen-binding fragment is pozelimuab; the non-competing C5 antibody or antigen-binding fragment is eculizumab; the non-competing C5 antibody or antigen-binding fragment is ravulizumab; the half-life of the non-competing antibody is about 11 days; and / or the half-life of the non-competing antibody is about 32 days.

[0039] In an embodiment of the invention, during treatment, the subject achieves or achieves and maintains any one or more of the following: hemoglobin stabilization; not receiving red blood cell transfusions; not having a decrease in hemoglobin of ≥ 2 g / dL; not experiencing breakthrough hemolysis; blood CH50 levels are completely suppressed compared to baseline (at 0 kIU / L) before treatment and / or during any breakthrough hemolytic event; absence of treatment-emergent adverse events; improvement in fatigue compared to before treatment; improvement in FACIT-Fatigue score > 5 points compared to before treatment; improvement in the European Organization for Research and Treatment of Cancer Physical Functioning Score: Quality of Life questionnaire; Core 30 items (EORTC) compared to before treatment. Improvement in GHS / QoL (General Health Status / Quality of Life Scale (GHS)) compared to pretreatment; decrease in lactate dehydrogenase (LDH) levels compared to pretreatment; achievement of LDH ≤ 1.5 x upper limit of normal (ULN) compared to pretreatment; achievement and maintenance of LDH ≤ 1.0 x ULN; decrease in blood bilirubin levels compared to pretreatment; reduction in reticulocyte count compared to pretreatment; decrease in alternative pathway hemolytic activity assay (AH50) compared to pretreatment; PNH compared to pretreatment Reduction in red blood cells and / or granulocytes; improvement in fatigue, shortness of breath, muscle weakness, headache, abdominal pain, back / leg pain, chest discomfort, difficulty sleeping, difficulty thinking clearly, and / or difficulty swallowing compared to before treatment; improvement in kidney function compared to before treatment as measured by estimated glomerular filtration rate (eGFR); reduction in free hemoglobin in the blood compared to before treatment; reduction in total C5 blood levels compared to before treatment; reduction in PNH clone size compared to before treatment; and / or increase in haptoglobin levels compared to before treatment.

[0040] In an embodiment of the invention, the C5-related disease or disorder is a disorder of inappropriate or unwanted complement activation; hemodialysis complications; pulmonary disease or disorder; neurological disorders; parasitic diseases; post-ischemic reperfusion states; proteinuric kidney disease; renal disorders; adult respiratory distress syndrome; adult respiratory distress syndrome (ARDS); age-related macular degeneration (AMD); allergies; Alport syndrome; Alzheimer's disease; autoimmune diseases or; immune complex disorders; inflammatory disorders; eye diseases; organic pneumoconiosis; blood disorders thrombosis and protein-losing enteropathy); asthma; Atherosclerosis; bronchoconstriction; bullous pemphigoid; C3 glomerulopathy; capillary leak syndrome; CHAPLE disease (CD55 deficiency with complement hyperactivation); chemical injury due to irritant gases and / or chemicals; chronic obstructive pulmonary disease (COPD); complement activation due to burns; 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; dry AMD; dyspnea; emphysema; epilepsy; fibroid Adult pneumoconiosis; geographic atrophy (GA); glomerulopathy; Goodpasture's syndrome; Guillain-Barré syndrome; hemolytic anemia; hemoptysis; hereditary angioedema; hyperacute allograft rejection; hypersensitivity pneumonitis; immune complex-associated inflammation; inflammatory diseases; autoimmune inflammation; hereditary CD59 deficiency; injury due to inert dust and / or minerals; 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 embolism; neuromyelitis optica; ocular neovascularization; Parkinson's disease; pneumonia; progressive renal failure; psoriasis; pulmonary embolism and infarction; pulmonary fibrosis; pulmonary vasculitis; renal ischemia; renal ischemia-reperfusion injury; rheumatoid arthritis; schizophrenia; SLE nephritis; smoke poisoning; stroke; systemic inflammatory response in post-pump syndrome due to cardiopulmonary or renal bypass surgery; systemic lupus erythematosus (SLE); burns; traumatic brain injury; uveitis; vasculitis; wet AMD; paroxysmal nocturnal hemoglobinuria (PNH); and / or xenograft rejection.

[0041] In an embodiment of the invention, the C5 iRNA and the anti-C5 antibody or antigen-binding fragment are combined into a combination drug, and both the antibody or fragment and the C5 iRNA are administered by a single injection of the combination drug.

[0042] In an embodiment of the invention, the combination has a pH of about 6.5. In an embodiment of the invention, the C5 iRNA and the anti-C5 antibody or antigen-binding fragment are combined into a combination comprising 100 mg / ml semdisiran and 100 mg / ml pozellimab; or 50 mg / ml semdisiran and 100 mg / ml pozellimab.

[0043] In an embodiment of the invention, the combination comprises semdisilane; pozelimab expressed and isolated from a mammalian host cell containing beta-hexosaminidase; a buffer; a viscosity-lowering agent; a stabilizer; a non-ionic surfactant, and an optional viscosity-lowering agent, at a pH of about 6.5.

[0044] In an embodiment of the invention, the subcutaneous injection is performed with a pre-filled syringe or an auto-injector.

[0045] In an embodiment of the invention, the subject suffers from aplastic anemia and / or myelodysplastic syndrome.

[0046] In embodiments of the invention, the subject has previously received subcutaneous pozelimab 400 mg and subcutaneous cemdisirane 200 mg, or embodiments of the invention relate to administering to the subject prior to (optionally any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days prior to), after, or during these administrations: further comprising administering: one or more doses of subcutaneous or intravenous pozeliman; one or more 400 mg subcutaneous doses of pozeliman; one or more doses of subcutaneous or intravenous anti-C5 antibody or antigen-binding fragment; one or more doses of subcutaneous or intravenous eculizumab; one or more doses of subcutaneous or intravenous ravulizumab; one or more doses of subcutaneous or intravenous semdisirane; subcutaneous or intravenous C5 one or more doses of iRNA; one or more subcutaneous doses of 800 mg pozeliimab; one or more subcutaneous doses of 800 mg anti-C5 antibody or antigen-binding fragment; one or more intravenous doses of 30 mg / kg body weight pozeliimab; one or more intravenous doses of 30 mg / kg body weight anti-C5 antibody or antigen-binding fragment; one or more intravenous doses of about 60 mg / kg body weight pozeliimab; one or more intravenous doses of about 60 mg / kg body weight anti-C5 antibody or antigen-binding fragment; one or more subcutaneous doses of about 800 mg pozeliimab; one or more subcutaneous doses of about 800 mg of a C5 antibody or antigen-binding fragment; one intravenous dose of about 60 mg / kg of body weight of pozeliimab followed by one or more subcutaneous doses of about 800 mg of pozeliimab; one intravenous dose of about 60 mg / kg of body weight of an anti-C5 antibody or antigen-binding fragment followed by one or more subcutaneous doses of about 800 mg of the anti-C5 antibody or antigen-binding fragment; one or more doses of ≥ 300, ≥ 600, ≥ 900, or ≥ 1200 mg of eculizumab intravenously; one or more doses of 200 mg of semdisiran subcutaneously; and / or one or more doses of 200 mg of C5 iRNA subcutaneously.

[0047] In embodiments of the invention, intravenous administration of the anti-C5 antibody or antigen-binding fragment is separated from subcutaneous administration of the anti-C5 antibody or antigen-binding fragment or C5 iRNA by about 30 minutes; subcutaneous administration of the anti-C5 antibody or antigen-binding fragment and C5 iRNA is followed by an observation period of about 30 minutes, 1 hour, or 2 hours; and / or subcutaneous administration of the C5 iRNA is followed by an observation period of about 30 minutes, 1 hour, or 2 hours.

[0048] In an embodiment of the invention, if a subject exhibits one or more of the following criteria: breakthrough hemolysis not attributable to a complement activation state; and / or an LDH increase of ≧2×ULN attributable to a complement activation state, the subject receives consolidation treatment further comprising one or more 30 mg / kg IV doses of an anti-C5 antibody or antigen-binding fragment.

[0049] In an embodiment of the invention, if a subject exhibits one or more of the following criteria: breakthrough hemolysis not attributable to a complement activation state; and / or an LDH increase of ≥ 2 x ULN attributable to a complement activation state, the subject undergoes consolidation treatment, including: (1) if the patient received a treatment regimen comprising about 400 mg of an anti-C5 antibody or antigen-binding fragment administered subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days) and about 200 mg of C5 iRNA administered subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days); administer a single 30 mg / kg IV dose of the anti-C5 antibody or antigen-binding fragment on the day of consolidation, and, starting on the day of consolidation, administer about 400 mg of an anti-C5 antibody or antigen-binding fragment administered subcutaneously about every 2 weeks (± 3, 4, 5, 6, or 7 days) and about 200 mg of C5 iRNA administered subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days); or (2) if the subject received a treatment regimen comprising about 400 mg of an anti-C5 antibody or antigen-binding fragment administered subcutaneously about every two weeks (± 3, 4, 5, 6, or 7 days) and about 200 mg of C5 iRNA administered subcutaneously about every four weeks (± 3, 4, 5, 6, or 7 days); administer a single 30 mg / kg IV dose of anti-C5 antibody or antigen-binding fragment on the day of consolidation, and start again on the day of consolidation with a treatment regimen comprising about 400 mg of an anti-C5 antibody or antigen-binding fragment administered subcutaneously about every two weeks (± 3, 4, 5, 6, or 7 days) and about 200 mg of C5 iRNA administered subcutaneously about every four weeks (± 3, 4, 5, 6, or 7 days).

[0050] In embodiments of the invention, the anti-C5 antibody or antigen-binding fragment or pozelimab is expressed in a mammalian host cell (e.g., a Chinese hamster ovary cell), and the iRNA or semdisirane is chemically synthesized.

[0051] In embodiments of the invention, the anti-C5 antibody or antigen-binding fragment and C5 iRNA are combined into a combination comprising: at most about 2.1 parts per million (ppm) molar ratio of beta-hexosaminidase to antibody or antigen-binding fragment; at most about 0.170 micrograms / ml of beta-hexosaminidase, at most about 0.04 micrograms / ml of beta-hexosaminidase; and / or at most 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 of beta-hexosaminidase; or at most any of such concentrations.

[0052] In an embodiment of the present invention, the anti-C5 antibody or antigen-binding fragment thereof is one of the following: (1) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10; (2) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 18, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 26; (3) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 34, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 42; (4) a light chain variable region (LCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 50. (5) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 58; (6) a light chain variable region (LCVR) comprising HCDR1, HCDR2, and HCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 66; and (7) a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 82. (7) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 98, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 106;(8) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 98, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 114; (9) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 122, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 106; (10) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 98, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 130; (11) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 138, and (12) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 146, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 106; (13) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 122, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 130; (14) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 146, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 114;(15) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 146, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 130; (16) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 138, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 130; (17) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 154, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 162; (18) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 170, (19) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 186 and a light chain variable region (LCVR) comprising LCDR1, LCDR2 and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 194; (20) a heavy chain variable region (HCVR) comprising the amino acid sequence set forth in SEQ ID NO: 202 and LCDR1, LCDR2 and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 202; (21) a heavy chain variable region (HCVR) comprising CDR1, HCDR2, and HCDR3, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 210; (22) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 218, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 226;(22) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 234, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 242; (23) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 250, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 258; (24) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 266, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 258; (25) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 274, (26) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 290, and a light chain variable region (LCVR) comprising LCDR1, LCDR2 and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 298; (27) a heavy chain variable region (HCVR) comprising the amino acid sequence set forth in SEQ ID NO: 306, and a light chain variable region (LCVR) comprising LCDR1, LCDR2 and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 306; (28) a heavy chain variable region (HCVR) comprising CDR1, HCDR2, and HCDR3, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 314; (29) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 322, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 330;and / or (29) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 338, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 346;

[0053] In embodiments of the invention, a C5 iRNA comprises an RNA strand complementary to an mRNA transcribed from the C5 gene sense strand DNA sequence AAGCAAGATATTTTTATAATA (nucleotides 782-802 of SEQ ID NO: 360). In embodiments of the invention, a 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 comprising at least 17 contiguous nucleotides that differs by at most 3 nucleotides from the nucleotide sequence 5'-UAUUAUAAAAAUAUCUUGCUUUU-3' (SEQ ID NO: 364), and 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 comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3' (SEQ ID NO: 406) and the antisense strand comprises 5'-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3' (SEQ ID NO: 369), wherein a, g, c, and u are 2'-O-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 the sense strand has a ligand at the 3' end.

[0054] [ka] It is conjugated to

[0055] In embodiments of the invention, the C5 iRNA and the antibody or antigen-binding fragment thereof that specifically binds to C5 are in a combination as specifically described herein.

[0056] In an embodiment of the invention, the C5 iRNA and the anti-C5 antibody or antigen-binding fragment thereof are in a single combination, and the single combination, when administered subcutaneously, is administered in one or more (e.g., two) injections of the combination.

[0057] Preferably, the C5 iRNA is semdisiran; and / or the anti-C5 antibody or antigen-binding fragment thereof is pozelimab.

[0058] Summary: Complement inhibitor naive: Day 1: Pozelimab at a single loading dose of 30 mg / kg intravenously (IV) and 400 mg subcutaneously (SC) and semdisirane 200 mg SC (combined maintenance dose); starting on Day 29: Pozelimab 400 mg SC every 4 weeks (q4W) and semdisirane 200 mg SC q4W (e.g., in a semdisirane / pozelimab combination). Switching from pozelimuab monotherapy to pozelimuab plus semdisirane combination therapy: Subjects begin receiving pozelimuab 400 mg SC every 4 weeks (q4W) and semdisirane 200 mg SC q4W (final dose of pozelimuab monotherapy) or when the next dose of pozelimuab monotherapy is scheduled; Switching from eculizumab therapy to pozelimuab plus semdisirane combination therapy: Day 1 (the day of the subject's scheduled eculizumab administration): semdisirane 200 mg SC and eculizumab ≥ 900 mg IV (subject's usual dose); for subjects receiving eculizumab q14w (labeled dosing regimen), Day 15: labeled eculizumab dose [for subjects receiving eculizumab more frequently than q14w: dose patients within 2 days of their usual scheduled dose; Day 29 (or when the next eculizumab is scheduled (if receiving eculizumab doses more frequent than q14w) or 2 weeks later): pozelimuab 60 mg / kg IV loading dose, plus pozelimuab 400 mg SC and semdisiran 200 mg SC; and starting on Day 57 (or 4 weeks later): pozelimuab 400 mg SC and semdisiran 200 mg SC q4W; Switching from ravulizumab therapy to pozelimuab + semdisiran combination therapy: Day 1 (4 weeks after the last dose of ravulizumab): semdisiran 200 mg SC; day 29 or 4 weeks later: pozelimbab 60 mg / kg single IV loading dose and pozelimbab 400 mg SC and semdisirane 200 mg SC; and starting on day 57 or 4 weeks later: pozelimbab 400 mg SC q4W and semdisirane 200 mg SC q4W. [Brief explanation of the drawings]

[0059] [Figure 1]Semdisilane structure. Sense and antisense strands of a double-stranded RNA with modified nucleotides, with the sense strand linked to a ligand (L96). [Figure 2] Stability of semdisirane (total impurities #1 and #2) over time at 5°C for the 75:100 and 100:100 combinations (semdisirane:pozelimab concentration (mg / ml)). [Figure 3] Stability of semdisilane (total impurities #1 and #2) over time at 40°C for the 75:100 and 100:100 combinations (semdisilane:pozelimab concentration (mg / ml)) along with a semdisilane-only control. [Figure 4] Chromatograms from dIPRP analysis of 100:100, 75:100 (semdisilane:pozelimab concentration (mg / ml)) and semdisilane only samples stored at 40°C for 3 months. [Figure 5] Structure representing semdisilane impurity 1, lacking one GalNAc (wavy line represents double-stranded RNA). [Figure 6] Semdisilane purity (by dIPRP) for combinations 75:100 and 100:100 (semdisilane:pozelimab concentrations (mg / ml)) manufactured from pozeliman Process 1 and 2 material and stored at 40°C. [Figure 7] Chromatograms from dIPRP analysis of two semdisilane-only formulations (±10 micrograms / ml beta-hexosaminidase) after 0.5 months at 40°C. [Figure 8] Total impurities (semdisilane impurities #1, #2, and #3) over time during storage at all three temperatures (from left to right: 40°C, 25°C, and 5°C) between two 50:100 combinations (semdisilane:pozelimab concentrations (mg / ml)) at pH 5.9 or pH 6.6. [Figure 9] Total impurities (semdisirane impurities #1, #2, and #3) over time during storage at 40°C between two 100:100 and two 50:100 combinations (semdisirane:pozelimab concentrations (mg / ml)) at pH 6.0 generated from Pozelimab Blot 3 or 4. The degradation progression is fitted to the curves for which equations are shown. [Figure 10] The DOE (design of experiments) study evaluated the properties varied in the 50:100 combination (pH, sucrose, arginine, pozelimab (REGN3918), semdisilane, histidine; and desirability). [Figure 11] The DOE (design of experiments) study evaluated the properties varied in the 100:100 combination (pH, sucrose, arginine, pozelimab (REGN3918), semdisilane, histidine; and desirability). [Figure 12] Percent change in high molecular weight species of pozellimab after stirring with two drug combinations (100:100 and 50:100) (semdisilane:pozellimab concentrations (mg / ml)) at various concentrations of polysorbate 80. [Figure 13] Total impurities (semdisilane impurities #1, #2, and #3) over time during storage at 40°C between two combinations at pH 6.0 (50:100 and 100:100) and two combinations at pH 6.5 (50:100 and 100:100) (semdisilane:pozelimab concentrations (mg / ml)). [Figure 14] Quantification of beta-hex (ng / ml) in different lots of pozelimab. [Figure 15] Assay calibration curve. [Figure 16] Dilution curve. [Figure 17] Schematic diagram showing the pozeliman plus semdisirane dosing regimen for patients who previously received pozeliman monotherapy, as described in Example 4. [Figure 18] Graph showing individual LDH (×ULN) values ​​over time for patients in Arm 1 (pozelimab Q4W + semdisirane) of the study described in Example 4. [Figure 19] Graph showing individual LDH (×ULN) values ​​over time for patients in Arm 2 (pozelimab Q2W + semdisirane) of the study described in Example 4. [Figure 20]Graph showing individual hemoglobin values ​​over time for patients in Arm 1 (pozelimab Q4W + semdisirane) and Arm 2 (pozelimab Q2W + semdisirane) of the study described in Example 4. Each line represents an individual patient. [Figure 21A] Graphs showing patient-reported outcomes over time for patients in the study described in Example 4. Figure 21A is a graph showing FACIT-Fatigue scores, Figure 21B is a graph showing EORTC-QLQ-C30 physical function scores, and Figure 21C is a graph showing EORTC-QLQ-C30 GHS / QoL scores. [Figure 21B] Same as above. [Figure 21C] Same as above. [Figure 22] Graph showing individual LDH (xULN) values ​​versus visit for patients in the study described in Example 5. Each line represents an individual patient. [Figure 23] Individual patient LDH values ​​for visits for patients in the study described in Example 5. [Figure 24] Individual patient hemoglobin values ​​for visits for patients in the study described in Example 5. [Figure 25] Study flow diagram for the study described in Example 5. [Figure 26] Study flow diagram for the study described in Example 6. [Figure 27] Study flow diagram for the study described in Example 7. [Figure 28] Spaghetti plot: results of LDH to ULN ratio (LDH / ULN) for visits (full analysis set), pozelimbab q2w + semdisiran q4w, and pozelimbab q4w + semdisiran q4w. [Figure 29] Spaghetti plot: CH50 results (full analysis set), pozelimbab q2w + semdisiran q4w, and pozelimbab q4w + semdisiran q4w, against visit. [Figure 30]Spaghetti plot: LDH (×ULN) results from Baseline Visit 2 (Day 1) through Visit 225 (Full Analysis Set), with 1.5×ULN and 1×ULN shown. [Figure 31] Individual LDH values ​​for visits (five patients completed the OLTP). Each line represents an individual patient. LDH, lactate dehydrogenase; ULN, upper limit of normal. [Figure 32] Individual hemoglobin values ​​for visits (five patients completed the OLTP). Each line represents an individual patient. [Figure 33] Percentage of patients with LDH ≤ 1.5 × ULN over time (at data cutoff, all 24 randomized patients had completed the OLTP and 23 patients were in the optional OLEP). Arm 1: Pozelimab 400 mg SC Q4W + Semdisirane 200 mg SC Q4W. Arm 2: Pozelimab 400 mg SC Q2W + Semdisirane 200 mg SC Q4W. LDH, lactate dehydrogenase; Q2W, every 2 weeks; Q4W, every 4 weeks; SC, subcutaneous; ULN, upper limit of normal. [Figure 34] Hemoglobin over time (at data cutoff, all 24 randomized patients had completed the OLTP and 23 were in the optional OLEP). Arm 1: Pozelimab 400 mg SC Q4W + semdisirane 200 mg SC Q4W. Arm 2: Pozelimab 400 mg SC Q2W + semdisirane 200 mg SC Q4W. SC, subcutaneous; SE, standard error; Q2W, every 2 weeks; Q4W, every 4 weeks. [Figure 35] Mean percent change in lactate dehydrogenase excretion rate (U / L) over time (vs. visit (weeks)) from baseline among patients (pozelimab 400mg SC Q4W + semdisiran 200mg SC Q4W and ravulizumab patients). [Figure 36]Spaghetti plots for receiving LDH / ULN results among patients (pozelimab 400 mg SC Q4W + semdisiran 200 mg SC Q4W and ravulizumab patients) - 1.5 and 1 × ULN levels are shown. Dose of combination or ravulizumab is shown. [Figure 37] Spaghetti plots of LDH / ULN results for receiving -1.5 and 1×ULN levels are shown among the 5 patients (pozelimab 400 mg SC Q4W + semdisiran 200 mg SC Q4W and ravulizumab patients) who failed to achieve adequate control of LDH by week 8. Dose of combination or ravulizumab is shown. [Figure 38] Spaghetti plot for visits of CH50 (U / ml) over time among patients (pozelimab 400 mg SC Q4W + semdisiran 200 mg SC Q4W and ravulizumab patients). Dose of combination or ravulizumab and CH50 measurements are shown. [Figure 39] Spaghetti plot of CH50 (U / ml) over time for visits among patients who were inadequate responders (pozelimab 400 mg SC Q4W + semdisiran 200 mg SC Q4W and ravulizumab patients) and who crossed over into the indicated study, R3918-PNH-2050. [Figure 40] LDH over time in poor responders in the ravulizumab arm before and after switching to the combination. [Figure 41] Protocol-compliant transfusions during the study between groups. One patient in each arm met the protocol definition for transfusion but did not receive a transfusion. [Figure 42] Spaghetti plot of red blood cell hemoglobin (g / l) versus visit in patients who completed week 26. Hb = hemoglobin; reference range (g / L): 110–155 for women, 125–170 for men. [Figure 43] Spaghetti plot of LDH (×ULN) versus visit for patients with a history of aplastic anemia (AA) or myelodysplastic syndrome (MDS). The solid line represents AA patients, and the dotted line represents MDS patients. [Figure 44] Chemical structures of the viscosity-lowering agents tested. Effect on viscosity in a 1:1 base formulation: 120 mg / mL semdisirane, 120 mg / mL pozellimab, 15 mM histidine, pH 6.2, and a 1:2 base formulation: 75 mg / mL semdisirane, 150 mg / mL pozellimab, 15 mM histidine, pH 6.2, compared to a control formulation lacking the viscosity-lowering agent, shown in parentheses. [Figure 45] Percentage of patients with ≤1.5 × ULN at visit (Cohort A) [Figure 46] Percentage of patients with ≤1.0 × ULN at visit (Cohort A) [Figure 47] Summary of the cohorts in the study presented in Example 7. [Figure 48] Spaghetti Plot-Cohort A Analysis of Red Blood Cell Hemoglobin (g / l) Results for Subjects Who Completed the Open-Label Treatment Period (OLTP, Visit Week 26). [Figure 49] LDH and CH50 response in poor LDH responders in the combination arm versus the ravulizumab arm. Combo patient ID: 158-007-102; ravulizumab patient IDs: 124-001-103; 158-001-101; 410-001-102; and 410-001-104. [Figure 50] Complement inhibitor-naive, eculizumab-switched, ravulizumab-switched, and pozelimbab monotherapy-switched regimens. Cem = semdisirane; Ecu = eculizumab; Pz = pozelimbab; SC = subcutaneous; IV = intravenous. In embodiments of the invention, each regimen is characterized by the timeline shown. DETAILED DESCRIPTION OF THE INVENTION

[0060] Combining two C5 inhibitor therapies with complementary mechanisms of action (pozelimab and semdisirane) offers the advantage of completely suppressing the C5 pathway at (relatively) low C5 expression levels, but various technical challenges must be overcome to arrive at a suitable dosing regimen and delivery vehicle for the drugs.

[0061] The superior C5 inhibition provided by the compositions and methods of the present disclosure results in less pozelimuab required, resulting in reduced SC volume of antibody injections, less frequent dosing, a wider drug administration window for the combination than pozelimuab monotherapy, and potentially fewer injection site reactions. For patients requiring chronic, long-term administration, the combination offers the potential for improved compliance and quality of life compared to pozelimuab monotherapy, while still providing maximal inhibition of C5 activity in a greater percentage of patients than eculizumab therapy. Furthermore, as discussed herein, the dosing regimen of the present disclosure avoids the risk of adverse events caused by the formation of large drug-target-drug complexes (e.g., eculizumab-C5-pozellimab). A combination of both agents also offers the convenience of administering both agents together with only a single subcutaneous injection.

[0062] The present disclosure provides a stable combination comprising an antibody or its antigen-binding fragment, such as pozelimab, and a C5 iRNA, such as semdisilane. Combining an antibody expressed from a mammalian host cell with an iRNA conjugated to a ligand bearing terminal N-acetylgalactosamine (GalNAc) and / or N-acetylglucosamine (GlcNAc) presents a technical challenge. Beta-hexosaminidase, a rare enzyme from such host cells that often contaminates antibody preparations, has been shown to catalyze the removal of terminal GalNAc residues from such iRNA ligands. The present disclosure provides a stable combination comprising such an antibody and an iRNA molecule that overcomes this problem, for example, by adjusting the pH from 6 (e.g., 6.5), adding GalNAc and / or GlcNAc, and / or adding arginine (e.g., L-arginine, such as L-arginine HCl).

[0063] The administration of anti-C5 antibodies and C5 iRNA in the disclosed methods is designed to rapidly and continuously suppress C5 concentrations to pharmacologically inactive levels. Anti-C5 monotherapy typically requires relatively high doses in PNH patients. The need for such high anti-C5 mAb doses arises from two factors. First, C5 levels are high, necessitating 100% inhibition, which can only be achieved through complete target engagement (Peffault de Latour R et al., Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab. Blood 2015;125(5):775-83). Second, to achieve 100% inhibition in a population-based setting, inter- and intra-patient variability in C5 concentrations and instances of enhanced complement activation (which may occur with concomitant illnesses) have been exploited. The combination of pozeliman and semdisirane achieves high complement inhibition with a relatively low antibody dose. Combining pozeliman with semdisirane also offers the advantage of achieving lower complement levels and administering less pozeliman (compared to pozeliman monotherapy), resulting in a reduced SC volume of injection, less frequent dosing, a wider drug administration window than that of pozeliman monotherapy, and potentially less injection site reactions.

[0064] The present disclosure includes a dosing regimen for switching from a previous anti-C5 antibody therapy (e.g., eculizumab or ravulizumab) to a C5 iRNA plus an anti-C5 antibody or its antigen-binding fragment therapy (e.g., pozelimuab + semdisirane) of the present disclosure. Pozelimab has been shown to bind to C5 noncompetitively with an antibody having the amino acid sequence of eculizumab (eculizumab*). Therefore, for example, in patients switching from eculizumab to pozelimuab therapy, heteromeric complexes containing large DTD immune complexes may form. Large DTD immune complexes are known to cause adverse events, such as serum sickness-like reactions and skin rashes. The dosing regimen of the present disclosure is designed to reduce the risk of forming large DTD complexes and the occurrence of such adverse events.

[0065] antigen-binding proteins The term "antibody," as used herein, refers to an immunoglobulin molecule (e.g., IgG) comprising four polypeptide chains, two heavy chains (HC) and two light chains (LC), interconnected by disulfide bonds - e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; crovalimab; eculizumab, tesidormab, muvozina or ravulizumab; preferably pozelimab. In embodiments of the present disclosure, each antibody heavy chain (HC) comprises a heavy chain variable region ("HCVR" or "VHCVR"). H" ) (e.g., SEQ ID NOs: 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 variants thereof) and a heavy chain constant region; each antibody light chain (LC) comprises a light chain variable region ("LCVR" or "VVR"); L " ) (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 a light chain constant region (CL). H and V L The regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more highly conserved, termed framework regions (FRs). H and V L comprises three CDRs and four FRs. Preferably, the antibody or antigen-binding fragment thereof in the combination of the present disclosure is expressed and isolated from a mammalian host cell, such as a Chinese hamster ovary (CHO) cell.

[0066] The antibodies referred to herein include, for example, monoclonal, recombinant, chimeric, human and / or humanized antibodies.

[0067] In embodiments of the present disclosure, the assignment of amino acids to each framework or CDR domain follows the definitions in Sequences of Proteins of Immunological Interest, Kabat et al.; National Institutes of Health, Bethesda, Md.; 5th ed.; 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 provides a method for identifying and characterizing the V H CDR and V L and the CDRs of the V H and V L comprises the amino acid sequence shown herein (or a variant thereof), whose CDRs are defined according to Kabat and / or Chothia.

[0068] In embodiments of the disclosure, the anti-C5 antigen-binding protein, e.g., antibody or antigen-binding fragment, comprises a heavy chain constant domain, e.g., of the IgA (e.g., IgA1 or IgA2), IgD, IgE, IgG (e.g., IgG1, IgG2, IgG3 and IgG4 (e.g., containing S228P and / or S108P mutations)), or IgM type. In embodiments of the disclosure, the antigen-binding protein, e.g., antibody or antigen-binding fragment, comprises a light chain constant domain, e.g., of the kappa or lambda type. The present disclosure provides antigen binding proteins comprising the variable domains set forth herein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H 12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; crovalimab; eculizumab, tesidolumab, muvozina or ravulizumab; preferably pozelimab).

[0069] "Isolated" antigen binding proteins (e.g., antibodies or antigen-binding fragments thereof), polypeptides, polynucleotides, and vectors are at least partially free of other biomolecules from the cell or cell culture in which they are produced. Such biomolecules include nucleic acids, proteins, other antibodies or antigen-binding fragments, lipids, carbohydrates, or other materials, such as cell debris and growth medium. Isolated antigen binding proteins may further be at least partially free of expression system components, such as biomolecules from the host cell or its growth medium. In general, the term "isolated" is not intended to refer to the complete absence of such biomolecules (e.g., small or insignificant amounts of impurities may remain), nor is it intended to refer to the absence of water, buffers, or salts, nor is it intended to refer to components of pharmaceutical formulations that include the antigen binding protein (e.g., antibody or antigen-binding fragment).

[0070] In embodiments of the present disclosure, an antibody or antigen-binding fragment thereof that specifically binds 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 one or more amino acids contained within WEVHLVPRRKQLQFALPDSL (SEQ ID NO: 354) (or at least 1, 2, 3, 4, or 5 amino acids therein), as determined by hydrogen / deuterium exchange. In embodiments of the present disclosure, an antibody or antigen-binding fragment thereof that specifically binds to complement factor 5 (C5) protein interacts with one or more amino acids contained within the alpha chain and / or beta chain of C5, as determined by hydrogen / deuterium exchange. For example, in embodiments of the present disclosure, the antibody or antigen-binding fragment does not interact with amino acids in the C5a anaphylatoxin region of C5, as determined by hydrogen / deuterium exchange. In embodiments of the present disclosure, an antibody or antigen-binding fragment thereof that specifically binds to complement factor 5 (C5) protein interacts with one or more amino acids contained within the alpha chain and / or beta chain of C5, as determined by hydrogen / deuterium exchange. (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) interacts with an amino acid sequence selected from the group consisting of:

[0071] The sequences of anti-C5 antibodies and antigen-binding fragments thereof (eg, their LCVRs and HCVRs or LCDRs and HCDRs) that can be included in the combinations or used in the methods are shown below.

[0072] [Table 1]

[0073] Polynucleotides encoding the chains shown in Table A are shown in Table B below.

[0074] [Table 2]

[0075] H2M11683N HCVR [ka] (SEQ ID NO: 2) HCDR1, HCDR2 and HCDR3 are shown 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

[0076] LCVR [ka] (SEQ ID NO: 10) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Ser Ile Ser Ser Trp; Lys Ala Ser; and Gln Gln Tyr Asn Thr Tyr Ser Tyr Thr

[0077] H2M11686N HCVR [ka] (SEQ ID NO: 18) HCDR1, HCDR2 and HCDR3 are shown 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

[0078] LCVR [ka] (SEQ ID NO: 26) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Ser Val Arg Ser Tyr; Asp Ala Ser; and Gln Gln Ser Gly Asn Trp Pro Leu Thr

[0079] H4H12159P HCVR [ka] (SEQ ID NO: 34) HCDR1, HCDR2 and HCDR3 are shown 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

[0080] LCVR [ka] (SEQ ID NO: 42) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Ser Ile Asn Arg Trp; Lys Ala Ser; and Gln Gln Tyr Asn Asp Tyr Ser Tyr Thr

[0081] H4H12161P HCVR [ka] (SEQ ID NO: 50) HCDR1, HCDR2 and HCDR3 are shown 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

[0082] LCVR [ka] (SEQ ID NO: 58) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Asn Ile Gly Ile Phe; Ala Ala Ser; and Gln Gln Thr Tyr Asn Thr Ile Phe Thr

[0083] H4H12163P HCVR [ka] (SEQ ID NO: 66) HCDR1, HCDR2 and HCDR3 are shown 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

[0084] LCVR [ka] (SEQ ID NO: 74) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Thr Ile Ser Asn Phe; Ala Ala Ser; and Gln Gln Ser Tyr Thr Thr Pro Leu Thr

[0085] H4H12164P HCVR [ka] (SEQ ID NO: 82) HCDR1, HCDR2 and HCDR3 are shown 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 Val

[0086] LCVR [ka] (SEQ ID NO: 90) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Asp Ile Thr Asn Ser; Asp Ala Ser; and Gln Gln Tyr Asp Asp Leu Pro Tyr Thr

[0087] H4H12166P HCVR [ka] (SEQ ID NO: 98) HCDR1, HCDR2 and HCDR3 are shown 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

[0088] LCVR [ka] (SEQ ID NO: 106) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Gly Ile Arg Asn Asp; Ala Ala Ser; and Leu Gln Asp Phe Asn Tyr Pro Trp Thr

[0089] H4H12166P2 HCVR [ka] (SEQ ID NO: 98) HCDR1, HCDR2 and HCDR3 are shown 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

[0090] LCVR [ka] (SEQ ID NO: 114) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Gly Ile Arg Asn Asp; Ala Ala Ser; and His Gln Asp Phe Asn Tyr Pro Trp Thr

[0091] H4H12166P3 HCVR [ka] (SEQ ID NO: 122) HCDR1, HCDR2 and HCDR3 are shown 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

[0092] LCVR [ka] (SEQ ID NO: 106) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Gly Ile Arg Asn Asp; Ala Ala Ser; and Leu Gln Asp Phe Asn Tyr Pro Trp Thr

[0093] H4H12166P4 HCVR [ka] (SEQ ID NO: 98) HCDR1, HCDR2 and HCDR3 are shown 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

[0094] LCVR [ka] (SEQ ID NO: 130) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Gly Ile Arg Asn Asp; Ala Ala Ser; and Leu Gln Asp Phe Asn Tyr Pro Trp His

[0095] H4H12166P5 HCVR [ka] (SEQ ID NO: 138) HCDR1, HCDR2 and HCDR3 are shown 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

[0096] LCVR [ka] (SEQ ID NO: 106) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Gly Ile Arg Asn Asp; Ala Ala Ser; and Leu Gln Asp Phe Asn Tyr Pro Trp Thr

[0097] H4H12166P6 HCVR [ka] (SEQ ID NO: 146) HCDR1, HCDR2 and HCDR3 are shown 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

[0098] LCVR [ka] (SEQ ID NO: 106) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Gly Ile Arg Asn Asp; Ala Ala Ser; and Leu Gln Asp Phe Asn Tyr Pro Trp Thr

[0099] H4H12166P7 HCVR [ka] (SEQ ID NO: 122) HCDR1, HCDR2 and HCDR3 are shown 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

[0100] LCVR [ka] (SEQ ID NO: 130) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Gly Ile Arg Asn Asp; Ala Ala Ser; and Leu Gln Asp Phe Asn Tyr Pro Trp His

[0101] H4H12166P8 HCVR [ka] (SEQ ID NO: 146) HCDR1, HCDR2 and HCDR3 are shown 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

[0102] LCVR [ka] (SEQ ID NO: 114) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Gly Ile Arg Asn Asp; Ala Ala Ser; and His Gln Asp Phe Asn Tyr Pro Trp Thr

[0103] H4H12166P9 HCVR [ka] (SEQ ID NO: 146) HCDR1, HCDR2 and HCDR3 are shown 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

[0104] LCVR [ka] (SEQ ID NO: 130) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Gly Ile Arg Asn Asp; Ala Ala Ser; and Leu Gln Asp Phe Asn Tyr Pro Trp His

[0105] H4H12166P10 HCVR [ka] (SEQ ID NO: 138) HCDR1, HCDR2 and HCDR3 are shown 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

[0106] LCVR [ka] (SEQ ID NO: 130) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Gly Ile Arg Asn Asp; Ala Ala Ser; and Leu Gln Asp Phe Asn Tyr Pro Trp His

[0107] H4H12167P HCVR [ka] (SEQ ID NO: 154) HCDR1, HCDR2 and HCDR3 are shown 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

[0108] LCVR [ka] (SEQ ID NO: 162) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Gly Ile Ser Ser Tyr; Thr Ala Ser; and Gln Gln Leu Asn Ser Tyr Pro Phe Thr

[0109] H4H12168P HCVR [ka] (SEQ ID NO: 170) HCDR1, HCDR2 and HCDR3 are shown 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

[0110] LCVR [ka] (SEQ ID NO: 178) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Asp Ile Ser Asn Phe; Thr Ala Ser; and Gln Lys Tyr Ala Gly Ala Leu Thr

[0111] H4H12169P HCVR [ka] (SEQ ID NO: 186) HCDR1, HCDR2 and HCDR3 are shown 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

[0112] LCVR [ka] (SEQ ID NO: 194) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Ser Ile Ser Thr Tyr; Asp Ala Ser; and Gln Gln Ser Tyr Ser Ala Pro Leu Thr

[0113] H4H12170P HCVR [ka] (SEQ ID NO: 202) HCDR1, HCDR2 and HCDR3 are shown 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

[0114] LCVR [ka] (SEQ ID NO: 210) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Ser Ile Ser Arg Trp; Lys Ala Ser; and Gln Gln Tyr Asn Thr Tyr Ser Tyr Thr

[0115] H4H12171P HCVR [ka] (SEQ ID NO: 218) HCDR1, HCDR2 and HCDR3 are shown 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

[0116] LCVR [ka] (SEQ ID NO: 226) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Ser Ile Ser Thr Tyr; Ala Ala Ser; and Gln Gln Ser Tyr Ser Thr Pro Tyr Thr

[0117] H4H12175P HCVR [ka] (SEQ ID NO: 234) HCDR1, HCDR2 and HCDR3 are shown 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

[0118] LCVR [ka] (SEQ ID NO: 242) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Asn Ile Asp Thr Tyr; Asp Ala Ser; and Gln Gln Asn Asp Asn Ile Leu His Pro Leu Thr

[0119] H4H12176P2 HCVR [ka] (SEQ ID NO: 250) HCDR1, HCDR2 and HCDR3 are shown 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

[0120] LCVR [ka] (SEQ ID NO: 258) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Ser Ile Ser Ser Tyr; Ala Ala Ser; and Gln Gln Ser Tyr Ser Thr Pro Pro Ile Thr

[0121] H4H12177P2 HCVR [ka] (SEQ ID NO: 266) HCDR1, HCDR2 and HCDR3 are shown 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

[0122] LCVR [ka] (SEQ ID NO: 258) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Ser Ile Ser Ser Tyr; Ala Ala Ser; and Gln Gln Ser Tyr Ser Thr Pro Pro Ile Thr

[0123] H4H12183P2 HCVR [ka] (SEQ ID NO: 274) HCDR1, HCDR2 and HCDR3 are shown 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

[0124] LCVR [ka] (SEQ ID NO: 282) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala; Gly Ala Ser Ser Arg Ala Thr; and Gln Gln Tyr Gly Ser Ser Pro Trp Thr

[0125] H2M11682N HCVR [ka] (SEQ ID NO: 290) HCDR1, HCDR2 and HCDR3 are shown 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

[0126] LCVR [ka] (SEQ ID NO: 298) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Gly Ile Arg Asn Asp; Ala Ala Ser; and Leu Gln His Asn Ser Tyr Pro Leu Thr

[0127] H2M11684N HCVR [ka] (SEQ ID NO: 306) HCDR1, HCDR2 and HCDR3 are shown 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

[0128] LCVR [ka] (SEQ ID NO: 314) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Asp Ile Asn Asn Phe; Asp Ala Ser; and Gln Gln Tyr Asp His Phe Pro Tyr Thr

[0129] H2M11694N HCVR [ka] (SEQ ID NO: 322) HCDR1, HCDR2 and HCDR3 are shown 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

[0130] LCVR [ka] (SEQ ID NO: 330) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Ser Val Ser Ser Asn; Gly Ala Ser; and Gln Gln Tyr Asn Asn Trp Pro Trp Thr

[0131] H2M11695N HCVR [ka] (SEQ ID NO: 338) HCDR1, HCDR2 and HCDR3 are shown below, respectively: Gly Asn Thr Leu Thr Glu Leu Ser; Phe Asp Pro Glu Asp Gly Asp Thr; and Ser Thr Val Gly Gly Pro Thr Ser Asp Cys

[0132] LCVR [ka] (SEQ ID NO: 346) LCDR1, LCDR2 and LCDR3 are shown below, respectively: Gln Asp Ile Ser Asn Tyr; Asp Ala Ser; and Gln Gln Tyr Asp Asn Leu Pro Ile Thr CDRs are underlined

[0133] In embodiments of the present disclosure, the antibody or antigen-binding fragment thereof that specifically binds to C5 in the combination of the present disclosure includes: (1) an HCVR comprising HCDR1, HCDR2 and HCDR3 of the HCVR comprising the amino acid sequence shown in SEQ ID NO: 2 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 10 (or a variant thereof); (2) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence shown in SEQ ID NO: 18 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 26 (or a variant thereof); (3) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 34 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 42 (or a variant thereof); (4) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 50 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 58 (or a variant thereof); (5) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 66 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 74 (or a variant thereof); (6) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 82 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 90 (or a variant thereof); (7) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 98 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 106 (or a variant thereof); (8) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 98 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 114 (or a variant thereof); (9) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 122 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 106 (or a variant thereof); (10) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 98 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof); (11) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 138 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 106 (or a variant thereof); (12) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 146 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 106 (or a variant thereof); (13) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 122 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof); (14) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 146 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 114 (or a variant thereof); (15) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 146 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof); (16) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 138 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof); (17) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 154 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 162 (or a variant thereof); (18) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 170 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 178 (or a variant thereof); (19) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 186 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 194 (or a variant thereof); (20) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 202 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 210 (or a variant thereof); (twenty one) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 218 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 226 (or a variant thereof); (twenty two) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 234 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 242 (or a variant thereof); (twenty three) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 250 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 258 (or a variant thereof); (twenty four) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 266 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 258 (or a variant thereof); (twenty five) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 274 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 282 (or a variant thereof); (26) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 290 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 298 (or a variant thereof); (27) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 306 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 314 (or a variant thereof); (28) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 322 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 330 (or a variant thereof); and / or (29) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 338 (or a variant thereof); and An LCVR comprising LCDR1, LCDR2 and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 346 (or a variant thereof).

[0134] In embodiments of the present disclosure, the antibody or antigen-binding fragment thereof that specifically binds to C5 in the combination of the present disclosure includes: (a) HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 4 (or a variant thereof); HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 6 (or a variant thereof); HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 8 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 12 (or a variant thereof); LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 14 (or a variant thereof); LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 16 (or a variant thereof) a light chain variable region comprising: (b) HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 20 (or a variant thereof); HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 22 (or a variant thereof); HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 24 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 28 (or a variant thereof); LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 30 (or a variant thereof); LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 32 (or a variant thereof) a light chain variable region comprising: (c) HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 36 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 44 (or a variant thereof); LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 46 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48 (or a variant thereof) a light chain variable region comprising: (d) HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 52 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 54 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 60 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 62 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64 (or a variant thereof) a light chain variable region comprising: (e) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 68 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 70 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 76 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 78 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 80 (or a variant thereof) a light chain variable region comprising: (f) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 84 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 86 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 88 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 92 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 94 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96 (or a variant thereof) a light chain variable region comprising: (h) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 100 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 102 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 104 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 108 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 110 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112 (or a variant thereof) a light chain variable region comprising: (j) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 100 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 102 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 104 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 118 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 120 (or a variant thereof) a light chain variable region comprising: (k) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 126 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 128 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 108 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 110 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112 (or a variant thereof) a light chain variable region comprising: (m) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 100 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 102 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 104 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 134 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136 (or a variant thereof) a light chain variable region comprising: (n) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 140 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 142 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 144 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 108 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 110 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112 (or a variant thereof) a light chain variable region comprising: (p) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 148 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 108 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 110 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112 (or a variant thereof) a light chain variable region comprising: (q) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 126 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 128 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 134 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136 (or a variant thereof) a light chain variable region comprising: (r) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 148 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 118 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 120 (or a variant thereof) a light chain variable region comprising: (s) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 148 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 134 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136 (or a variant thereof) a light chain variable region comprising: (t) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 140 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 142 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 144 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 134 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136 (or a variant thereof) a light chain variable region comprising: (u) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 156 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 158 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 160 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 164 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 166 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 168 (or a variant thereof) a light chain variable region comprising: (v) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 172 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 174 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 176 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 180 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 182 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 184 (or a variant thereof) a light chain variable region comprising: (w) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 188 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 190 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 192 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 196 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 198 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 200 (or a variant thereof) a light chain variable region comprising: (x) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 204 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 206 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 208 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 212 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 214 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 216 (or a variant thereof) a light chain variable region comprising: (y) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 220 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 222 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 224 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 228 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 230 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 232 (or a variant thereof) a light chain variable region comprising: (z) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 236 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 238 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 240 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 244 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 246 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 248 (or a variant thereof) a light chain variable region comprising: (aa) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 252 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 254 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 256 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 260 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 262 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 264 (or a variant thereof) a light chain variable region comprising: (ab) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 268 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 270 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 272 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 260 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 262 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 264 (or a variant thereof) a light chain variable region comprising: (ac) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 276 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 278 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 280 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 284 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 286 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 288 (or a variant thereof) a light chain variable region comprising: (ad) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 292 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 294 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 296 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 300 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 302 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 304 (or a variant thereof) a light chain variable region comprising: (ae) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 308 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 310 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 312 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 316 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 318 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 320 (or a variant thereof) a light chain variable region comprising: (af) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 324 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 326 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 328 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 332 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 334 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 336 (or a variant thereof) a light chain variable region comprising: and / or (ag) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 340 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 342 (or a variant thereof); HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 344 (or a variant thereof) a heavy chain variable region comprising: and LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 348 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 350 (or a variant thereof); LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 352 (or a variant thereof) a light chain variable region comprising:

[0135] In embodiments of the present disclosure, the antibody or antigen-binding fragment thereof that specifically binds to C5 in the combination of the present disclosure includes: (i) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 2 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 10 (or a variant thereof); (ii) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 18 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 26 (or a variant thereof); (iii) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 34 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 42 (or a variant thereof); (iv) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 50 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 58 (or a variant thereof); (v) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 66 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 74 (or a variant thereof); (vi) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 82 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 90 (or a variant thereof); (vii) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 98 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 106 (or a variant thereof); (viii) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 98 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 114 (or a variant thereof); (ix) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 122 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 106 (or a variant thereof); (x) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 98 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof); (xi) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 138 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 106 (or a variant thereof); (xii) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 146 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 106 (or a variant thereof); (xiii) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 122 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof); (xiv) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 146 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 114 (or a variant thereof); (xv) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 146 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof); (xvi) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 138 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof); (xvii) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 154 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 162 (or a variant thereof); (xviii) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 170 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 178 (or a variant thereof); (xix) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 186 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 194 (or a variant thereof); (xx) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 202 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 210 (or a variant thereof); (xxi) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 218 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 226 (or a variant thereof); (xxii) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 234 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 242 (or a variant thereof); (xxiii) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 250 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 258 (or a variant thereof); (xxiv) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 266 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 258 (or a variant thereof); (xxv) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 274 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 282 (or a variant thereof); (xxvi) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 290 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 298 (or a variant thereof); (xxvii) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 306 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 314 (or a variant thereof); (xxviii) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 322 (or a variant thereof); and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 330 (or a variant thereof); and / or (xxix) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 338 (or a variant thereof); and A light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 346 (or a variant thereof).

[0136] In an embodiment of the present disclosure, the antibody or antigen-binding fragment thereof that specifically binds to C5 in the combination of the present disclosure is

[0137] A heavy chain comprising the following amino acid sequence: [ka] (SEQ ID NO: 358)

[0138] A light chain comprising the following amino acid sequence: [ka] (SEQ ID NO: 359); such antibodies are sometimes referred to herein as pozelimab or REGN3918 (variable regions and CDRs are underlined).

[0139] "H2M11683N"; "H2M11686N"; "H4H12159P"; "H4H12161P"; "H4H12163P"; "H4H12164P"; "H4H12166P"; "H4H12166P2"; "H4H12166P3"; "H4H12166P4" ";"H4H12166P5";"H4H12166P6";"H4H12166P7";"H4H12166P8";"H4H121 66P9";"H4H12166P10";"H4H12167P";"H4H12168P";"H4H12169P";"H4H1 "H4H12170P"; "H4H12171P"; "H4H12175P"; "H4H12176P2"; "H4H12177P2"; "H4H12183P2"; "H2M11682N"; "H2M11684N"; "H2M11694N" or "H2M11695N" refer to, unless otherwise specified, anti-C5 antigen-binding proteins, e.g., antibodies and antigen-binding fragments thereof (including multispecific antigen-binding proteins), that specifically bind to C5, and are set forth in Table A herein or Table 1 of WO2017 / 218515 (and the sequences set forth therein). Among them, H2M11683N;H2M11686N;H4H12159P;H4H12161P;H4H12163P;H4H12164P;H4H12166P;H4H12166P2;H4H12166P3;H4H12166P4;H4H12166P5;H4H12166P6;H4H12166P7;H4H12166P8;H4H12166P9;H4H12166P10;H4H12167P;H4H12168P;H4H12169P;H4H12170P;H4H12171P;H4H12175P;H4H12176P2 an immunoglobulin heavy chain or variable region thereof (V) comprising an amino acid sequence specifically set forth herein corresponding to: H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N or H2M11695N (e.g., SEQ ID NOs: 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); H), and / or in Table A herein or Table 1 of WO2017 / 218515 (and the sequences set out therein), H2M11683N;H2M11686N;H4H12159P;H4H12161P;H4H12163P;H4H12164P;H4H12166P;H4H1216 6P2;H4H12166P3;H4H12166P4;H4H12166P5;H4H12166P6;H4H12166P7;H4H12166P 8;H4H12166P9;H4H12166P10;H4H12167P;H4H12168P;H4H12169P;H4H12170P;H4H1 an immunoglobulin light chain or variable region thereof (V) comprising an amino acid sequence as specifically set forth herein corresponding to: H2M11682N; H2M11684N; H2M11694N; or H2M11695N (e.g., SEQ ID NOs: 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); L ) and / or a V comprising a heavy chain or its CDRs (CDR-H1 (or a variant thereof), CDR-H2 (or a variant thereof) and CDR-H3 (or a variant thereof)); H , and / or a V comprising a light chain or its CDRs (CDR-L1 (or a variant thereof), CDR-L2 (or a variant thereof), and CDR-L3 (or a variant thereof)). L In an embodiment of the present disclosure, V H is linked to an IgG constant heavy chain domain (e.g., IgG1 or IgG4 (e.g., IgG4 (S228P mutant))), and / or V L is linked to a lambda or kappa constant variable light chain domain.

[0140] An "anti-C5" antibody or antigen-binding fragment, or an antibody or antigen-binding fragment that "specifically binds" to C5, has a K of at least 1 nM (i.e., an affinity of 1 nM or higher), e.g., a K of about 0.1 or 0.2 nM. D and binds to human C5.

[0141] In an embodiment of the invention, the anti-C5 antibody or antigen-binding fragment lacks the C-terminal lysine of the heavy chain.

[0142] Interfering RNA (iRNA) The present disclosure provides anti-C5 antibodies or antigen-binding fragments thereof (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H1216 Provided is a combination drug comprising: 8P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; crovalimab; eculizumab, tesidolumab, muvozina or ravulizumab; preferably pozelimab); and iRNA (C5 iRNA) that performs RNA-induced silencing complex (RISC)-mediated cleavage of the RNA transcript of C5 gene, such as semdisiran (for example, semdisiran / pozelimab).C5 gene can be present in a cell, for example, a cell in a subject's body, such as a human. The present disclosure provides iRNA agents for inclusion in the disclosed combination agents that effect RNA-induced silencing complex (RISC)-mediated cleavage of the RNA transcript of the complement component C5 gene.

[0143] Semdisilane is a chemically synthesized double-stranded oligonucleotide glycoconjugate covalently linked to a ligand containing three GalNAc residues to facilitate targeted delivery to the liver (see, for example, Figure 1). All nucleosides are modified with 2'-deoxy, 2'-methoxy, or 2'-fluoro groups and are connected by 3'→5' phosphodiester linkages, resulting in the sugar-phosphate backbone of the oligonucleotide.

[0144] 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 by a phosphodiester linkage to a triantennary GalNAc moiety (designated L96).

[0145] 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. 21 nucleotides of the sense strand hybridize with complementary 21 nucleotides of the antisense strand, resulting in a 21-nucleotide base-pair duplex with a four-base overhang at the 3' end of the antisense strand. The bases involved in base pairing are connected by bullets. The semdisilane is preferably in salt form, e.g., Na + Although the present disclosure is directed to other salt forms, e.g., Ca 2+ Embodiments include semdisilanes in free acid form as well as salt forms.

[0146] When the concentration of RNAi in a composition such as a combination drug of the present disclosure is expressed herein as mass per volume (e.g., mg / ml), the RNAi is in salt form or free acid form. Preferably, when referring to semdisilane itself, semdisilane is in salt form, preferably Na + It is in salt form. +Counterions are present due to the net negative charge of the ribonucleotide phosphate backbone. The amount of semdisilane free acid form is determined by the amount of semdisilane Na + It can be obtained by multiplying the concentration of the salt form by 0.9443.

[0147] The structure of sodium semdisilane (ALN-62643) is shown below, with A-125167 at the top (5'-3') and A-125647 at the bottom (3'-5'): [ka] Af, Gf and Uf = 2'-F ribonucleosides Am, Cm and Um-2'-OMe ribonucleosides dT = thymidine S = phosphorothioate

[0148] L96 is [ka] is.

[0149] The C5 iRNA that can be included in the combination of the present disclosure is about 30 nucleotides in length or less, for example, 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, The RNA strand (e.g., the antisense strand) comprises a region that is 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, which region is substantially complementary to at least a portion of an mRNA transcript of the C5 gene.

[0150] In embodiments of the present disclosure, C5 iRNA is a glycoconjugate comprising a double-stranded RNA complementary to a region of C5 conjugated (e.g., by a linker) to a terminal mono-, di-, or tri-antennary N-acetylgalactosamine (GalNAc) group, preferably a tri-antennary N-acetylgalactosamine.

[0151] In an embodiment of the present disclosure, an iRNA agent that can be included in the combination of the present disclosure comprises a single-stranded RNA that interacts with a target RNA sequence, such as a C5 target mRNA sequence, to direct cleavage of the target RNA. Without wishing to be bound by theory, it is believed that long double-stranded RNA introduced into cells is degraded into siRNAs by a type III endonuclease known as Dicer (Sharp et al. (2001) Genes Dev. 15:485). Dicer, a ribonuclease-III-like enzyme, processes dsRNA into 19-23 base pair small interfering RNAs with characteristic two-base 3' overhangs (Bernstein et al. (2001) Nature 409:363). The siRNA is then incorporated into the RNA-induced silencing complex (RISC), where one or more helicases unwind the siRNA duplex, allowing 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 RISC cleave the target, inducing silencing (Elbashir et al., (2001) Genes Dev. 15:188). Thus, in one aspect, the present disclosure relates to a single-stranded RNA (siRNA) generated within a cell, which promotes the formation of a RISC complex to silence a target gene, i.e., the C5 gene. Thus, the term "siRNA" is also used herein to refer to the iRNA described above.

[0152] In another embodiment, the iRNA agent that can be included in the combination of the present disclosure can be a single-stranded siRNA introduced into a cell or organism to inhibit target mRNA. The single-stranded iRNA agent binds to the RISC endonuclease Argonaute 2, which then cleaves the target mRNA. Single-stranded siRNAs are generally 15-30 nucleotides long and chemically modified. The design and testing of single-stranded siRNAs is described in U.S. Patent No. 8,101,348 and Lima et al. (2012) Cell 150:883-894, the entire contents of each of which are hereby incorporated by reference. Any of the antisense nucleotide sequences described herein can be used as single-stranded siRNAs as described herein, or chemically modified by the methods described in Lima et al. (2012) Cell 150:883-894.

[0153] In another embodiment, the iRNA for use in the compositions, uses, and methods of the present disclosure is 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 containing two antiparallel, substantially complementary nucleic acid strands, referred to as having "sense" and "antisense" orientations relative to the target RNA, i.e., the C5 gene. In some embodiments of the present disclosure, the double-stranded RNA (dsRNA) induces degradation of the target RNA, e.g., mRNA, by a post-transcriptional gene silencing mechanism called RNA interference or iRNA.

[0154] In an embodiment of the invention, the iRNA is a double-stranded ribonucleic acid (dsRNA), wherein the dsRNA comprises a sense strand and an antisense strand, and the sense strand has the nucleotide sequence of C5 (open reading frame underlined):

[0155] [ka] [ka] [ka] [ka] (SEQ ID NO: 360), and the antisense strand comprises the nucleotide sequence:

[0156] [ka] [ka] [ka] (SEQ ID NO: 361) that differs by no more than 3 nucleotides (e.g., at least 15 contiguous nucleotides).

[0157] In embodiments of the disclosure, the C5 iRNA (e.g., dsRNA) has the structure: [ka] wherein the sequence formula is: X is 2'-deoxy-2'-fluoro, X is 2'-O-methyl; Z is thymidine,

[0158] -teeth, [ka] and = is [ka] and R1- is [ka] and R- is [ka] is.

[0159] See International Nonproprietary Names for Pharmaceutical Substances (INN) (Proposed INN: List 114), WHO Drug Information, Volume 29, Issue 4, 2015.

[0160] The present disclosure includes an iRNA that can be included in a combination agent of the present disclosure, the iRNA being a double-stranded ribonucleic acid (dsRNA) agent (e.g., having a complementary region of 19-23 nucleotides in length and / or having a strand length of at most 30 nucleotides) for inhibiting expression of complement component C5, wherein the dsRNA agent comprises a sense strand and an antisense strand, the antisense strand comprising a complementary region comprising at least 17 contiguous nucleotides that differ by at most 3 nucleotides from the nucleotide sequence 5'-UAUUAUAAAAAUAUCUUGCUUUU-3' (SEQ ID NO: 364), and one or more of the dsRNA nucleotides are modified. The dsRNA agent can include at least one modified nucleotide, e.g., having a 2'-deoxy, 2'-methoxy, and / or 2'-fluoro group; for example, substantially all of the nucleotides in the sense and antisense strands are modified nucleotides. Additionally, the sense strand may be conjugated to a ligand attached to the 3' end, for example, terminally modified with a triantennary GalNAc moiety.

[0161] The modified nucleotide that can be contained in dsRNA includes 3'-terminal deoxy-thymine (dT) nucleotide, 2'-O-methyl modified nucleotide, 2'-fluoro modified nucleotide, 2'-deoxy modified nucleotide, locked nucleotide, abasic nucleotide, 2'-amino modified nucleotide, 2'-alkyl modified nucleotide, morpholino nucleotide, phosphoramidate, non-natural base containing nucleotide, nucleotide that contains 5'-phosphorothioate group, and terminal nucleotide that is linked to cholesteryl derivative or dodecanoic acid bisdecylamide group.dsRNA can contain phosphorothioate and / or methylphosphonate internucleotide linkage.

[0162] A dsRNA is double-stranded, but may contain one or more overhangs (eg, 2 or more nucleotides of overhang), such as at the 3' end of one or more strands.

[0163] The double-stranded RNA of the present disclosure can be linked to a ligand (e.g., an N-acetylgalactosamine (GalNAc) derivative, [ka] In an embodiment of the present disclosure, the ligand is conjugated to the 3' end of the sense strand of the dsRNA.

[0164] In one aspect, the present disclosure provides a double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5, which can be included in a combination agent of the present disclosure, comprising a sense strand and an antisense strand, wherein the sense strand comprises the nucleotide sequence 5'-AAGCAAGAUAUAUUUUUAUAAUA-3' (SEQ ID NO: 365) and the antisense strand comprises the nucleotide sequence 5'-UAUUAUAAAAAUAUCUUGCUUUU-3' (SEQ ID NO: 364), e.g., one or more of the dsRNA nucleotides are modified, e.g., with a 2'-deoxy, 2'-methoxy, and / or 2'-fluoro group, and / or are terminally modified with a triantennary GalNAc moiety. In one embodiment, the dsRNA agent comprises at least one modified nucleotide as described herein.

[0165] In one aspect, the disclosure provides a double-stranded iRNA agent for inhibiting expression of complement component C5, which can be included in a combination agent of the disclosure, the double-stranded iRNA agent comprising a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises at least 15 contiguous nucleotides that differ 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 that differ by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO: 364, wherein substantially all of the nucleotides in the sense strand and substantially all of the nucleotides in the antisense strand are modified nucleotides, and the sense strand is conjugated to a ligand attached to its 3' end. In one embodiment, the dsRNA agent comprises at least one modified nucleotide as described herein.

[0166] In one embodiment, substantially all of the nucleotides in the sense strand are modified nucleotides selected from the group consisting of 2'-O-methyl modified, 2'-fluoro modified, and 3'-terminal deoxythymine (dT) nucleotides. In another embodiment, substantially all of the nucleotides in the antisense strand are modified nucleotides selected from the group consisting of 2'-O-methyl modified, 2'-fluoro modified, and 3'-terminal deoxythymine (dT) nucleotides. In another embodiment, the modified nucleotides are short sequences of deoxythymine (dT) nucleotides. In another embodiment, the sense strand comprises two phosphorothioate internucleotide linkages at the 5'-end. In one embodiment, the antisense strand comprises two phosphorothioate internucleotide linkages at the 5'-end and two phosphorothioate internucleotide linkages at the 3'-end. In yet another embodiment, the sense strand is conjugated to one or more GalNAc derivatives attached via a branched bivalent or trivalent linker at the 3'-end.

[0167] 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-containing nucleotide, a nucleotide comprising a 5'-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or a dodecanoic acid bisdecylamide group.

[0168] In another embodiment, the modified nucleotides include a short sequence of 3'-terminal deoxy-thymine (dT) nucleotides.

[0169] 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 at most 30 nucleotides in length. In one embodiment, at least one strand includes a 3' overhang of at least 1 nucleotide. In another embodiment, at least one strand includes a 3' overhang of at least 2 nucleotides. In one embodiment, the dsRNA agent further includes 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 [ka] is.

[0170] In one embodiment, the dsRNA agent has the following schematic diagram: [ka] wherein X is O or S. In one embodiment, X is O.

[0171] In embodiments of the invention, the C5 iRNA comprises an RNA strand that is complementary to an mRNA transcribed from the C5 gene sense strand DNA sequence AAGCAAGATATTTTTATAATA, e.g., the iRNA is a dsRNA that comprises a separate hybridized RNA strand.

[0172] In another aspect, the disclosure provides a double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5, the dsRNA agent comprising a sense strand and an antisense strand, wherein the sense strand comprises the nucleotide sequence 5'-AAGCAAGAUAUAUUUUUAUAAUA-3' (SEQ ID NO: 366) and the antisense strand comprises the nucleotide sequence 5'-UAUUAUAAAAAUAUCUUGCUUUUdTdT-3' (SEQ ID NO: 367).

[0173] In another aspect, the disclosure provides a double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5, comprising a sense strand and an antisense strand, wherein the sense strand comprises the nucleotide sequence asasGfcAfaGfaUfAfUfuUfuuAfuAfauaL96 (SEQ ID NO: 368) and the antisense strand comprises the nucleotide sequence usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT (SEQ ID NO: 369).

[0174] In embodiments of the present disclosure, the sense or antisense strand of dsRNA that can be included in the formulation of the present disclosure is 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-11 In one embodiment, the dsRNA agent comprises a sequence selected from the group consisting of: A-9332, 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.

[0175] [Table 3-1] [Table 3-2]

[0176] In the table, A = adenosine 3'-phosphate 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 T = 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 N = any nucleotide (G, A, C, T, or U) a = 2'-O-methyladenosine-3'-phosphate as = 2'-O-methyladenosine-3'-phosphorothioate c = 2'-O-methylcytidine-3'-phosphate cs = 2'-O-methylcytidine-3'-phosphorothioate g = 2'-O-methylguanosine-3'-phosphate gs = 2'-O-methylguanosine-3'-phosphorothioate t=2'-O-methyl-5-methyluridine-3'-phosphate ts = 2'-0-methyl-5-methyluridine-3'-phosphorothioate u = 2'-O-methyluridine-3'-phosphate us = 2'-O-methyluridine-3'-phosphorothioate s = phosphorothioate linkage L96 = N-[tris(GalNAc-alkyl)-aminododecanoyl]-4-hydroxyprolinol Hyp-(GalNAc-alkyl)3 (dt) = deoxythymine

[0177] In embodiments of the present disclosure, the dsRNA comprises two of the following paired strands: A-118320 and A-118321 A-118316 and A-118317 A-118332 and A-118333 A-118396 and A-118397 A-118386 and A-118387 A-118312 and A-118313 A-118324 and A-118325 A-119324 and A-119325 A-119332 and A-119333 A-119328 and A-119329 A-119322 and A-119323 A-119324 and A-119325 A-119334 and A-119335 A-119330 and A-119331 A-119326 and A-119327 A-125167 and A-125173 or A-125647 A-125157 and A-125173 or A-125647 A-125127 and A-125173 or A-125647

[0178] In embodiments of the disclosure, C5 iRNA (e.g., semdisilane) has the structure: [ka] (wherein the wavy double helix-like structure represents the RNA portion of the molecule, and X is O or X is S); e.g., [ka] However, in embodiments of the present disclosure, the combination of the present disclosure further comprises degradation products lacking one, two, or three of the terminal N-acetylgalactosamines (GalNAc), represented by one or more of the following structures (the wavy lines represent double-stranded RNA structures):

[0179] [ka] (Semdisilane Impurity 1)

[0180] [ka] (Semdisilane impurity 2)

[0181] [ka] (Semdisilane impurity 3).

[0182] The iRNAs of this disclosure can be chemically linked through 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 lipid moieties, such as cholesterol moieties (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), thioethers, such as beryl-S-tritylthiol (Manoharan et al., Ann. NY Acad. Sci., 1992, 660:306-309; Manoharan et al., Biorg. Med. Chem. Let., 1993, 3:2765-2770), thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20:533-538), aliphatic chains, such as dodecanediol 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), phospholipids, such as 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), polyamines or polyethylene glycol chains (Manoharan et al., Nucleosides & Nucleotides, 1995, 14:969-973), or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654), palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264:229-237), or octadecylamine or hexylamino-carbonyloxycholesterol moiety (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277:923-937).

[0183] The ligand can be carbohydrate. Carbohydrate-conjugated RNA is advantageous for in vivo delivery of nucleic acid. As used herein, "carbohydrate" ligand refers to either a carbohydrate itself, which is composed of one or more monosaccharide units (can be linear, branched, or cyclic), with at least six carbon atoms, each of which is bound to an oxygen, nitrogen, or sulfur atom; or a compound that has a carbohydrate moiety as part thereof, which is composed of one or more monosaccharide units, each of which is bound to an oxygen, nitrogen, or sulfur atom (can be linear, branched, or cyclic). Representative carbohydrates include sugars (monosaccharides, disaccharides, trisaccharides, and oligosaccharides containing about 4, 5, 6, 7, 8, or 9 monosaccharide units), and polysaccharides, such as starch, glycogen, cellulose, and polysaccharide gums. Particular monosaccharides include C5 and higher (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).

[0184] In one embodiment, the carbohydrate conjugate for use in the compositions and methods of the present disclosure is a monosaccharide. In one embodiment, the monosaccharide is N-acetylgalactosamine, for example, when one of X or Y is an oligonucleotide, the other is hydrogen.

[0185] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is.

[0186] In some embodiments, the conjugates or ligands described herein can be attached to the iRNA oligonucleotides by various linkers, which can be cleavable or non-cleavable. The term "linker" or "linking group" refers to an organic moiety that connects two parts of a compound, e.g., covalently bonds two parts of a compound.A linker is typically a direct bond, or an atom, such as oxygen or sulfur, a unit, such as NR, C(O), C(O)NH, SO, SO, SONH, or a chain of atoms, including, 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, alkenylheteroarylalkynyl, alkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkenyl, alkylheterocyclylalkynyl, alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, and heterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, alkynylhetereroaryl, in which one or more methylenes may be interrupted or terminated by O, S, S(O), SO, N(R), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic; where R is hydrogen, acyl, aliphatic, or substituted aliphatic.In one embodiment, the linker is between about 1 and 24 atoms, between 2 and 24 atoms, between 3 and 24 atoms, between 4 and 24 atoms, between 5 and 24 atoms, between 6 and 24 atoms, between 6 and 18 atoms, between 7 and 18 atoms, between 8 and 18 atoms, between 7 and 17 atoms, between 6 and 16 atoms, between 7 and 16 atoms, or between 8 and 16 atoms. The linker may comprise a redox-cleavable linking group, a phosphate-based cleavable linking group, an acid-cleavable linking group, an ester-based linking group, and / or a peptide-based cleavage group.

[0187] [ka] (where x = 1 to 30, and y = 1 to 15);

[0188] [ka] (where y = 1 to 30, and y = 1 to 15);

[0189] [ka] (where x = 0-30, and y = 1-15);

[0190] [ka] (where x = 0-30, y = 1-15, and z = 1-20);

[0191] [ka] (where x = 1 to 30, y = 1 to 15, and z = 1 to 20);

[0192] [ka] (wherein x=1-30, y=1-15, and z=1-20); when one of X or Y is an oligonucleotide, the other is hydrogen. In certain embodiments of the compositions and methods of the present disclosure, the ligand is one or more GalNAc (N-acetylgalactosamine) derivatives attached via a bivalent or trivalent branched linker.

[0193] combination drug The present disclosure provides a method for producing a C5 antibody or antigen-binding fragment thereof comprising administering to a patient a pharmaceutically acceptable carrier and, separately, (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; H4H12166P 9;H4H12166P10;H4H12167P;H4H12168P;H4H12169P;H4H12170P;H4H12171P;H4H12175P;H4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N;H2M11695N;crovalimab;eculizumab, tesidolumab, muvozina or ravulizumab;preferably, pozelimab) and; (ii) a C5 iRNA, preferably a glycoconjugate, such as semdisilane.

[0194] The combination may be designated as antibody / iRNA; for example, "pozelimab / semdisirane" or "semdisirane / pozelimab" refers to a combination of the present disclosure that includes pozeliimab and semdisirane.

[0195] As used herein, a combination or pharmaceutical combination refers to a formulation comprising an anti-C5 antigen-binding protein (e.g., an antibody or antigen-binding fragment thereof), a C5 iRNA, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may include, for example, one or more excipients. In an embodiment of the present disclosure, the combination of the present disclosure is aqueous, i.e., comprises water.

[0196] Pharmaceutical formulations comprising anti-C5 antigen binding proteins can be prepared by mixing the antigen binding protein with one or more excipients (e.g., Hardman et al. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman et al. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipients, Marcel Dekker, NY). (See Toxicity and Safety, Marcel Dekker, Inc., New York, NY).

[0197] The present invention provides a method for producing a combination drug, comprising: + a salt; for example, C5 iRNA is reconstituted with water from its lyophilized composition); an antibody that specifically binds to C5 (e.g., pozelimab) or an antigen-binding fragment thereof; a buffering agent (e.g., histidine); a viscosity-reducing agent (e.g., L-arginine); a stabilizer (e.g., sucrose); and a non-ionic surfactant (e.g., polysorbate 80), and optionally adjusting the pH of the combination to a pH greater than or less than about 6 (e.g., about 6.5±0.2); and optionally, sterile filtering the combination.

[0198] The present disclosure provides a method for producing a combination of the present disclosure, the method comprising combining an RNAi (e.g., semdisiran) with an antibody or antigen-binding fragment (e.g., pozelimab) (e.g., containing a detectable amount of beta-hexosaminidase contaminant), and (i) adding GalNAc to the combination, and / or (ii) adjusting the pH of the combination to about 6 or less (e.g., within a range of 0.5 or greater). In embodiments of the present disclosure, other excipients, such as buffers, viscosity-reducing agents, stabilizers, and / or surfactants, are also added. A combination (e.g., semdisiran / pozelimab) produced by such a method is part of the present disclosure. In embodiments of the present disclosure, the antibody or fragment to be combined with other components is initially present in a lot containing beta-hexosaminidase contaminants and is diluted 0.25, 0.5, or 0.75 times when incorporated into the combination.

[0199] Various viscosity-reducing agents for use with combination preparations are known in the art. Viscosity-reducing agents are agents that can reduce the viscosity of a formulation. Viscosity-reducing agents can also function as tonicity agents that modulate the osmolality of a formulation. Such viscosity-reducing agents include adipic acid; amino acids or their salts; (D- or L-) arginine; L-arginine HCl; (D- or L-) alanine; benzenesulfonic acid; caffeine; dicarboxylic acids; esters of citric acid; (D- or L-) glutamic acid; glycine; (D- or L-) histidine; inorganic salts; L-ornithine; (D- or L-) lysine; proline; (D- or L-) phenylalanine; (D- or L-) serine; NaCl; pyridoxamine; pyridoxine; thiamine phosphate chloride dihydrate; triethyl citrate; (D- or L-) valine; and / or xanthine. In an embodiment of the present disclosure, the amino acid is an L-amino acid, such as L-arginine. L-arginine acts as a tonicity agent, stabilizer, and viscosity reducer. Arginine HCl can reduce the degradation of semdisilane, allowing for a nearly isotonic solution.

[0200] Stabilizers include agents that help reduce degradation, e.g., aggregation, of, for example, antibodies or antigen-binding fragments, such as sugars or polyols. Polyols are sugar alcohols with multiple hydroxyl groups. Stabilizers include sugars or polyols, such as trehalose, sorbitol, mannitol, taurine, propanesulfonic acid, L-proline, sucrose, glycerin, threitol, maltitol, and / or polyethylene glycol (PEG; e.g., PEG3350).

[0201] Nonionic surfactants contain molecules with an uncharged head group. Nonionic surfactants include polyoxyethylene moieties; sorbitan; polyoxyethylene glycol alkyl ethers, such as octaethylene glycol monododecyl ether; pentaethylene glycol monododecyl ether; polyoxypropylene glycol alkyl ethers; glucoside alkyl ethers, such as decyl glucoside, lauryl glucoside, and octyl glucoside; polyoxyethylene glycol octylphenol ethers, such as Triton X-100; polyoxyethylene glycol alkylphenol ethers, such as nonoxynol-9; glycerin alkyl esters, such as glycerin laurate. Nonionic surfactants include ceryl; polyoxyethylene glycol sorbitan alkyl esters, such as polysorbates; sorbitan alkyl esters, such as span; cocamide MEA, cocamide DEA, dodecyldimethylamine oxide; block copolymers of polyethylene glycol and polypropylene glycol, such as poloxamers; and polyethoxylated tallowamine (POEA); poloxamer 188, polyethylene glycol 3350, polyethylene glycol (e.g., PEG 3350), or polysorbates, such as polysorbate 80 (PS80) or polysorbate 20 (PS20). In an embodiment of the present disclosure, the nonionic surfactant is polysorbate-20 (PS20) or polysorbate-80 (PS80).

[0202] A buffer is a mixture of a weak acid and its conjugate base, or conversely, a conjugate acid and its weak base, which resists changes in pH and thus maintains a nearly constant pH. Various buffers, such as histidine-based buffers, phosphate buffers, or citrate buffers, can be used in the combinations of the present disclosure. Histidine-based buffers are buffers containing histidine. Examples of histidine buffers include histidine chloride, histidine hydrochloride, histidine acetate, histidine phosphate, and histidine sulfate.

[0203] The present disclosure encompasses combinations having any of the specifically recited ingredients, for example, in the specifically recited concentrations, wherein the pH of the combination is about 6.5.

[0204] In an embodiment of the present disclosure, the combination contains the impurity beta-hexosaminidase in an amount of, for example, about 0.04 to about 0.17 micrograms / ml, for example, when the pH of the combination is lower or higher than about 6 (e.g., at least 0.5), e.g., 6.5.

[0205] For example, the present disclosure provides a pharmaceutical combination (e.g., semdisirane / pozelimab) comprising: one or more C5 iRNAs, such as those described herein (e.g., semdisilane, preferably Na + form), for example, about 20-100, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg / ml (or higher, for example, 110, 115, 120, 130, 140, 150, 155, 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, or 400 mg / ml) (free acid form content is Na +can be determined by multiplying the concentration of the form by 0.9443); one or more C5 antibodies or antigen-binding fragments thereof (e.g., pozelimab), for example, at a concentration of 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 6;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;19 5;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); a viscosity-reducing agent, such as L-arginine (e.g., L-arginine HCl) (e.g., at a concentration of about 40 to 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); stabilizers, for example, sugars or polyols (for example, at a concentration of about 0.8 to about 3.6% (w / v), for example, about 1%) (for example, 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)); 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))); a buffering agent, e.g., a histidine-based buffering agent (e.g., at a concentration of about 10 to about 50 mM, e.g., 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; or 50 mM)); Includes; pH between about 5.5 and about 7.0, for example about 6.5; or a pH in the range of 6.0 to 0.5 or higher The present invention also includes a pharmaceutical combination having the formula:

[0206] In embodiments of the disclosure, the combination drug (e.g., semdisirane / pozelimab) is (e.g., together with a detectable amount of beta-hexosaminidase as discussed herein): a double-stranded C5 iRNA conjugated to a triantennary GalNAc moiety; and An anti-C5 antibody or antigen-binding fragment thereof expressed and isolated from a mammalian host cell containing beta-hexosaminidase; pH higher or lower than 6.0 (at least 0.5); C5 iRNA (e.g., conjugated to a triantennary GalNAc moiety), an anti-C5 antibody or antigen-binding fragment thereof (e.g., expressed and isolated from a mammalian host cell that contains beta-hexosaminidase); buffering agents, viscosity reducers, stabilizers, and nonionic surfactants; C5 iRNA (e.g., conjugated to a triantennary GalNAc moiety), an anti-C5 antibody or antigen-binding fragment thereof (e.g., expressed and isolated from a mammalian host cell that contains beta-hexosaminidase); histidine-based buffers, L-arginine, stabilizers, and nonionic surfactants; C5 iRNA (e.g., conjugated to a triantennary GalNAc moiety), an anti-C5 antibody or antigen-binding fragment thereof (e.g., expressed and isolated from a mammalian host cell that contains beta-hexosaminidase); histidine-based buffers, L-arginine, a sugar or polyol, and nonionic surfactants; Semudisilane, Pozelimab (e.g., expressed and isolated from a mammalian host cell that contains beta-hexosaminidase), histidine-based buffers, L-arginine, stabilizers, and nonionic surfactants, pH about 6.5; Semudisilane, Pozelimab (e.g., expressed and isolated from a mammalian host cell that contains beta-hexosaminidase), histidine-based buffers, L-arginine, sucrose, and Polysorbate 80, pH about 6.5; 100 (±10) mg / mL C5 iRNA, e.g., semdisilane (Na + form), 100 (±10) mg / mL anti-C5 antibody or antigen-binding fragment thereof, e.g., pozelimb (e.g., expressed and isolated from a mammalian host cell containing beta-hexosaminidase), 50 (±10) mM viscosity-reducing agent, e.g., L-arginine (e.g., L-arginine HCl), 10(±2) mM buffer, e.g., histidine-based buffer; 1.0 (±0.2)% stabilizer, e.g., sucrose, 0.075 (±0.00375)% nonionic surfactant, e.g., PS80, pH 6.5; 75 (±7.5) mg / mL C5 iRNA, e.g., semdisilane (Na + form), 150 (±15) mg / mL anti-C5 antibody or antigen-binding fragment thereof, e.g., pozelimb (e.g., expressed and isolated from a mammalian host cell containing beta-hexosaminidase), 75 (±15) mM viscosity-reducing agent, e.g., L-arginine (e.g., L-arginine HCl), 15(±3) mM buffer, e.g., a histidine-based buffer; 1.5 (±0.3)% stabilizer, e.g., sucrose, 0.1125 (±0.056)% nonionic surfactant, e.g., PS80, pH 6.5; 50 (±5) mg / mL C5 iRNA, e.g., semdisilane (Na + form), 100 (±10) mg / mL anti-C5 antibody or antigen-binding fragment thereof, e.g., pozelimb (e.g., expressed and isolated from a mammalian host cell containing beta-hexosaminidase), 75 mM (±15%) viscosity-reducing agent, e.g., L-arginine (e.g., L-arginine HCl), 15(±3) mM buffer, e.g., a histidine-based buffer; 1.5 (±0.3)% stabilizer, e.g., sucrose, 0.1125(±0.056)% nonionic surfactant, e.g., PS80; pH 6.5; 50 (±5) mg / mL C5 iRNA, e.g., semdisilane (Na + form), 100 (±10) mg / mL anti-C5 antibody or antigen-binding fragment thereof, e.g., pozelimb (e.g., expressed and isolated from a mammalian host cell containing beta-hexosaminidase), 75 (±15) mM viscosity-reducing agent, e.g., L-arginine (e.g., L-arginine HCl), 35(±7) mM buffer, e.g., a histidine-based buffer; 1.5 (±0.3)% stabilizer, e.g., sucrose, 0.1125 (±0.056)% nonionic surfactant, e.g., PS80, pH 6.5; 100 (±10) mg / mL C5 iRNA, e.g., semdisilane (Na+ form), 100 (±10) mg / mL anti-C5 antibody or antigen-binding fragment thereof, e.g., pozelimb (e.g., expressed and isolated from a mammalian host cell containing beta-hexosaminidase), 50 (±10) mM viscosity-reducing agent, e.g., L-arginine (e.g., L-arginine HCl), 30(±6) mM buffer, e.g., histidine-based buffer; 1 (±0.2)% stabilizer, e.g., sucrose, 0.075 (±0.00375)% nonionic surfactant, e.g., PS80, pH 6.5; 50 (±5) mg / mL C5 iRNA, e.g., semdisilane (Na + form), 100 (±10) mg / mL anti-C5 antibody or antigen-binding fragment thereof, e.g., pozelimb (e.g., expressed and isolated from a mammalian host cell containing beta-hexosaminidase), 90 (±18) mM viscosity-reducing agent, e.g., L-arginine (e.g., L-arginine HCl), 30(±6) mM buffer, e.g., histidine-based buffer; 1 (±0.2)% stabilizer, e.g., sucrose, 0.075 (±0.00375)% nonionic surfactant, e.g., PS80, pH 6.5; 100mg / mL semdisilane (Na + form), 100 mg / mL pozelimab, 50 mM L-arginine (e.g., L-arginine HCl), 30mM histidine-based buffer, 1% (w / v) sucrose, 0.075% (w / v) PS80, pH 6.5; 50mg / mL semdisilane (Na + form), 100 mg / mL pozelimab, 90 mM L-arginine (e.g., L-arginine HCl), 30mM histidine-based buffer, 1% (w / v) sucrose, 0.075% (w / v) PS80, pH 6.5; 100mg / mL semdisilane (Na + form), 100 mg / mL pozelimab, 50 mM L-arginine (e.g., L-arginine HCl), 10mM histidine-based buffer, 1.0% sucrose, 0.075%PS80, pH 6.5; 75mg / mL semdisilane (Na + form), 150 mg / mL pozelimab, 75 mM L-arginine (e.g., L-arginine HCl), 15mM histidine-based buffer, 1.5% sucrose, 0.1125%PS80, pH 6.5; 50mg / mL semdisilane (Na + form), 100 mg / mL pozelimab, 75 mM L-arginine (e.g., L-arginine HCl), 15mM histidine-based buffer, 1.5% sucrose, 0.1125%PS80; pH 6.5; 50mg / mL semdisilane (Na + form), 100 mg / mL pozelimab, 75 mM L-arginine (e.g., L-arginine HCl), 35mM histidine-based buffer, 1.5% sucrose, 0.1125%PS80, pH 6.5; 100mg / mL semdisilane (Na + form), 100 mg / mL pozelimab, 50 mM L-arginine (e.g., L-arginine HCl), 30mM histidine-based buffer, 1% sucrose, 0.075%PS80, pH 6.5; Na + 47.2 mg / mL semdisilane (free acid form (FAF)) molecule, which may be in any salt form such as 100 mg / mL pozelimab, 30mM histidine, 90mM L-arginine, 1% (w / v) sucrose, 0.075% (w / v) polysorbate 80 (e.g., highly purified grade (SR)), pH 6.5 50mg / mL semdisilane (Na + form), 100 mg / mL pozelimab, 90 mM L-arginine (e.g., L-arginine HCl), 30 mM buffer, e.g., a histidine-based buffer; 1% stabilizer, e.g., sucrose, 0.075%PS80, pH 6.5 Includes; Optionally, any of the combinations provided herein further comprise GalNAc or GlcNAc, for example, about 5% (w / v).

[0207] In embodiments of the present disclosure, the combination drug of the present disclosure comprises an antibody and an iRNA in association with an additional therapeutic agent, such as, for example, an anticoagulant, warfarin, aspirin, heparin, phenindione, fondaparinux, idraparinux, a thrombin inhibitor, argatroban, lepirudin, bivalirudin, dabigatran, an anti-inflammatory drug, a corticosteroid, a nonsteroidal anti-inflammatory drug (NSAID), an antihypertensive drug, angiotensin-converting enzyme inhibitor, an immunosuppressant, vincristine, cyclosporine A, or methotrexate, a thrombolytic 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-TNF-alpha agent, infliximab, an anticonvulsant, magnesium sulfate, a C3 inhibitor, and / or an antithrombotic agent.

[0208] The term "in association with" indicates that the combination is provided with (2) one or more additional therapeutic agents, e.g., methotrexate, which can be formulated in a single composition, e.g., for simultaneous delivery, or can be formulated separately into two or more compositions (e.g., a kit including each component, e.g., a kit in which the additional therapeutic agents are in separate formulations). Components administered in association with each other can be administered to a subject at the same time or at a different time than when the other components are administered; for example, each administration can be administered simultaneously (e.g., together in a single composition or essentially simultaneously during the same administration session), or can be administered non-concurrently at one or more intervals over a given period of time. Furthermore, separate components administered in association with each other can be administered to a subject by the same route or by different routes. Thus, the present disclosure includes combinations in association with additional therapeutic agents, as well as methods of treating or preventing a C5-related disease or disorder (e.g., PNH, MG, or CHAPLE) in a subject by administering a combination of the present disclosure in association with an additional therapeutic agent to a subject in need thereof.

[0209] The present disclosure includes combinations described herein in which the antibody and / or iRNA concentration is ±10% of the indicated value; the surfactant concentration is ±50% of the indicated value; and / or any other excipient concentration (e.g., viscosity-lowering agent, buffer, stabilizer) or pH is ±20% of the indicated value.

[0210] In an embodiment of the present disclosure, the combination drug of the present disclosure comprises: Contains about 0.04 to 0.17 micrograms / ml (e.g., about 0.04; 0.05; 0.06; 0.06; 0.0605; 0.0605; 0.0605; 0.063; 0.07; 0.07; 0.0765; 0.078; 0.08; 0.14; 0.141; 0.15; 0.1525; 0.166; or 0.17 micrograms / ml (or at most such amount)) of beta-hexosaminidase; ·It is a clear to slightly translucent liquid; ·Essentially free of visible particulates; · Colorless to yellow; characterized by a ratio of semdisirane concentration:pozelimab concentration of about 1:1, 1:2, 1:3, 1:4, 1:5, or 2:3, e.g., a viscosity of less than about 20 cP or less than about 30 cP at 20°C; · have a viscosity of <30 cP (at 20°C) (e.g., about 6, 10, 20, or 30 cP); having an osmolality of 266 to 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) mOsm / kg; · having a density of about 1.1 or 1.061 g / ml; ·Has a pH of approximately 6.5 ± 0.2; ·Having a pH higher than 6, which results in a significant reduction in semdisilane decomposition at 40°C, 25°C, and 2-8°C compared to pH 6; dIPRP demonstrates semdisirane purity (%) of approximately 90.5% at t=0; 91.1% after 1 month of storage at 2-8°C; 90.8% after 3 months of storage at 2-8°C; 90% after 6 months of storage at 2-8°C; 88.8% after 9 months of storage at 2-8°C; 88.7% after 12 months of storage at 2-8°C; 89% after 18 months of storage at 2-8°C; 89.4% after 24 months of storage at 2-8°C; and / or 87.4% after 36 months of storage at 2-8°C, e.g., the combination was liquid (aqueous) during storage and contains 100 mg / ml semdisirane and 100 mg / ml pozelimab (e.g., at pH 6.0); e.g., the combination contains approximately 60.5 ng / ml beta-hex; dIPRP demonstrates semdisirane purity (%) of approximately 90.8% at t=0; 90.6% after 1 month of storage at 2-8°C; 90.5% after 3 months of storage at 2-8°C; 89.4% after 6 months of storage at 2-8°C; 88.3% after 9 months of storage at 2-8°C; 87.8% after 12 months of storage at 2-8°C; 87.8% after 18 months of storage at 2-8°C; and / or 87.4% after 24 months of storage at 2-8°C and / or approximately 85.4% after 36 months of storage at 2-8°C; e.g., the combination was liquid (aqueous) during storage and contains 75 mg / ml semdisirane and 150 mg / ml pozelimab (e.g., at pH 6.0); e.g., the combination contains approximately 60.5 ng / ml beta-hex; dIPRP shows semdisirane single-chain purity (%) of approximately 90.5% at t=0; 90.2% after 1 month of storage at 25°C and 60% RH (relative humidity); 87.8% after 3 months of storage at 25°C and 60% RH; 85.1% after 6 months of storage at 25°C and 60% RH; 90% after 0.5 months of storage at 40°C and 75% RH; 88.9% after 1 month of storage at 40°C and 75% RH; and 85.8% after 3 months of storage at 40°C and 75% RH; for example, the combination was liquid (aqueous) during storage and contains 100 mg / ml semdisirane and 100 mg / ml pozelimab (e.g., at pH 6.0); for example, the combination contains approximately 60.5 ng / ml beta-hex; - exhibiting a semdisilane single-chain purity (%) of about 91.4% after about 48 hours of stirring and / or about 90.7% after about 4 freeze-thaw cycles by dIPRP, e.g., the combination was liquid (aqueous) and contained 100 mg / ml semdisilane and 100 mg / ml pozelimab (e.g., at pH 6.0); dIPRP shows semdisilane purity (%) of approximately 90.8% at t=0; 88.8% after 1 month of storage at 25°C and 60% RH; 85.9% after 3 months of storage at 25°C and 60% RH; 82.3% after 6 months of storage at 25°C and 60% RH; 88.9% after 0.5 months of storage at 40°C and 75% RH; 87.3% after 1 month of storage at 40°C and 75% RH; and 82.3% after 3 months of storage at 40°C and 75% RH; e.g., the combination was liquid (aqueous) during storage and contains 75 mg / ml semdisilane and 150 mg / ml pozelimab (e.g., at pH 6.0); e.g., the combination contains approximately 60.5 or 91 ng / ml beta-hex; - exhibiting a semdisilane purity (%) of about 90.7% after about 48 hours of stirring and / or about 91.2% after about 4 freeze-thaw cycles by dIPRP, e.g., the combination was liquid (aqueous) and contained 75 mg / ml semdisilane and 150 mg / ml pozelimab (e.g., at pH 6.0); After 48 hours of agitation on an orbital shaker at 250 rpm, the presence of 0.025% nonionic surfactant (e.g., polysorbate 80) does not show a significant increase (e.g., within 5%) in detectable high molecular weight species (HMW species) compared to the presence of 0.050, 0.075, 0.100, 0.125, 0.150, 0.175, or 0.200% (w / v); for example, a combination of 50 or 100 mg / mL semdisilane and 100 mg / mL Pozellimab, for example, 100 mg / mL semdisiran, 100 mg / mL pozellimab, 50 mM arginine HCl, 30 mM histidine, 1% sucrose, X% PS80, pH 6.5, or 50 mg / mL semdisiran, 100 mg / mL pozellimab, 90 mM arginine HCl, 30 mM histidine, 1% sucrose, X% PS80, pH 6.5 (where X is about 0.025% to about 0.2% (w / v), for example, 0.075%); dIPRP shows semdisilane purity (%) of about 90.9% at t=0; about 90.1% after 1 month of storage at 25°C and 60% RH; about 90.9% after 3 months of storage at 25°C and 60% RH; about 90.4% after 6 months of storage at 25°C and 60% RH; about 89.9% after 0.5 months of storage at 40°C and 75% RH; about 89.7% after 1 month of storage at 40°C and 75% RH; and / or about 89.5% after 3 months of storage at 40°C and 75% RH; for example, the combination was liquid (aqueous) during storage and contained 50 mg / ml semdisilane and 100 mg / ml pozelimab, pH 6, and 5% GlcNAc; for example, the combination contains about 78 ng / ml beta-hex; dIPRP shows semdisilane purity (%) of about 90.8% at t=0; about 90.2% after 1 month of storage at 25°C and 60% RH; about 90.8% after 3 months of storage at 25°C and 60% RH; about 90.3% after 6 months of storage at 25°C and 60% RH; about 89.5% after 0.5 months of storage at 40°C and 75% RH; about 89.6% after 1 month of storage at 40°C and 75% RH; and / or about 89.1% after 3 months of storage at 40°C and 75% RH; for example, the combination was liquid (aqueous) during storage and contained 50 mg / ml semdisilane and 100 mg / ml pozelimab, pH 6, and 5% GalNAc; for example, the combination contains about 78 ng / ml beta-hex; exhibiting a semdisilane purity (%) of about 90.5% at t=0 by dIPRP; about 89.9% after 1 month of storage at 25°C and 60% RH; about 90.8% after 3 months of storage at 25°C and 60% RH; about 90.4% after 6 months of storage at 25°C and 60% RH; about 90.1% after 0.5 months of storage at 40°C and 75% RH; about 89.6% after 1 month of storage at 40°C and 75% RH; and / or about 89.9% after 3 months of storage at 40°C and 75% RH; e.g., the combination was liquid (aqueous) during storage and contained 100 mg / ml semdisilane and 100 mg / ml pozelimab, pH 6, and 5% GlcNAc; e.g., the combination contains about 78 ng / ml beta-hex; and / or dIPRP shows semdisilane purity (%) of about 91.1% at t=0; about 90% after 1 month of storage at 25°C and 60% RH; about 91% after 3 months of storage at 25°C and 60% RH; about 90.7% after 6 months of storage at 25°C and 60% RH; about 90% after 0.5 months of storage at 40°C and 75% RH; about 89.7% after 1 month of storage at 40°C and 75% RH; and / or about 89.9% after 3 months of storage at 40°C and 75% RH; for example, the combination was liquid (aqueous) during storage and contained 100 mg / ml semdisilane and 100 mg / ml pozelimab, pH 6, and 5% GalNAc; for example, the combination contains about 78 ng / ml beta-hex.

[0211] Anti-C5 and C5 iRNA Combination Therapy Dosing Regimen The present disclosure includes methods (combination therapies of the present disclosure) comprising administering to a subject in need thereof having a disease, disorder, or condition associated with C5 an anti-C5 antibody or antigen-binding fragment thereof in combination with a C5 iRNA (e.g., in the form of a combination drug comprising both the antibody or fragment and the iRNA, e.g., as described herein), at dosages and frequencies that achieve a safe and effective therapeutic response.

[0212] In some embodiments, the present disclosure relates to administering 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., semdisiran). Preferably, the administration is in a combination of the present disclosure (as discussed herein), e.g., 100:100 or 50:100 (semdisiran mg / ml:pozelimab mg / ml), e.g., in an injection volume of about 2 ml.

[0213] Generally, combinations comprising semdisirane and pozelimab may be referred to herein in the following formats: 100:100, 75:150, or 50:100. When referring to such combinations in this format, the first number indicates mg / ml of semdisirane and the second number indicates mg / ml of pozelimab.

[0214] "Dosing regimen" or "combination therapy dosing regimen" refers to a method for treating or preventing a C5-related disease or disorder or condition (preferably PNH) comprising administering an amount of the combination therapy of the present disclosure at a frequency discussed herein.

[0215] For example, the disclosure encompasses methods for administering an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA, comprising introducing the agents into a subject's body, e.g., by injection, e.g., by subcutaneous injection or intravenous infusion, e.g., according to a schedule conforming to any of the dosing regimens discussed herein (e.g., about 400 mg of an anti-C5 antibody or antigen-binding fragment (e.g., pozeliman) subcutaneously about every 2-4 weeks (± 3, 4, 5, 6, or 7 days) and about 200 mg of an iRNA (e.g., semdisiran) subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days)).

[0216] Accordingly, the present disclosure provides a method for treating or preventing a C5-related disease or disorder (e.g., dry AMD or MG; preferably, PNH) in a subject in need thereof, comprising administering to the subject an anti-C5 antibody or antigen-binding fragment thereof ("anti-C5 Ab") and a C5 iRNA according to the following: (i) one or more doses of about 400 mg of an anti-C5 Ab (e.g., pozelimab) subcutaneously and about 200 mg of a C5 iRNA (e.g., semdisiran) subcutaneously; (ii) about 400 mg of an anti-C5 Ab (e.g., pozelimab) is administered subcutaneously about every two weeks, and about 200 mg of a C5 iRNA (e.g., semdisiran) is administered subcutaneously about every four weeks, preferably with a single injection of a combination comprising the anti-C5 Ab and the C5 iRNA administered every four weeks (Q4W), and a separate additional injection of the anti-C5 Ab, but not the C5 iRNA, administered once every two weeks (Q2W); (iii) about 400 mg of an anti-C5 Ab (e.g., pozelimab) administered subcutaneously about every four weeks and about 200 mg of a C5 iRNA (e.g., semdisirane) administered subcutaneously about every four weeks, preferably a single injection of a combination comprising an anti-C5 Ab and a C5 iRNA administered subcutaneously about every four weeks; or (iv) About 400 mg of anti-C5 Ab (e.g., pozelimab) and about 200 mg of C5 iRNA (e.g., semdisiran) administered subcutaneously in a 50:100 combination of about 4 ml about every 4 weeks.

[0217] In an embodiment of the present disclosure, the subject Approximately 400 mg of anti-C5 antibody or antigen-binding fragment (e.g., pozelimab) subcutaneously approximately every 2 to 4 weeks (± 3, 4, 5, 6, or 7 days); and Approximately 200 mg of iRNA (e.g., semdisilane) subcutaneously every 2 to 4 weeks (e.g., 4 weeks) (± 3, 4, 5, 6, or 7 days) are administered in parallel.

[0218] The present disclosure relates to a method for manufacturing a device comprising: Approximately 400 mg of anti-C5 antibody or antigen-binding fragment subcutaneously approximately every 2 weeks (± 3, 4, 5, 6, or 7 days); and A 200 mg dose of C5 iRNA subcutaneously every 4 weeks (± 3, 4, 5, 6, or 7 days) are administered concurrently.

[0219] This disclosure is directed to: Approximately 400 mg of anti-C5 antibody or antigen-binding fragment subcutaneously approximately every 4 weeks (± 3, 4, 5, 6, or 7 days); and A 200 mg dose of C5 iRNA subcutaneously every 4 weeks (± 3, 4, 5, 6, or 7 days) (Sometimes referred to herein as "pozelimab Q4W and semdisirane" or "pozelimab 400 mg SC Q4W + semdisirane 200 mg SC Q4W") are administered concurrently.

[0220] Switching from pozelimab monotherapy For example, a dosing regimen provided herein comprising anti-C5 and C5 iRNA for a subject who has previously received pozeliman monotherapy, e.g., a dosing regimen for treating a C5-related disease or disorder or condition, e.g., PNH, may be referred to herein as a "pozeliman monotherapy switch" regimen.

[0221] In an embodiment of the invention, the regimen is as follows: On Day 1 (7-8 days after the last dose of pozeliman monotherapy) or when the next dose of pozeliman monotherapy is scheduled, the subject receives: (1) Pozelimab 400 mg SC every 4 weeks (Q4W) and semdisiran 200 mg SC Q4W; or (2) Pozelimab 400 mg SC every 2 weeks (Q2W) and semdisiran 200 mg SC Q4W You will begin to receive either of the following.

[0222] Pozelimab monotherapy includes treatment of a C5-associated disease or disorder or condition (preferably PNH) with pozeliimab (e.g., not with both pozeliimab and eculizumab) as the only C5-specific inhibitor, or more specifically, an anti-C5 antibody or antigen-specific fragment. In embodiments of the present disclosure, prior to receiving the combination therapy discussed herein, 400 mg anti-C5 antibody or antigen-binding fragment SC about every 2, 3, or 4 weeks and about 400 mg C5 iRNA SC about every 4 weeks, the subject has completed a dosing regimen conforming to the following: (i) intravenously (IV) one or more doses of about 30 mg / kg of the antigen binding protein; then (ii) one or more doses of about 800 mg of pozelimab subcutaneously (SC) (e.g., once weekly) [sometimes referred to as the maintenance phase]; e.g., if the subject has PNH; or (a) intravenously (IV) one or more doses, preferably only one dose, of about 30 mg / kg of pozelimab; then (b) one or more doses of 10 mg / kg pozelimab subcutaneously (SC) (e.g., once weekly) [sometimes called the maintenance phase]; For example, if the subject suffers from CHAPLE; or (a) intravenously (IV) one or more doses, preferably only one dose, of about 30 mg / kg of pozelimab; then (b) Subcutaneously (SC), one or more doses of pozelimab (e.g., once weekly) according to the following: - Body weight (BW) < approx. 10 kg: approx. 125 mg; - BW ≥ 10 kg and < approx. 20 kg: approx. 200 mg; - BW ≥ 20 kg and < approx. 40 kg: approx. 350 mg; - BW ≥ 40 kg and < approximately 60 kg: approximately 500 mg; and - For BW ≥ 60 kg: approximately 800 mg; [Sometimes called the maintenance phase] For example, if the subject suffers from CHAPLE; The subject may complete one or more of these doses and transition to combination therapy at any time (e.g., from the maintenance phase). In embodiments of the present disclosure, the subject may begin receiving the combination of anti-C5 and C5 iRNA on the day the next dose of pozeliman monotherapy is scheduled to be administered, and discontinue monotherapy at that time. For example, the subject may: (i) one or more doses of approximately 800 mg of subcutaneously (SC) pozelimab; (ii) one or more doses of about 30 mg / kg intravenously (IV) pozelimab; (iii) one or more doses of approximately 125 mg of subcutaneously (SC) pozelimab; (iv) one or more doses of approximately 200 mg of subcutaneously (SC) pozelimab; (v) one or more doses of approximately 350 mg of subcutaneously (SC) pozelimab; (vi) one or more doses of about 500 mg of subcutaneously (SC) pozeli- mab; (vii) one or more doses of approximately 800 mg of subcutaneously (SC) pozelimab; (viii) one or more doses of 10 mg / kg subcutaneously (SC) pozelimab and then transition from pozeliman monotherapy and receive the first dose of the combination, e.g., receive the first dose of the combination on the day that the dose labeled in (i), (ii), (iii), (iv), (v), (vi), (vii), or (viii) would have been scheduled or about 1 week after receiving the last dose of pozeliman monotherapy.

[0223] In an embodiment of the disclosure, the subcutaneous pozelimab monotherapy dose is about: Pozelimab 161-274 mg / ml or more, a pharmaceutically acceptable carrier, including a buffer; L-arginine; water; and optionally an oligosaccharide (e.g., sucrose, mannitol, dextrose, glycerin, TMAO (trimethylamine N-oxide), trehalose, ethylene glycol, glycine betaine, xylitol, or sorbitol); and optionally a non-ionic surfactant (e.g., polysorbate-20, polysorbate-80). and a pH of up to about 5.8, 6.1, or 5.5-6.1; and a viscosity of about 6.8, about 9.6, about 11.9, about 13.2, about 16.7, about 20.6, about 33.0, about 48.4, about 13.2-16.7, or about 6.8-48.4 at 20° C. An intravenous dose of pozeliman monotherapy can be administered after incorporating the formulation into an aqueous intravenous solution (e.g., 0.9% saline).

[0224] Complement inhibitor naive Naive or complement inhibitor-naive patients have not received complement inhibitor therapy (e.g., eculizumab, ravulizumab, pozelimab) in the past or recently (e.g., within the last 1, 2, 3, 4, 5, or 6 months or at least about 4 or 5 half-lives of the last complement inhibitor they received).

[0225] In an embodiment of the present disclosure, a complement inhibitor naive subject is administered a C5-associated disease or disorder or condition (preferably PNH) with: Day 1: Pozelimab 30 mg / kg intravenously (IV) in a single loading dose and (e.g., optionally followed by a delay of at least about 30 minutes) 400 mg subcutaneously (SC) with semdisirane 200 mg SC (combined maintenance dose); Starting on day 29 or approximately 4 weeks later: Pozelimab 400 mg SC every 4 weeks (q4W) and semdisiran 200 mg SC q4W (e.g., semdisiran / pozelimab combination). The subject is treated by a method comprising administering

[0226] In an embodiment of the present disclosure, a complement inhibitor naive subject is administered a C5-associated disease or disorder or condition (preferably PNH) with: (i) on day 1, a single loading dose of about 30 mg / kg intravenously (IV) of an anti-C5 antibody or antigen-binding fragment, preferably pozelimab, followed by about 400 mg subcutaneously (SC) of an anti-C5 antibody or fragment and about 200 mg SC of a C5 iRNA, preferably semdisiran; and (ii) beginning on about day 29, about a 400 mg SC dose of anti-C5 antibody or fragment Q4W and about a 200 mg SC dose of C5 iRNA Q4W The subject is treated by a method comprising administering

[0227] During the transition from eculizumab or ravulizumab to a therapy including an anti-C5 Ab (e.g., pozelimulab) and a C5 iRNA (e.g., semdisiran), an additional dose of pozelimulab (e.g., a dose of 30 or 60 mg / kg IV) may be administered in situations such as when an adverse event (AE) potentially due to large drug-target-drug (DTD) immune complexes is possible or suspected to have occurred and / or when systemic corticosteroids are administered for a Type III hypersensitivity reaction. This additional dose will establish a state of circulating pozelimulab excess, thereby minimizing the risk of further immune complex formation.

[0228] Switching from eculizumab therapy For example, a dosing regimen for a subject who has previously received eculizumab, such as that described above, may be referred to herein as an "eculizumab switch" regimen. Preferably, the subject is undergoing treatment for a disease or disorder or condition associated with C5, such as PNH.

[0229] In an embodiment of the present disclosure, the eculizumab switching regimen has the following induction loading phase and switching phase:

[0230] introduction Initially, subjects will continue to receive eculizumab background treatment at their usual dose / usual frequency, and semdisirane alone will be introduced as follows: On Day 1 (the day of scheduled eculizumab administration for subjects, preferably those receiving a q2w eculizumab maintenance regimen): semdisiran 200 mg SC and eculizumab ≥ 900 mg IV (subject's usual dose). Note: If semdisiran is not administered on Day 1, eculizumab can be administered up to 2 days after semdisiran; On day 15 (± 2 days), for subjects receiving eculizumab q14 days (labeled dose regimen): labeled eculizumab dose [for subjects receiving eculizumab more frequently than q14 days: dose patients within 2 days of their usually scheduled dose]; switching On day 29 (or week 4, counting from day 1, or approximately 2 weeks later, or when the next eculizumab dose is scheduled, or approximately 1 to 2 half-lives of eculizumab): pozelimuab 60 mg / kg IV loading dose and (e.g., followed, optionally with a delay of at least about 30 minutes) pozelimuab 400 mg SC and semdisiran 200 mg SC (e.g., in a semdisiran / pozelimab combination); and Starting on day 57 (or day 8; or approximately 4 weeks later): Pozelimab 400 mg SC and semdisirane 200 mg SC q4W maintenance regimen (± 7 days) (e.g., with semdisirane / pozelimab combination) [sometimes called the maintenance phase].

[0231] In embodiments of the invention, the eculizumab half-life (e.g., in a subject with PNH) is about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days, e.g., about 11 days (Wijnsma et al., Pharmacology, Pharmacokinetics and Pharmacodynamics of Eculizumab, and Possibilities for an Individualized Approach to Eculizumab. Clin Pharmacokinet. 2019 Jul;58(7):859-874; Al-Ani et al., Eculizumab in the management of paroxysmal nocturnal hemoglobinuria: patient selection and special considerations. Ther Clin Risk Manag. 2016 Aug 1;12:1161-70).

[0232] In an embodiment of the present disclosure, the dosing regimen includes: (i) the first dose of eculizumab intravenously (on day 1; e.g., on the day the next dose of eculizumab is scheduled or within 2 days before) (at the subject's usual dose, e.g., ≥ approximately 900 mg) and approximately 200 mg of C5 iRNA subcutaneously; (ii) a second dose of eculizumab (at the subject's usual dose, e.g., ≥ about 900 mg) until approximately 14 days (± 2 days) later; (iii) on about day 29 (week 4): intravenously (IV) anti-C5 Ab at a dose of about 60 mg / kg, followed by subcutaneous anti-C5 Ab at a dose of about 400 mg and subcutaneous C5 iRNA at a dose of about 200 mg; and (iv) From day 57 (week 8) onwards, anti-C5 Ab at a dose of about 400 mg subcutaneously approximately every 4 weeks (± 3, 4, 5, 6 or 7 days) and C5 iRNA at a dose of about 200 mg subcutaneously approximately every 4 weeks (± 3, 4, 5, 6 or 7 days).

[0233] The prescribed dosing regimen for treatment of PNH with eculizumab (e.g., for subjects aged 18 years and older) is as follows: 600 mg once a week for the first 4 weeks, followed by 900 mg for the fifth dose one week later, then · 900mg every 2 weeks thereafter.

[0234] The prescribed dosing regimen for the treatment of aHUS with eculizumab is as follows: 900 mg once a week for the first 4 weeks, followed by 1200 mg for the fifth dose one week later, then · 1200mg every 2 weeks thereafter.

[0235] The prescribed dosing regimen for eculizumab for the treatment of generalized myasthenia gravis or neuromyelitis optica is as follows: 900 mg once a week for the first 4 weeks, followed by 1200 mg for the fifth dose one week later, then · 1200mg every 2 weeks thereafter. See Soliris® prescribing information. In embodiments of the present disclosure, the subject has previously received at least 12 weeks of eculizumab treatment.

[0236] In an embodiment of the disclosure, eculizumab is administered to a subject at a dose obtained from a pharmaceutical formulation comprising 300 mg of eculizumab, polysorbate 80 (6.6 mg) (vegetable source), sodium chloride (263.1 mg), sodium phosphate dibasic (53.4 mg), sodium phosphate monobasic (13.8 mg), and water for injection, USP, at a pH of 7 and in a volume of 30 mL. See Soliris® prescribing information.

[0237] Switching from ravulizumab therapy A dosing regimen for a subject who has previously received ravulizumab, such as those described above, may be referred to herein as a "ravulizumab switch" regimen. Preferably, the subject is undergoing treatment for a disease, disorder, or condition associated with C5, such as PNH.

[0238] In an embodiment of the disclosure, the ravulizumab switching regimen is as follows: Day 1 (4 weeks after the last dose of ravulizumab, preferably if the subject is receiving a q8w ravulizumab maintenance regimen): semdisiran 200 mg SC; On day 29 or 4 weeks later or 8 weeks after the last dose of ravulizumab or 1 to 2 half-lives of ravulizumab: pozelimuab 30 mg / kg or 60 mg / kg single IV loading dose and (e.g., followed, optionally with a delay of at least about 30 minutes) pozelimuab 400 mg SC and semdisirane 200 mg SC (e.g., in a semdisirane / pozelimab combination); and Starting on day 57 or 4 weeks later or 1–2 half-lives after ULTOMIRIS: Start a maintenance regimen of pozelimab 400 mg SC q4W and semdisirane 200 mg SC (e.g., semdisirane / pozelimab combination) q4W.

[0239] In embodiments of the invention, the half-life of ravulizumab (e.g., in subjects with PNH) is about 32 days (Stern et al., Ravulizumab: a novel C5 inhibitor for the treatment of paroxysmal nocturnal hemoglobinuria. Ther Adv Hematol. 2019 Sep 10;10:2040620719874728; Lee et al., Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2019 Feb 7;133(6):530-539; Lee et al., Immediate, complete, and sustained inhibition of C5 with ALXN1210 reduces complement-mediated hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH): interim analysis of a dose-escalation study). study[abstract].Blood.2016;128(22).Abstract 2428).

[0240] In embodiments of the present disclosure, a subject is treated for a C5-associated disease or disorder or condition (preferably PNH), and the subject previously received ravulizumab (e.g., according to a prescribed dosing regimen) and is switching to a treatment regimen with a different anti-C5 antibody or antigen-binding fragment (anti-C5 Ab), preferably pozelimab, and a C5 iRNA (C5 iRNA), preferably semdisirane, and is administered: (i) Day 1 (e.g., 4 weeks (± 7 days) or 26 days (± 7 days) or 27 days (± 7 days) or 28 days (± 7 days) after the last dose of ravulizumab), C5 iRNA 200 mg SC; (ii) On about day 29, a single IV loading dose of anti-C5 Ab at 30 mg / kg or 60 mg / kg. This IV loading dose may be followed by a 30-minute observation period. The IV dose is followed by an additional loading dose of anti-C5 Ab 400 mg SC and C5 iRNA 200 mg SC; (iii) On about day 57, a maintenance regimen of anti-C5 Ab 400 mg SC and C5 iRNA 200 mg SC may be initiated and followed; (iv) Approximately every 4 weeks thereafter, administer 400 mg SC of anti-C5 Ab and 200 mg SC of C5 iRNA.

[0241] The ULTOMIRIS loading dose on Day 1 may depend on the patient's weight (≥40 kg to <60 kg, 2400 mg IV; ≥60 kg to <100 kg, 2700 mg IV; ≥100 kg, 3000 mg IV). The initial maintenance dose, administered 2 weeks after the loading dose, is as follows: (≥40 kg to <60 kg, 3000 mg IV; ≥60 kg to <100 kg, 3300 mg IV; ≥100 kg, 3600 mg IV). Thereafter, maintenance doses should be administered IV Q8W (±7 days).

[0242] The subcutaneous maintenance dose of ULTOMIRIS is 490 mg once weekly for adult patients weighing 40 kg or more, e.g., for adult patients with PNH or aHUS. The subcutaneous dosing schedule may vary by ±1 day on the scheduled dose, but subsequent doses should be administered according to the original schedule.

[0243] The prescribed dosing regimen for the treatment of PNH with ULTOMIRIS is as follows: · For patients weighing less than 5 to 10 kg, a loading dose of 600 mg and a maintenance dose of 300 mg every 4 weeks; · For patients weighing 10 to less than 20 kg, a loading dose of 600 mg and a maintenance dose of 600 mg every 4 weeks; · For patients weighing less than 20 to 30 kg, a loading dose of 900 mg and a maintenance dose of 2,100 mg every 8 weeks; · For patients weighing less than 30-40 kg, a loading dose of 1,200 mg and a maintenance dose of 2,700 mg every 8 weeks; · For patients weighing 40 to less than 60 kg, a loading dose of 2,400 mg and a maintenance dose of 3,000 mg every 8 weeks; For patients weighing 60 to less than 100 kg, a loading dose of 2,700 mg and a maintenance dose of 3,300 mg every 8 weeks; and For patients weighing 100 kg or more, a loading dose of 3,000 mg and a maintenance dose of 3,600 mg every 8 weeks. See Ultomiris® prescribing information.

[0244] The subcutaneous ravulizumab maintenance dose can be 490 mg once weekly for adult PNH patients weighing 40 kg or more. Patients not currently receiving ravulizumab or eculizumab treatment who weigh ≥ 40 kg at the time of treatment initiation can begin a subcutaneous dose of ravulizumab approximately two weeks after the intravenous ravulizumab loading dose. Patients currently being treated with eculizumab who weigh ≥ 40 kg at the time of their next scheduled eculizumab dose can begin a subcutaneous dose of ravulizumab approximately two weeks after the intravenous ravulizumab loading dose. Patients currently being treated with intravenous (IV) ravulizumab can begin a subcutaneous dose of ravulizumab approximately eight weeks after the final intravenous ravulizumab maintenance dose. In an embodiment of the present disclosure, the subject has previously received at least 24 weeks of ravulizumab treatment.

[0245] [Table 4]

[0246] As discussed, the subject may have previously received pozelimuab monotherapy, e.g., subcutaneously (SC) at a dosage of about 800 mg every 1, 2, 3, or 4 weeks (which may have been preceded by a loading dose of pozelimuab, e.g., intravenously), or ravulizumab or eculizumab, e.g., according to a prescribed dosing regimen. Patients who have previously received pozelimuab monotherapy, ravulizumab, or eculizumab may be in any phase of the prescribed antibody dosing regimen before switching to the combination therapy of the present disclosure. For example, the subject may have received one or more loading doses and / or one or more maintenance doses of eculizumab. In an embodiment of the invention, when a subject is switching from eculizumab or ravulizumab or another anti-C5 antibody or antigen-binding fragment thereof, the subject receives an intravenous loading dose of pozelimuab (e.g., 30 mg / kg or 60 mg / kg) and / or a single SC dose of semdisirane (e.g., 200 mg) before or on the same day as starting treatment with a monthly regimen of pozelimuab 400 mg and semdisirane 200 mg. The transition period reduces the risk of formation of large DTD (drug-target-drug) immune complexes of eculizumab-C5-pozelimab during switch from eculizumab to the pozelimuab + semdisirane combination, or of ravulizumab-C5-pozelimab during switch from ravulizumab.

[0247] Pozelimab binds to C5 noncompetitively with eculizumab and therefore has the potential to form heteromeric complexes, including large DTD immune complexes. In vitro, neither pozelimuab nor eculizumab individually form higher-order multimers with C5 larger than a 1:2 mAb:C5 complex. Pozelimab was added to preformed in-house eculizumab:C5 complexes under conditions of an excess of pozelimuab relative to C5 (5:1:1 pozelimuab:in-house eculizumab:C5) and equimolar amounts of total mAb (1:1:2 pozelimuab:in-house eculizumab:C5). Under the pozelimuab excess condition, the majority of the sample (approximately 86%) contained free antibody and either trimeric or pentameric complexes (2:1 or 3:2 mAb:C5 molar ratios, respectively), with the remainder containing large HMW complexes. At equimolar ratios of total mAb and C5, the majority of samples (approximately 86%) had large HMW complexes larger than pentamers. Although eculizumab and pozelimb in combination can form heteromeric complexes with C5, the presence of excess pozelimb reduced the formation of large, higher-order immune complexes compared to conditions where total mAb and C5 were present at equimolar concentrations.

[0248] When switching from a regimen containing an antibody that does not significantly compete with pozelimuab for binding to C5 (a non-competing antibody or antigen-binding fragment thereof (N / C Ab), e.g., eculizumab or ravulizumab), a transition period is designed to mitigate the potential risk of forming large DTD immune complexes, eculizumab-C5-pozellimab, during the switch from eculizumab to the pozelimuab / semdisirane combination. The transition period may include an induction semdisirane dose followed by a pozelimuab IV loading dose (60 mg / kg) that is higher than that used in high / treatment-naive patients (30 mg / kg). The first dose of semdisirane (e.g., given on day 1) reduces C5 production, thereby lowering circulating levels of total C5 available for potential large DTD complex formation before the introduction of pozelimuab. To further minimize risk, a 60 mg / kg IV loading dose of pozelimuab establishes a high pozelimuab:eculizumab molar ratio. This excess concentration of pozelimuab ensures saturation of C5 binding sites by pozelimuab, thereby reducing the formation of higher-order DTD immune complexes compared to equimolar molar concentrations of total antibody and C5. This IV loading dose results in a molar ratio of pozelimuab to eculizumab of approximately 17:1, based on the reported mean eculizumab trough concentration of 97 mg / L (Soliris® Eculizumab (prescribing information)) and the predicted pozelimuab concentration.

[0249] An additional dose of about 30 mg / kg IV of anti-C5 antibody or antigen-binding fragment, preferably pozelimb, can be included in situations where adverse events [AEs] potentially due to large DTD (drug-target-drug) immune complexes are suspected and / or where systemic corticosteroids are administered for Type III hypersensitivity reactions. This additional dose will likely establish a state of circulating pozelimbab excess, thereby minimizing the risk of further immune complex formation.

[0250] Thus, the present disclosure includes: methods for reducing the likelihood of large DTD complex formation and / or establishing an excess of pozelimbab (e.g., a ratio of >1:1::pozellimab:N / C Ab (higher than equimolar), e.g., about 17:1::pozellimab:N / C Ab) in a subject prior to initiation of a regimen comprising semdisiran and pozelimb (e.g., as provided herein, pozelimbab 400 mg SC Q4W and semdisiran 200 mg SC Q4W); and A method for treating or preventing a C5-related disease or disorder (preferably PNH) in a subject in need thereof, comprising administering to the subject therapeutically effective amounts of pozeliman and a C5 iRNA (preferably semdisirane), wherein the subject has previously received a treatment regimen comprising an antibody or antigen-binding fragment thereof that does not compete with pozeliman for binding to C5 (a non-competitive antibody or antigen-binding fragment thereof (N / C Ab), e.g., eculizumab or ravulizumab), and wherein the subject: (1) A dose of C5 iRNA (e.g., semdisiran) is administered after a dose of N / C Ab (e.g., eculizumab or ravulizumab) but before the first dose of pozelimbab (e.g., pozelimbab IV (e.g., 60 mg / kg) and / or pozelimbab 400 mg SC Q4W and semdisiran 200 mg SC Q4W); or (1) A dose of C5 iRNA (e.g., semdisiran) is administered after the dose of N / C Ab but before the first dose of pozelimab; then (2) an intravenous loading dose of pozeli- mab (e.g., 60 mg / kg) is administered; or (1) An intravenous loading dose of pozelimb (e.g., 60 mg / kg) is administered with doses of pozelimb 400 mg SC Q4W and semdisiran 200 mg SC Q4W; then (2) approximately 4 weeks later (and continued every 4 weeks thereafter), pozelimab 400 mg SC Q4W and semdisiran 200 mg SC Q4W; or (1) a dose of C5 iRNA (e.g., semdisiran) is administered with doses of pozelimab 400 mg SC Q4W and semdisiran 200 mg SC Q4W after the dose of N / C Ab has been administered and approximately 4 weeks before an intravenous loading dose of pozelimab (e.g., 60 mg / kg); then (2) approximately 4 weeks later (and continued every 4 weeks thereafter), pozelimab 400 mg SC Q4W and semdisiran 200 mg SC Q4W; or (1) a dose of C5 iRNA (Semdisiran) and a dose of non-competing antibody or fragment (N / C Ab) was administered on the day the dose of N / C Ab was scheduled; (2) the next dose of N / C Ab is administered on the day such dose is scheduled; (3) a pozelimbab IV loading dose (e.g., 60 mg / kg) and pozelimbab 400 mg SC and semdisiran 200 mg SC were administered after approximately 1–2 half-lives of the N / C Ab or when the next dose of the N / C Ab was scheduled; (4) starting 4 weeks later (and continuing every 4 weeks thereafter), pozelimab 400 mg SC Q4W and semdisiran 200 mg SC Q4W; or (1) A dose of C5 iRNA (e.g., semdisiran) is administered approximately 1-2 half-lives after the final dose of N / C Ab; or on the day the next dose of N / C Ab is scheduled; or after half the inter-dose interval has elapsed since the final dose of N / C Ab; (2) after approximately 1–2 additional half-lives of N / C Ab, a pozelimb IV loading dose (e.g., 60 mg / kg), pozelimb 400 mg SC, and semdisiran 200 mg SC are administered; and (3) starting 4 weeks later (and continuing every 4 weeks thereafter), pozelimab 400 mg SC Q4W and semdisiran 200 mg SC Q4W; method.

[0251] Generally, the first dose(s) that do not recur may be referred to as a "loading" dose, and subsequent doses that recur may be referred to as "maintenance" doses.

[0252] In an embodiment of the invention, a large DTD complex refers to a complex that is larger than a pentameric complex (eg, 2:1 or 3:2::mAb:C5 molar ratio) or has a molecular weight of 1000 kDa or greater.

[0253] In an embodiment of the invention, excess pozelimb relative to an N / C Ab, e.g., eculizumab or ravulizumab, refers to a molar excess (e.g., 17:1) of 1:1:: pozelimb:N / C Ab.

[0254] A dosing regimen including monthly doses of both an anti-C5 antibody or antigen-binding fragment thereof (e.g., pozelimab; e.g., about 400 mg) and a C5 iRNA (e.g., semdisiran; e.g., about 200 mg) is sometimes referred to as a q4w or Q4W regimen.

[0255] A dosing regimen comprising a dose of an anti-C5 antibody or antigen-binding fragment thereof (e.g., about 400 mg) every two weeks and a monthly dose of a C5 iRNA (e.g., 200 mg) may be referred to as a q2w or Q2W regimen.

[0256] The term "4 weeks" or "months" refers, in embodiments of the present invention, to approximately 28, 29 or 30 days (± 3, 4, 5, 6 or 7 days).

[0257] The term "two weeks" refers, in embodiments of the present invention, to approximately 14 days (+ / - 3, 4, 5, 6, or 7 days).

[0258] Anti-C5 antibody or antigen-binding fragment thereof 400 mg SC Q4W refers to subcutaneous administration of about 400 mg of the antibody or fragment (e.g., pozeliman) approximately every month, four weeks, or 28 days (± 3, 4, 5, 6, or 7 days).

[0259] Anti-C5 antibody or antigen-binding fragment thereof 400 mg SC Q2W refers to subcutaneous administration of about 400 mg of the antibody or fragment (e.g., pozeliimab) approximately every 2 weeks or 14 days (± 3, 4, 5, 6, or 7 days).

[0260] C5 iRNA 200 mg SC Q4W refers to the subcutaneous administration of 200 mg of iRNA (e.g., semdisiran) approximately every 4 weeks or 28 days (± 3, 4, 5, 6, or 7 days).

[0261] As provided herein, any dosing episode (e.g., involving multiple doses of a drug) may be followed by an observation period of 30 minutes to 2 hours after the final administration, or however long the treating physician determines, to ensure that adverse events are unlikely to occur acutely. Typically, on a given day in which a subject receives an intravenous dose and one or more subcutaneous doses, the intravenous dose is administered first; however, the scope of the present disclosure includes embodiments in which the doses are administered in any order, for example, SC, then IV, then SC.

[0262] In embodiments of the present disclosure, a subject receiving combination therapy of anti-C5 Ab and C5 iRNA achieves, or achieves and maintains, one or more of the following while receiving the therapy: Hemoglobin stabilization; · Not receiving red blood cell transfusions; ·Failure to accumulate detectable and / or clinically significant amounts of drug-target-drug conjugates (e.g., pozelimab-C5-pozelimab); ·Do not accumulate detectable and / or clinically significant amounts of eculizumab-C5-pozelimab conjugates, for example, if a subject switches from eculizumab therapy to combination therapy; · Not experiencing adverse events attributable to large DTD complexes, such as rash, fever, fatigue, rash, or polyarthralgia; No decrease in hemoglobin of ≥ 2 g / dL; - Not experiencing breakthrough hemolysis; CH50 levels in the blood are completely suppressed compared to baseline before treatment and / or during any breakthrough hemolytic events; ·Improvement of fatigue compared to before treatment; ·>5-point improvement in FACIT-Fatigue score compared to pre-treatment; ·Improved physical function scores in Europeans; ·EORTC Quality of Life Questionnaire; Core 30 items (EORTC QLQ-C30)) compared with pre-treatment; ·Improvement in GHS / QoL (General Health Status / Quality of Life Scale (GHS)) compared to before treatment; ·Decreased lactate dehydrogenase (LDH) levels compared to before treatment; · Achievement of LDH ≤ 1.5 × upper limit of normal (ULN) compared with pretreatment; ·Achieving and maintaining LDH ≤ 1.0 × ULN; ·Decreased blood bilirubin levels compared to before the procedure; · A decrease in reticulocyte count compared to before treatment; · Reduction in alternative pathway hemolytic activity assay (AH50) compared to pretreatment; · A decrease in PNH red blood cells and / or granulocytes compared to before treatment; Improvement compared to before treatment in fatigue, shortness of breath, muscle weakness, headache, abdominal pain, back / leg pain, chest discomfort, difficulty sleeping, difficulty thinking clearly, and / or difficulty swallowing; ·Improvement of renal function compared to before treatment, as measured by estimated glomerular filtration rate (eGFR); A reduction in free hemoglobin in the blood compared to before treatment; and / or · Increased haptoglobin levels compared to before treatment.

[0263] In embodiments of the present disclosure, a subject receiving combination therapy of anti-C5 Ab and C5 iRNA achieves, or achieves and maintains, one or more of the following while receiving the therapy: An increase in FACIT-Fatigue score of approximately 13 when receiving a q4w regimen; or an increase of approximately 11 when receiving a q2w regimen, for example, from the start of treatment to approximately 2 weeks; An increase in FACIT-Fatigue score of approximately 8 when receiving a q4w regimen; or an increase of approximately 8 when receiving a q2w regimen, for example, by approximately 4 weeks from the start of treatment; An increase in FACIT-Fatigue score of approximately 11 when receiving a q4w regimen; or approximately 7 when receiving a q2w regimen, for example, from the start of treatment to approximately 8 weeks; An increase in FACIT-Fatigue score of approximately 11 when receiving a q4w regimen; or approximately 8 when receiving a q2w regimen, for example, from the start of treatment to approximately 12 weeks; An increase in FACIT-Fatigue score of approximately 12 when receiving a q4w regimen; or approximately 9 when receiving a q2w regimen, for example, from the start of treatment to approximately 16 weeks; An increase in FACIT-Fatigue score of approximately 11 when receiving a q4w regimen; or approximately 4 when receiving a q2w regimen, for example, from the start of treatment to approximately 20 weeks; An increase in FACIT-Fatigue score of approximately 12 when receiving a q4w regimen; or approximately 11 when receiving a q2w regimen, for example, from the start of treatment to approximately 24 weeks; An increase in FACIT-Fatigue score of approximately 11 when receiving a q4w regimen; or approximately 9 when receiving a q2w regimen, for example, from the start of treatment to approximately 28 weeks; an increase in EORTC-QLQ-C30 physical function score, for example, of approximately 23 when receiving a q4w regimen or approximately 14 when receiving a q2w regimen, at approximately 2 weeks after starting treatment; an increase in EORTC-QLQ-C30 physical function score, for example, of approximately 19 when receiving a q4w regimen or approximately 13 when receiving a q2w regimen, at approximately 4 weeks after starting treatment; an increase in EORTC-QLQ-C30 physical function score of approximately 22 when receiving a q4w regimen or approximately 14 when receiving a q2w regimen, for example, at approximately 8 weeks from the start of treatment; an increase in EORTC-QLQ-C30 physical function score of approximately 20 when receiving a q4w regimen or approximately 17 when receiving a q2w regimen, for example, at approximately 12 weeks from the start of treatment; an increase in EORTC-QLQ-C30 physical function score of approximately 19 when receiving a q4w regimen or approximately 14 when receiving a q2w regimen, for example, at approximately 16 weeks from the start of treatment; an increase in EORTC-QLQ-C30 physical function score of approximately 23 when receiving a q4w regimen or approximately 11 when receiving a q2w regimen, for example, at approximately 20 weeks from the start of treatment; an increase in EORTC-QLQ-C30 physical function score of approximately 20 points when receiving a q4w regimen or approximately 15 points when receiving a q2w regimen, for example, at approximately 24 weeks from the start of treatment; an increase in EORTC-QLQ-C30 physical function score, for example, of approximately 24 when receiving a q4w regimen or approximately 20 when receiving a q2w regimen, at approximately 28 weeks from the start of treatment; an increase in EORTC-QLQ-C30 GHS / QoL score, e.g., by approximately 2 weeks from the start of treatment, of approximately 15 when receiving a q4w regimen or approximately 14 when receiving a q2w regimen; an increase in EORTC-QLQ-C30 GHS / QoL score, e.g., by approximately 4 weeks from the start of treatment, of approximately 10 when receiving a q4w regimen or approximately 15 when receiving a q2w regimen; an increase in EORTC-QLQ-C30 GHS / QoL score, for example, by approximately 8 weeks from the start of treatment, of approximately 9 when receiving a q4w regimen or approximately 9 when receiving a q2w regimen; an increase in EORTC-QLQ-C30 GHS / QoL score, e.g., by approximately 12 weeks from the start of treatment, of approximately 11 when receiving a q4w regimen or approximately 12 when receiving a q2w regimen; an increase in EORTC-QLQ-C30 GHS / QoL score, e.g., by approximately 16 weeks from the start of treatment, of approximately 12 when receiving a q4w regimen or approximately 8 when receiving a q2w regimen; an increase in EORTC-QLQ-C30 GHS / QoL score, e.g., by approximately 20 weeks from the start of treatment, of approximately 17 when receiving a q4w regimen or approximately 6 when receiving a q2w regimen; an increase in EORTC-QLQ-C30 GHS / QoL score, e.g., of approximately 15 when receiving a q4w regimen or approximately 13 when receiving a q2w regimen, from the start of treatment to approximately 24 weeks; an increase in EORTC-QLQ-C30 GHS / QoL score, for example, of approximately 14 when receiving a q4w regimen or approximately 13 when receiving a q2w regimen, from the start of treatment to approximately 28 weeks; For example, by the second week after starting treatment, a FACIT-fatigue score of approximately 45 (±4) when receiving, for example, a q4w regimen, or a score of 43 (±8) when receiving, for example, a q2w regimen; - A FACIT-fatigue score of approximately 40 (±11) by the fourth week after starting treatment, for example, when receiving a q4w regimen, or a score of 40 (±10) when receiving a q2w regimen; For example, by week 8 after the start of treatment, a FACIT-fatigue score of approximately 43 (±7) when receiving, for example, a q4w regimen, or a score of 39 (±11) when receiving, for example, a q2w regimen; For example, by week 12 after the start of treatment, a FACIT-fatigue score of approximately 44 (±7) when receiving, for example, a q4w regimen, or a score of 40 (±9) when receiving, for example, a q2w regimen; For example, by week 16 after the start of treatment, a FACIT-fatigue score of approximately 44 (±5) when receiving, for example, a q4w regimen, or a score of 41 (±11) when receiving, for example, a q2w regimen; For example, by week 20 after the start of treatment, a FACIT-fatigue score of approximately 43 (±7) when receiving, for example, a q4w regimen, or a score of 37 (±13) when receiving, for example, a q2w regimen; For example, by 24 weeks after the start of treatment, a FACIT-fatigue score of approximately 44 (±7) when receiving, for example, a q4w regimen, or a score of 43 (±9) when receiving, for example, a q2w regimen; For example, by 28 weeks after the start of treatment, a FACIT-fatigue score of approximately 44 (±7) when receiving, for example, a q4w regimen, or a score of 42 (±10) when receiving, for example, a q2w regimen; For example, by the second week after starting treatment, an EORTC-QLQ-C30 physical function score of approximately 94 (±9) when receiving, for example, a q4w regimen, or a score of 85 (±19) when receiving, for example, a q2w regimen; For example, by the fourth week after starting treatment, an EORTC-QLQ-C30 physical function score of approximately 90 (±9) when receiving, for example, a q4w regimen, or a score of 84 (±19) when receiving, for example, a q2w regimen; For example, by week 8 after the start of treatment, an EORTC-QLQ-C30 physical function score of approximately 93 (±7) when receiving, for example, a q4w regimen, or a score of 84 (±19) when receiving, for example, a q2w regimen; For example, by 12 weeks after the start of treatment, an EORTC-QLQ-C30 physical function score of approximately 91 (±9) when receiving, for example, a q4w regimen, or a score of 88 (±16) when receiving, for example, a q2w regimen; For example, by week 16 after the start of treatment, an EORTC-QLQ-C30 physical function score of approximately 90.0 (±9.6) when receiving, for example, a q4w regimen, or a score of 85.0 (±19.9) when receiving, for example, a q2w regimen; For example, by week 20 after the start of treatment, an EORTC-QLQ-C30 physical function score of approximately 94 (±8) when receiving, for example, a q4w regimen, or a score of 82 (±19) when receiving, for example, a q2w regimen; For example, by 24 weeks after the start of treatment, an EORTC-QLQ-C30 physical function score of approximately 91 (±9) when receiving, for example, a q4w regimen, or a score of 86 (±19) when receiving, for example, a q2w regimen; For example, by 28 weeks after the start of treatment, an EORTC-QLQ-C30 physical function score of approximately 95 (±6) when receiving, for example, a q4w regimen, or a score of 91 (±17) when receiving, for example, a q2w regimen; For example, by the second week after starting treatment, an EORTC-QLQ-C30 GHS / QoL score of approximately 76 (±18) when receiving, for example, a q4w regimen, or a score of 75 (±17) when receiving, for example, a q2w regimen; For example, by the fourth week after starting treatment, an EORTC-QLQ-C30 GHS / QoL score of approximately 71 (±26) when receiving, for example, a q4w regimen, or a score of 76 (±23) when receiving, for example, a q2w regimen; For example, by week 8 after the start of treatment, an EORTC-QLQ-C30 GHS / QoL score of approximately 69 (±21) when receiving, for example, a q4w regimen, or a score of 70 (±26) when receiving, for example, a q2w regimen; For example, by week 12 after the start of treatment, an EORTC-QLQ-C30 GHS / QoL score of approximately 72 (±15) when receiving, for example, a q4w regimen, or a score of 73 (±20) when receiving, for example, a q2w regimen; For example, by week 16 after the start of treatment, an EORTC-QLQ-C30 GHS / QoL score of approximately 72 (±22) when receiving, for example, a q4w regimen, or a score of 69 (±29) when receiving, for example, a q2w regimen; For example, by week 20 after the start of treatment, an EORTC-QLQ-C30 GHS / QoL score of approximately 77 (±20) when receiving, for example, a q4w regimen, or a score of 67 (±25) when receiving, for example, a q2w regimen; an EORTC-QLQ-C30 GHS / QoL score of approximately 76 (±19.0) when receiving, for example, a q4w regimen, or a score of 74 (±29) when receiving, for example, a q2w regimen, by 24 weeks after the start of treatment; and / or For example, by 28 weeks after starting treatment, an EORTC-QLQ-C30 GHS / QoL score of approximately 75 (±17) when receiving, for example, a q4w regimen, or a score of 74 (±24) when receiving, for example, a q2w regimen. Achieving a given score or improvement in score (e.g., with respect to EORTC-QLQ-C30 GHS / QoL score; EORTC-QLQ-C30 physical function score or FACIT-Fatigue score) includes embodiments in which the subject's condition is measured, for example, according to a relevant questionnaire or scale; and embodiments that are not measured by a questionnaire or scale, but in which the subject's condition would achieve such a score or improvement if measured by the questionnaire or scale.

[0264] In embodiments of the present disclosure, even when treated with the combination therapy of the present disclosure, a subject can be administered a transfusion of red blood cells (RBCs), for example, according to the following: Transfuse RBCs if the hemoglobin level is ≤9 g / dL and new onset or worsening of signs or symptoms attributable to anemia is of sufficient severity to warrant transfusion; or · Transfuse RBCs if hemoglobin level is ≤7 g / dL, regardless of the presence or absence of signs or symptoms of anemia.

[0265] In embodiments of the present disclosure, patients receiving the combination therapy of the present disclosure undergo "consolidation" treatment, for example, if the subject experiences breakthrough hemolysis not due to a complement-activating condition (e.g., a concomitant infection) and / or if the subject experiences a persistent inadequate LDH response (i.e., LDH > 1.5 x ULN) (e.g., on two consecutive measurements over at least about two weeks). Consolidation treatment includes, in addition to the doses specified for the combination therapy discussed herein, one or more doses of an anti-C5 antibody or antigen-binding fragment, preferably pozelimab, and / or a C5 iRNA, preferably semdisiran, e.g., For subjects receiving pozelimas 400 mg SC Q4W (± 3, 4, 5, 6, or 7 days) and semdisiran 200 mg SC Q4W (± 3, 4, 5, 6, or 7 days), subjects will receive a single dose of pozelimas 30 mg / kg intravenously (IV) on the day of consolidation and receive the consolidation pozelimas regimen of 400 mg Q2W (± 3, 4, 5, 6, or 7 days) with semdisiran 200 mg Q4W (± 3, 4, 5, 6, or 7 days) starting on the day of consolidation. For subjects receiving pozelimab 400 mg SC Q2W (± 3, 4, 5, 6, or 7 days) and semdisiran 200 mg SC Q4W (± 3, 4, 5, 6, or 7 days), subjects will receive a single dose of pozelimab 30 mg / kg IV on the day of intensification and reinitiate the combination regimen of pozelimab 400 mg SC Q2W (± 3, 4, 5, 6, or 7 days) and semdisiran 200 mg SC Q4W (± 3, 4, 5, 6, or 7 days) starting on the day of intensification.

[0266] In embodiments of the disclosure, subjects undergoing consolidation treatment (e.g., who were receiving an eculizumab switch regimen) preferably receive pozelimbab 30 mg / kg IV on the day of initiation (e.g., which can begin on or after day 57) for the treatment of PNH, in addition to a maintenance regimen of reduced dosing frequency pozelimbab 400 mg SC Q2W (±3, 4, 5, 6, or 7 days) with semdisirane 200 mg SC Q4W (±3, 4, 5, 6, or 7 days) for a period of 32 weeks, beginning on the day of initiation.

[0267] In some embodiments, the disclosed combination therapy comprises administering an anti-C5 antibody or antigen-binding fragment thereof to a subject in need thereof at one or more doses administered about 4 times per week, twice per week, once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, or less frequently if a therapeutic response is achieved. In one embodiment, the disclosed anti-C5 antibody or antigen-binding fragment thereof (e.g., pozeliman) is administered to a subject once every 2 weeks or once every 4 weeks.

[0268] As used herein, the term "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 term includes sequential or concurrent administration of the anti-C5 antibody or antigen-binding fragment thereof and the C5 iRNA.

[0269] In some embodiments, when an anti-C5 antibody or antigen-binding fragment thereof is administered "prior to" a C5 iRNA, the anti-C5 antibody or antigen-binding fragment thereof may be administered more than 12 weeks, about 12 weeks, about 11 weeks, about 10 weeks, about 9 weeks, about 8 weeks, about 7 weeks, about 6 weeks, about 5 weeks, about 4 weeks, about 3 weeks, about 2 weeks, about 1 week, about 150 hours, about 100 hours, about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before administration of the C5 iRNA.

[0270] In some embodiments, when an anti-C5 antibody or antigen-binding fragment thereof is administered "after" a C5 iRNA, the anti-C5 antibody or antigen-binding fragment thereof may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 5 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, or more than 12 weeks after administration of the C5 iRNA.

[0271] As used herein, "concurrent" administration means that an anti-C5 antibody or antigen-binding fragment thereof (e.g., pozelimab) and a C5 iRNA (e.g., semdisirane) are administered to a subject in a single dosage form (e.g., combined) or in separate dosage forms that are administered to a subject within about 1 or 2 hours or 30 minutes or less of each other (i.e., before, after, or simultaneously), such as about 15 minutes or less, or about 5 minutes or less, during the same treatment episode. When administered in separate dosage forms, each dosage form may be administered by the same route (e.g., both intravenously, subcutaneously, etc.); or alternatively, each dosage form may be administered by a different route. In either case, administration of components in a single dosage form in separate dosage forms by the same route or in separate dosage forms by different routes is all considered "concurrent" administration for the purposes of this disclosure. In an embodiment of the present disclosure, concurrent subcutaneous doses of an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA are administered by injection into separate arms.

[0272] As used herein, "sequential" administration means that each dose of a selected therapy is administered to a subject at different times, for example, on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). Illustratively, sequential administration can include administering a first dose of an anti-C5 antibody or antigen-binding fragment thereof (or C5 iRNA), followed by one or more second doses of C5 iRNA (or anti-C5 antibody or antigen-binding fragment thereof), optionally followed by one or more third doses of an anti-C5 antibody or antigen-binding fragment thereof (or C5 iRNA). Illustratively, sequential administration can include administering a first dose of an anti-C5 antibody or antigen-binding fragment thereof (or C5 iRNA), followed by one or more second doses of C5 iRNA (or anti-C5 antibody or antigen-binding fragment thereof), optionally followed by one or more third doses of C5 iRNA (or anti-C5 antibody or antigen-binding fragment thereof).

[0273] As used herein, " first " dose, " second " dose and " third " dose refer to the time sequence of administration.Therefore, " first " dose is the dose that is administered at the beginning of treatment regimen (also called " baseline dose "); " second dose " is administered after the first dose; " third " dose is administered after the second dose.The first, second and third doses can all contain the same amount of selected therapy, or can contain different amounts of selected therapy.

[0274] Treatment and Administration The disclosed combinations and / or combination therapies (e.g., semdisiran / pozelimab) are useful for treating or preventing C5-related diseases, disorders, or conditions, including administering a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment and a C5 iRNA, preferably in combination, e.g., by parenteral route, e.g., intramuscular (IM), subcutaneous (SC), intravenous (IV), or intravitreal (IVT) or intraocular injection. Preferably, about 400 mg of the antibody, preferably pozelimab, is administered about every 2-4 (e.g., 2, 3, or 4) weeks, while about 200 mg of the iRNA, preferably semdisiran, is administered about every 4 weeks.

[0275] In some embodiments, the disclosed combination drug and / or combination therapy (e.g., semdisiran / pozelimab), for example, a 100:100 combination, can be used to treat or prevent myasthenia gravis (MG). Signs and symptoms of MG include, but are not limited to, weakness of the eye muscles (ocular myasthenia), drooping eyelids in one or both eyes (ptosis), blurred or double vision (diplopia), changes in facial expression, difficulty swallowing, shortness of breath, impaired speech (dysarthria), and weakness of the arms, hands, fingers, lower limbs, and / or neck. Sometimes, the severe weakness of myasthenia gravis can lead to respiratory failure. Accordingly, the present disclosure includes a method for treating or preventing MG in a subject in need thereof, comprising administering to the subject (e.g., by SC, IM, or IV injection) a therapeutically effective amount of the combination drug of the present disclosure. In embodiments of the invention, such a therapeutically effective amount is any of the dosing regimens set forth herein (e.g., one or more doses of pozeliman 400 mg SC and semdisiran 200 mg SC (e.g., every 4 weeks)).

[0276] In some embodiments, the disclosed combinations and / or combination therapies (e.g., semdisiran / pozelimab) of the present disclosure are useful for treating or preventing atypical hemolytic uremic syndrome (aHUS). 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 kidney damage, abdominal pain, confusion, edema, fatigue, nausea / vomiting, diarrhea, and microangiopathic anemia. Accordingly, the present disclosure includes a method for treating or preventing aHUS in a subject in need thereof, comprising administering to the subject (e.g., by SC, IM, or IV injection) a therapeutically effective amount of the combination of the present disclosure. In embodiments of the invention, such a therapeutically effective amount is any of the dosing regimens set forth herein (e.g., one or more doses of pozeliman 400 mg SC and semdisiran 200 mg SC (e.g., every 4 weeks)).

[0277] In some embodiments, the disclosed combinations and / or combination therapies (e.g., semdisiran / pozelimab), for example, a 50:100 combination (semdisiran mg / ml:pozelimab mg / ml), can be used to treat or prevent paroxysmal nocturnal hemoglobinuria (PNH). 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 the urine, symptoms of anemia such as fatigue, shortness of breath and palpitations, abdominal pain, and difficulty swallowing. Accordingly, the present disclosure includes a method for treating or preventing PNH in a subject in need thereof, comprising administering to the subject (e.g., by SC, IM, or IV injection) a therapeutically effective amount of the combination of the present disclosure. In embodiments of the invention, such a therapeutically effective amount is any of the dosing regimens set forth herein (e.g., one or more doses of pozeliman 400 mg SC and semdisiran 200 mg SC (e.g., every 4 weeks)).

[0278] In some embodiments, the disclosed combinations and / or combination therapies are useful in treating PNH patients (including PNH patients transitioned from pozeliman monotherapy), e.g., by controlling hemolysis without any breakthrough hemolytic events, achieving hemoglobin stabilization, and / or maintaining LDH normalization for an extended period of time (e.g., at least 28 weeks). In some embodiments, the disclosed combinations and / or combination therapies are useful in treating PNH patients (including PNH patients transitioned from pozeliman monotherapy), e.g., by improving patient fatigue, improving general health status (GHS) / quality of life (QoL), and / or improving physical function compared to baseline.

[0279] In some embodiments, the disclosed combinations and / or combination therapies (e.g., semdisiran / pozelimab) can be used to treat or prevent CHAPLE disease (CD55 deficiency accompanied by complement hyperactivation, hematologic thrombosis, and protein-losing enteropathy). CHAPLE disease is characterized by symptoms such as inflammatory bowel disease, protein-losing enteropathy (which may be associated with hypoalbuminemia), hypogammaglobulinemia, intestinal lymphangiectasia, and / or thrombotic events. Accordingly, the present disclosure includes methods for treating or preventing CHAPLE in a subject in need thereof, comprising administering to the subject (e.g., by SC, IM, or IV injection) a therapeutically effective amount of the combination of the present disclosure. In embodiments of the present invention, such a therapeutically effective amount is any of the dosing regimens set forth herein (e.g., one or more doses (e.g., every four weeks) of pozelimab 400 mg SC and semdisiran 200 mg SC).

[0280] In some embodiments, the disclosed combinations and / or combination therapies (e.g., semdisiran / pozelimab) can be used to treat or prevent (including reducing or eliminating signs or symptoms, or reducing complement activation associated therewith) diseases, disorders, or conditions associated with C5, such as inappropriate or undesired complement activation disorders; systemic inflammatory responses in post-pump syndrome resulting from cardiopulmonary or renal bypass; neurological disorders; renal disorders; hemodialysis complications; inflammatory disorders; inflammation in autoimmune diseases; burns; immune complex disorders; autoimmune diseases or proteinuric kidney diseases. Accordingly, the present disclosure includes methods for treating or preventing any of such disorders in a subject in need thereof, comprising administering to the subject (e.g., by SC, IM, or IV injection) a therapeutically effective amount of the combination of the present disclosure. In embodiments of the present invention, such therapeutically effective amount is any of the dosing regimens set forth herein (e.g., one or more doses (e.g., every four weeks) of pozelimab 400 mg SC and semdisiran 200 mg SC).

[0281] In some embodiments, the disclosed combinations and / or combination therapies (e.g., semdisiran / pozelimab) are used to treat C5-associated diseases or disorders or conditions, such as complement activation due to burns; hereditary CD59 deficiency; renal ischemia; post-ischemic reperfusion states; adult respiratory distress syndrome; Alport syndrome; Alzheimer's disease; atherosclerosis; bullous pemphigoid; C3 glomerulopathy; capillary leak syndrome; Crohn's disease; diabetes; diabetic nephropathy; epilepsy; glomerulopathy; Guillain-Barré syndrome; hemolytic anemia; hyperacute allograft rejection; infectious diseases; interleukin-2-induced toxicity during IL-2 therapy; lupus nephritis; membranoproliferative glomerulonephritis; membranoproliferative nephritis; aortic reconstruction surgery. The combination of the present invention can be used to treat or prevent (including reducing or eliminating signs or symptoms thereof, or reducing complement activation associated therewith) mesenteric artery reperfusion after myocardial infarction, neuromyelitis optica, complement activation due to obesity, Parkinson's disease, progressive renal failure, psoriasis, renal ischemia-reperfusion injury, rheumatoid arthritis, schizophrenia, SLE nephritis, stroke, systemic lupus erythematosus (SLE), traumatic brain injury, vasculitis, xenograft rejection, CHAPLE disease / syndrome (CD55 deficiency with complement hyperactivation, hematopathic thrombosis, and PLE), complement activation due to frostbite, and complement activation due to sepsis. Accordingly, the present disclosure includes a method for treating or preventing any of such conditions or diseases in a subject in need thereof, comprising administering to the subject (e.g., by SC, IM, or IV injection) a therapeutically effective amount of the combination of the present disclosure. In embodiments of the invention, such a therapeutically effective amount is any of the dosing regimens set forth herein (e.g., one or more doses of pozeliman 400 mg SC and semdisiran 200 mg SC (e.g., every 4 weeks)).

[0282] In some embodiments, the disclosed combination drug and / or combination therapy (e.g., semdisirane / pozelimab) of the present disclosure is used to treat a C5-associated disease or disorder or condition, for example, a pulmonary disease or disorder, e.g., dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosing pneumoconiosis, injury caused by inert dusts and minerals (e.g., silicon, coal dust, beryllium, and asbestos), pulmonary fibrosis, organic pneumoconiosis, chemical injury (e.g., irritant gases and The present disclosure is useful for treating or preventing (including reducing or eliminating signs or symptoms, or reducing complement activation associated therewith) conditions such as pulmonary arterial vein irritation, pulmonary vein irritation, and pulmonary vein irritation caused by chemicals, e.g., chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, and hydrochloric acid), smoke hazard, burns (e.g., burns or freezing), asthma, allergies, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, hereditary angioedema, or immune complex-associated inflammation. Accordingly, the present disclosure includes a method for treating or preventing any of such conditions or diseases in a subject in need thereof, comprising administering to the subject (e.g., by SC, IM, or IV injection) a therapeutically effective amount of a combination of the present disclosure. In embodiments of the present disclosure, such a therapeutically effective amount is any of the dosing regimens set forth herein (e.g., one or more doses (e.g., every four weeks) of pozeliman 400 mg SC and semdisiran 200 mg SC).

[0283] In some embodiments, the disclosed combinations and / or combination therapies (e.g., semdisiran / pozelimab) of the present disclosure are useful for treating or preventing (including reducing or eliminating signs or symptoms thereof, or reducing complement activation associated therewith) C5-related diseases or disorders or conditions, such as ocular diseases, e.g., age-related macular degeneration (AMD), diabetic macular edema (DME), diabetic retinopathy, ocular neovascularization (new blood vessels in the eye affecting the choroid, nuclear membrane, or retinal tissue), geographic atrophy (GA), uveitis, and neuromyelitis optica. The disclosed combinations can be used to treat or alleviate at least one sign and / or symptom of dry AMD or wet AMD. Accordingly, the present disclosure includes methods for treating or preventing any of such conditions or diseases in a subject in need thereof, comprising administering to the subject (e.g., by parenteral injection; or preferably, by intraocular or intravitreal injection) a therapeutically effective amount of the disclosed combination. In embodiments of the invention, such a therapeutically effective amount is any of the dosing regimens set forth herein (e.g., one or more doses of pozeliman 400 mg SC and semdisiran 200 mg SC (e.g., every 4 weeks)).

[0284] "Treat" or "treating" means administering a combination of the present disclosure (e.g., semdisiran / pozelimab) to a subject having a C5-related disease or disorder or condition to reduce or eliminate one or more signs or symptoms thereof in the subject, e.g., reducing complement activation associated therewith.

[0285] The therapeutically effective dose or amount of the anti-C5 antibody and C5 iRNA in the combination for treating a C5-related disease, disorder, or condition ranges from about 10 to 800 mg of each, administered once every 1, 2, 3, 4, 5, 6, 7, or 8 weeks.

[0286] A subject or patient—used interchangeably herein—refers to a mammal, preferably a human. In an embodiment of the present disclosure, the subject suffers from a C5-related disease, disorder, or condition, such as PNH, MG, aHUS, or CHAPLE. In an embodiment of the present disclosure, the subject is receiving or has previously received a therapeutic agent for treating a disease or disorder (e.g., a complement inhibitor, such as clovalimab; eculizumab, tesidolumab, muvozina, and / or ravulizumab) before switching to a combination therapy of the present disclosure containing a different agent (e.g., semdisiran / pozelimab). In an embodiment of the present disclosure, the subject is a treatment "naive" who has never previously received a complement inhibitor or has not recently received a complement inhibitor, for example, within 1, 2, 3, 4, 5, or 6 months. In an embodiment of the present disclosure, the subject has a diagnosis of paroxysmal nocturnal hemoglobinuria confirmed by a history of high-sensitivity flow cytometry. In an embodiment of the disclosure, the subject has a lactate dehydrogenase level of at least 1.5×ULN (upper limit of normal). Sahin et al., Pesg PNH diagnosis, follow-up and treatment guidelines. Am J Blood Res 2016;6(2):19-27. In an embodiment of the disclosure, the subject or patient does not have any one or more of the following characteristics: History of bone marrow transplant or organ transplant recipient Weight < 40kg Any two of the following three abnormalities: a. Peripheral blood absolute neutrophil count (ANC) < 500 / μL [0.5 × 10 9 / L]; or b. Peripheral blood platelet count <20,000 / μL; or c. Abnormal peripheral blood reticulocyte count defined as <20,000 / μL or <1% Hypoplastic bone marrow based on history of decreased age-adjusted bone marrow cellularity and / or bone marrow cellularity ≤25% No documented evidence of meningococcal vaccination Unable to take antibiotics to prevent meningococcal disease Any active ongoing infection or recent infection requiring ongoing systemic treatment with antibiotics, antivirals, or antifungals within the last two weeks · History of systemic fungal disease or unresolved tuberculosis (TB), or active or latent tuberculosis infection (LTBI) Hepatitis B surface antigen or hepatitis C virus RNA positive History of human immunodeficiency virus (HIV) infection ·SARS-CoV-2 infection Hereditary complement deficiency History of active, uncontrolled, ongoing systemic autoimmune disease Current cirrhosis or history of liver disease with evidence of liver dysfunction or ALT or AST (unrelated to PNH) greater than 3 × ULN ·<30mL / min / 1.73m 2 eGFR (according to the Chronic Kidney Disease Epidemiology Collaborative Inquiry Equation 2009 [CKD-EPI]) -The need for major surgery is anticipated Cancer within the past 5 years, except for adequately treated basal cell skin cancer, cutaneous squamous cell carcinoma, or cervical intraepithelial carcinoma Hypersensitivity to pozelimab or semdisiran Documented functional or anatomical asplenia Pregnant or breastfeeding women Women of childbearing age who are not willing to use highly effective contraception Not been vaccinated against Streptococcus pneumoniae and / or Haemophilus influenzae type B

[0287] In an embodiment of the present disclosure, the subject is receiving or has received a blood transfusion.

[0288] In embodiments of the present disclosure, a subject receiving the combination drug of the present disclosure to treat a C5-related disease or disorder or condition achieves a decrease in intravascular hemolysis or blood lactate dehydrogenase (LDH) levels, and / or a decrease in receiving blood transfusions, compared to before the start of treatment.

[0289] device The present disclosure also provides an injection device containing the combination (e.g., semdisirane / pozelimab) of the present disclosure. An injection device is a device for introducing a substance into a patient's body via a parenteral route, such as intramuscular, subcutaneous, intravitreal, intraocular, or intravenous route. For example, the injection device may be a syringe (e.g., a prefilled or autoinjector) that includes, for example, a cylinder or barrel for holding the fluid to be injected (e.g., the combination), a needle for piercing the skin and / or a blood vessel for fluid injection, and a plunger for forcing the fluid from the cylinder through the lumen of the needle. In embodiments of the present disclosure, the injection device containing the combination is suitable for subcutaneous, intravitreal, or intravenous (IV) injection. Such a device contains the combination in a cannula or trocar / needle that can be attached to a tube that can be attached to a bag or reservoir for holding the fluid (e.g., saline; or lactated Ringer's solution containing NaCl, sodium lactate, KCl, CaCl, and optionally glucose) to be introduced into the patient's body through the cannula or trocar / needle.

[0290] In an embodiment of the present d...

Claims

1. A combination drug comprising: a C5 iRNA conjugated to a ligand comprising one or more terminal N-acetylgalactosamine (GalNAc) and / or N-acetylglucosamine (GlcNAc) residues; Antibody (anti-C5) or antigen-binding fragment thereof that specifically binds to C5 isolated from mammalian host cells Including; a pH greater than or less than about 6; and Pharmaceutically acceptable carrier A combination drug having the formula:

2. A combination drug, C5 iRNA and an antibody or antigen-binding fragment thereof that specifically binds to C5; a buffer; a viscosity reducing agent; a stabilizer; a nonionic surfactant; a pH greater than or less than about 6; A combination drug containing

3. 3. The combination according to claim 1, having a pH of at or about 6.5, or a pH in the range of 6.0 to 0.5 or higher.

4. 4. The combination according to claim 1, further comprising a buffer selected from the group consisting of a histidine-based buffer, a citrate-based buffer, a phosphate-based buffer and / or an acetate-based buffer.

5. 5. The combination of any one of claims 1 to 4, comprising about 10-35, 35-45, 20-50, 20, 25, 30, 35, 40, 45, or 50 mM buffer.

6. 6. The combination of claim 1, further comprising a viscosity-reducing agent which is an inorganic salt and / or an amino acid.

7. 7. The combination of claim 1, comprising a viscosity-lowering agent selected from the group consisting of (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, and (D- or L-)glutamic acid, and salts thereof; an inorganic salt, NaCl, pyridoxamine, L-ornithine, thiamine phosphate chloride dihydrate, benzenesulfonic acid, and / or pyridoxine.

8. 8. The combination of any one of claims 1 to 7 comprising about 20 to 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-lowering agent.

9. 9. The combination according to claim 1, further comprising a stabilizer which is a polyol or a sugar.

10. 10. The combination of claim 1, further comprising a stabilizer that is trehalose, sorbitol, mannitol, taurine, propanesulfonic acid, L-proline, sucrose, glycerin, threitol, maltitol, polyethylene glycol (PEG), and / or PEG 3350.

11. 11. The combination of any one of claims 1 to 10, comprising about 0.8 to 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.

12. 12. The combination according to any one of claims 1 to 11, comprising a nonionic surfactant that is a polyoxyethylene glycol alkyl ether; a glucoside alkyl ether; a polyoxyethylene glycol octylphenol ether; a polyoxyethylene glycol alkylphenol ether; a glycerin alkyl ester; a polyoxyethylene glycol sorbitan alkyl ester; a sorbitan alkyl ester; a block copolymer of polypropylene glycol; a block copolymer of polyethylene glycol; and / or a polysorbate.

13. 13. The combination according to any one of claims 1 to 12, comprising a nonionic surfactant selected from the group consisting of octaethylene glycol monododecyl ether; pentaethylene glycol monododecyl ether; polyoxypropylene glycol alkyl ether; decyl glucoside, lauryl glucoside, octyl glucoside; Triton X-100; nonoxynol-9; glyceryl laurate; cocamide MEA, cocamide DEA, dodecyl dimethylamine oxide; poloxamer; polyethoxylated tallowamine (POEA); polysorbate-20 (PS20) and / or polysorbate-80 (PS80).

14. 14. The combination of any one of claims 1 to 13, comprising about 0.025, 0.05, 0.075, 0.1, 0.125, 0.15, 0.175% (w / v) non-ionic surfactant.

15. 15. The combination of any one of claims 1 to 14, further comprising one or more viscosity reducing agents.

16. 16. The combination of any one of claims 1 to 15, further comprising one or more viscosity-lowering agents each at a concentration of about 5 mM to about 100 mM.

17. 17. The combination of any one of claims 1 to 16, further comprising one or more viscosity-lowering agents each at a concentration of about 50 mM to about 75 mM.

18. A combination according to any one of claims 15 to 17, which comprises a viscosity reducing agent, one or more of the following: amino acids, dicarboxylic acids, inorganic salts, esters of citric acid and / or xanthines.

19. Viscosity reducers, one or more of the following: Arginine; Adipic acid; NaCl; Lysine; Proline; Histidine; Caffeine; phenylalanine; and / or triethyl citrate, The combination according to any one of claims 15 to 18.

20. 20. The combination of any one of claims 15 to 19, wherein the viscosity-lowering agent is an amino acid, and the amino acid is either its L-enantiomer or its D-enantiomer.

21. 21. The combination of any one of claims 15 to 20, wherein the viscosity reducing agent is a conjugate base of an acid viscosity reducing agent or a salt thereof.

22. 22. The combination of any one of claims 1 to 21, comprising an anti-C5 antibody or antigen-binding fragment purity of about 96% or greater as assessed by size exclusion chromatography after about one month at 2-8°C.

23. 23. The combination of any one of claims 10 to 22, comprising a C5 iRNA purity of about 94% or greater as assessed by anion exchange chromatography after about one month at 2-8°C.

24. 24. The combination of any one of claims 1 to 23, comprising a 1:1 milliliter per milligram concentration ratio of C5 iRNA and anti-C5 antibody or antigen-binding fragment.

25. 25. The combination of claim 24, wherein the viscosity-lowering agent is arginine, adipate, NaCl, lysine, aspartic acid, proline, histidine, caffeine, phenylalanine, and / or triethyl citrate.

26. 26. The combination of claim 25, wherein the viscosity-lowering agent is 75 mM arginine, 75 mM adipate, 75 mM NaCl, 75 mM lysine, 75 mM aspartic acid, 75 mM proline, 50 mM histidine (if the buffer is histidine-based, the total histidine concentration of the combination is 50 mM), 50 mM caffeine, 50 mM phenylalanine, and / or 75 mM triethyl citrate.

27. 27. The combination of any one of claims 1 to 26, comprising a 1:2 milliliter per milligram concentration ratio of C5 iRNA and anti-C5 antibody or antigen-binding fragment.

28. 28. The combination of claim 27, wherein the viscosity-lowering agent is arginine, adipate, NaCl, lysine and / or aspartic acid.

29. 29. The combination of claim 28, wherein the viscosity-lowering agent is 75 mM arginine, 75 mM adipate, 75 mM NaCl, 75 mM lysine, and / or 75 mM aspartic acid.

30. An antibody that specifically binds to C5 (anti-C5) or an antigen-binding fragment thereof: (1) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence shown in SEQ ID NO: 2, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence shown in SEQ ID NO: 10; (2) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 18, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 26; (3) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 34, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 42; (4) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 50, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 58; (5) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 66, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 74; (6) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 82, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 90; (7) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 98, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 106; (8) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 98, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 114; (9) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 122, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 106; (10) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 98, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 130; (11) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 138, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 106; (12) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 146, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 106; (13) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 122, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 130; (14) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 146, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 114; (15) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 146, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 130; (16) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 138, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 130; (17) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 154, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 162; (18) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 170; and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 178; (19) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 186, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 194; (20) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 202, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 210; (21) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 218, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 226; (22) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 234, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 242; (23) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 250; and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 258; (24) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 266, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 258; (25) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 274, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 282; (26) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 290; and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 298; (27) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 306, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 314; (28) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 322, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 330; and / or (29) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 338, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO:

346. The combination according to any one of claims 1 to 29, comprising:

31. The antibody that specifically binds to C5 (anti-C5) or its antigen-binding fragment is (i) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 8, and a light chain variable region comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; (ii) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 20, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 22, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 24, and a light chain variable region comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 30, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 32; (iii) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 36, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40, and a light chain variable region comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 46, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48; (iv) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 52, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 54, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56, and a light chain variable region comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 60, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 62, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64; (v) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 68, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 70, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72, and a light chain variable region comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 76, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 78, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 80; (vi) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 84, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 86, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 88, and a light chain variable region comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 92, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 94, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; (vii) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 100, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 102, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 104, and a light chain variable region comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 108, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 110, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112; (viii) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 100, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 102, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 104, and a light chain variable region comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 118, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 120; (ix) a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 126, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 128, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 108, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 110, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112; (x) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 100, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 102, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 104, and a light chain variable region comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 132, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 134, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136; (xi) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 140, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 142, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 144, and a light chain variable region comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 108, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 110, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112; (xii) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 148, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152, and a light chain variable region comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 108, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 110, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112; (xiii) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 126, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 128, and a light chain variable region comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 132, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 134, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136; (xiv) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 148, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152, and a light chain variable region comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 118, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 120; (xv) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 148, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152, and a light chain variable region comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 132, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 134, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136; (xvi) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 140, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 142, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 144, and a light chain variable region comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 132, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 134, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136; (xvii) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 156, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 158, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 160, and a light chain variable region comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 164, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 166, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 168; (xviii) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 172, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 174, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 176, and a light chain variable region comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 180, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 182, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 184; (xix) a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 188, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 190, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 192, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 196, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 198, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 200; (xx) a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 204, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 206, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 208, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 212, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 214, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 216; (xxi) a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 220, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 222, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 224, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 228, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 230, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 232; (xxii) a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 236, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 238, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 240, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 244, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 246, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 248; (xxiii) a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 252, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 254, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 256, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 260, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 262, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 264; (xxiv) a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 268, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 270, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 272, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 260, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 262, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 264; (xxv) a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:276, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:278, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:280, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:284, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:286, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:288; (xxvi) a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 292, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 294, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 296, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 300, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 302, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 304; (xxvii) a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 308, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 310, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 312, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 316, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 318, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 320; (xxviii) a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 324, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 326, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 328, and a light chain variable region comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 332, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 334, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 336; or (xxix) A heavy chain variable region comprising HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 340, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 342, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 344; and a light chain variable region comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 348, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 350, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:

352. The combination according to any one of claims 1 to 30, comprising:

32. An antibody that specifically binds to C5 (anti-C5) or an antigen-binding fragment thereof: (1) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 2, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 10; (2) a heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 18, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 26; (3) a heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 34, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 42; (4) a heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 50, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 58; (5) a heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 66, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 74; (6) a heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 82, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 90; (7) A heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 98, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 106; (8) A heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 98, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 114; (9) A heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 122, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 106; (10) A heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 98, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 130; (11) A heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 138, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 106; (12) A heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 146, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 106; (13) A heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 122, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 130; (14) A heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 146, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 114; (15) A heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 146, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 130; (16) A heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 138, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 130; (17) A heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 154, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 162; (18) A heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 170, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 178; (19) A heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 186, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 194; (20) A heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 202, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 210; (21) A heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 218, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 226; (22) A heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 234, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 242; (23) A heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 250, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 258; (24) A heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 266, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 258; (25) A heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 274, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 282; (26) A heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 290, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 298; (27) A heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 306, and a light chain variable region comprising the amino acid sequence represented by SEQ ID NO: 314; (28) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 322, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 330; or (29) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 338, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:

346. The combination according to any one of claims 1 to 31, comprising:

33. 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, if 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 of the antibody or antigen-binding fragment.

34. C5 iRNA is Double-stranded ribonucleic acid (dsRNA) agents comprising a sense strand and an antisense strand and the antisense strand comprises a region of complementarity comprising at least 17 contiguous nucleotides that differ by at most 3 nucleotides from the nucleotide sequence 5'-UAUUAUAAAAUAUCUUGCUUUU-3' (SEQ ID NO: 364); The dsRNA agent comprises at least one modified nucleotide. The combination according to any one of claims 1 to 33.

35. C5 iRNA is a double-stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3' (SEQ ID NO:406) and the antisense strand comprises 5'-usAfsUfuAfuaAfaAfauaUfcUfuGfcuusususudTdT-3' (SEQ ID NO:369); In the array formula: a, g, c, and u are 2'-O-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; The sense strand has a ligand at the 3' end. 【Chemistry 1】 is conjugated to The combination according to any one of claims 1 to 34.

36. C5 iRNA is a semdisilane or its Na ＋ The combination according to any one of claims 1 to 35, which is in the form of a salt.

37. 37. The combination of any one of claims 1 to 36, comprising a C5 iRNA that is a semdisilane and one or more of semdisilane impurity 1, semdisilane impurity 2, and semdisilane impurity 3.

38. Approximately 20 to 100, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 13 0, 140, 150, 155, 160, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 2 38. The combination of any one of claims 1 to 37, comprising 30, 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, or 400 mg / ml of C5 iRNA.

39. 39. A combination according to any one of claims 1 to 38, having a viscosity of <30 cP at 20°C; and / or an osmolality of 240 to 450 mOsm / kg.

40. 40. The combination of claim 39, having a viscosity of ≦20 cP at 20° C.

41. double-stranded C5 iRNA; and an anti-C5 antibody or an antigen-binding fragment thereof; a pH higher or lower than (at least 0.5) 6.0; C5 iRNA, an anti-C5 antibody or an antigen-binding fragment thereof; buffering agents, viscosity reducers, stabilizers, and nonionic surfactants; C5 iRNA, an anti-C5 antibody or an antigen-binding fragment thereof; histidine-based buffers, L-arginine, stabilizers, and nonionic surfactants; C5 iRNA, an anti-C5 antibody or an antigen-binding fragment thereof; histidine-based buffers, L-arginine, a sugar or polyol, and nonionic surfactants; Semudisilane, Pozelimab, histidine-based buffers, L-arginine, stabilizers, and nonionic surfactants, pH about 6.5; Semudisilane, Pozelimab, histidine-based buffers, L-arginine, sucrose, and Polysorbate 80, pH about 6.5; 100 (±10) mg / mL C5 iRNA, 100 (±10) mg / mL anti-C5 antibody or antigen-binding fragment thereof, 50 (±5) mM viscosity-reducing agent, 10 (±1) mM buffer, 1.0 (±0.1)% stabilizer, 0.075 (±0.0075)% nonionic surfactant, pH 6.5; 75 (±7.5) mg / mL C5 iRNA, 150 (±15) mg / mL anti-C5 antibody or antigen-binding fragment thereof, 75 (±7.5) mM viscosity-reducing agent, 15 (±1.5) mM buffer, 1.5 (±0.15)% stabilizer, 0.1125 (±0.01125)% nonionic surfactant, pH 6.5; 50 (±5) mg / mL C5 iRNA, 100 (±10) mg / mL anti-C5 antibody or antigen-binding fragment thereof, 75mM (±7.5) viscosity reducing agent, 15 (±1.5) mM buffer, 1.5 (±0.15)% stabilizer, 0.1125 (±0.01125)% nonionic surfactant; pH 6.5; 50 (±5) mg / mL C5 iRNA, 100 (±10) mg / mL anti-C5 antibody or antigen-binding fragment thereof, 75 (±7.5) mM viscosity-reducing agent, 35 (±3.5) mM buffer, 1.5 (±0.15)% stabilizer, 0.1125 (±0.01125)% nonionic surfactant, pH 6.5; 100 (±10) mg / mL C5 iRNA, 100 (±10) mg / mL anti-C5 antibody or antigen-binding fragment thereof, 50 (±5) mM viscosity-reducing agent, 30 (±3) mM buffer, 1 (±0.1)% stabilizer, 0.075 (±0.0075)% nonionic surfactant, pH 6.5; 50 (±5) mg / mL C5 iRNA, 100 (±10) mg / mL anti-C5 antibody or antigen-binding fragment thereof, 90 (±9) mM viscosity-reducing agent, 30 (±3) mM buffer, 1 (±0.1)% stabilizer, 0.075 (±0.0075)% nonionic surfactant, pH 6.5; 100 mg / mL semdisilane, 100 mg / mL pozelimab, 50 mM L-arginine, 30 mM histidine-based buffer, 1% (w / v) sucrose, 0.075% (w / v) PS80, pH 6.5; 50 mg / mL semdisilane, 100 mg / mL pozelimab, 90 mM L-arginine, 30 mM histidine-based buffer, 1% (w / v) sucrose, 0.075% (w / v) PS80, pH 6.5; 100 mg / mL semdisilane, 100 mg / mL pozelimab, 50 mM L-arginine, 10 mM histidine-based buffer, 1.0% sucrose, 0.075%PS80, pH 6.5; 75 mg / mL semdisilane, 150 mg / mL pozelimab, 75 mM L-arginine, 15mM histidine-based buffer, 1.5% sucrose, 0.1125%PS80, pH 6.5; 50 mg / mL semdisilane, 100 mg / mL pozelimab, 75 mM L-arginine, 15mM histidine-based buffer, 1.5% sucrose, 0.1125%PS80; pH 6.5; 50 mg / mL semdisilane, 100 mg / mL pozelimab, 75 mM L-arginine, 35 mM histidine-based buffer, 1.5% sucrose, 0.1125%PS80, pH 6.5; 100 mg / mL semdisilane, 100 mg / mL pozelimab, 50 mM L-arginine, 30 mM histidine-based buffer, 1% sucrose, 0.075%PS80, pH 6.5; 50 mg / mL semdisilane, 100 mg / mL pozelimab, 90 mM L-arginine, 30 mM histidine-based buffer, 1% sucrose, 0.075%PS80, pH 6.5; optionally further comprising GalNAc and / or GlcNAc; 120mg / mL C5 iRNA, 120 mg / mL anti-C5 antibody or antigen-binding fragment thereof, viscosity reducers; 15 mM histidine, pH 6.2; 75mg / mL C5 iRNA, 150 mg / mL anti-C5 antibody or antigen-binding fragment thereof, viscosity reducers; 15 mM histidine, pH 6.2; 120mg / mL C5 iRNA, 120 mg / mL anti-C5 antibody or antigen-binding fragment thereof, 15 mM histidine, pH 6.2; 75mg / mL C5 iRNA, 150 mg / mL anti-C5 antibody or antigen-binding fragment thereof, 15 mM histidine, pH 6.2; 120 mg / mL semdisilane, 120 mg / mL pozelimab, 15 mM histidine, pH 6.2; 120 mg / mL semdisilane, 120 mg / mL pozelimab, 75 mM arginine, 15 mM histidine, pH 6.2; 120 mg / mL semdisilane, 120 mg / mL pozelimab, 75 mM adipate, 15 mM histidine, pH 6.2; 120 mg / mL semdisilane, 120 mg / mL pozelimab, 75 mM NaCl, 15 mM histidine, pH 6.2; 120 mg / mL semdisilane, 120 mg / mL pozelimab, 75 mM lysine, 15 mM histidine, pH 6.2; 120 mg / mL semdisilane, 120 mg / mL pozelimab, 75 mM aspartic acid, 15 mM histidine, pH 6.2; 120 mg / mL semdisilane, 120 mg / mL pozelimab, 75 mM proline, 15 mM histidine, pH 6.2; 120 mg / mL semdisilane, 120 mg / mL pozelimab, 50 mM histidine, pH 6.2; 120 mg / mL semdisilane, 120 mg / mL pozelimab, 50mM caffeine, 15 mM histidine, pH 6.2; 120 mg / mL semdisilane, 120 mg / mL pozelimab, 50 mM phenylalanine, 15 mM histidine, pH 6.2 120 mg / mL semdisilane, 120 mg / mL pozelimab, 50 mM triethyl citrate, 15 mM histidine, pH 6.2; 75 mg / mL semdisilane, 150 mg / mL pozelimab, 15 mM histidine, pH 6.2; 75 mg / mL semdisilane, 150 mg / mL pozelimab, 75 mM arginine, 15 mM histidine, pH 6.2; 75 mg / mL semdisilane, 150 mg / mL pozelimab, 75 mM adipate, 15 mM histidine, pH 6.2; 75 mg / mL semdisilane, 150 mg / mL pozelimab, 75 mM NaCl, 15 mM histidine, pH 6.2; 75 mg / mL semdisilane, 150 mg / mL pozelimab, 75 mM lysine, 15 mM histidine, pH 6.2; or 75 mg / mL semdisilane, 150 mg / mL pozelimab, 75 mM aspartic acid, 15 mM histidine, pH 6.2 The combination according to any one of claims 1 to 40, comprising:

42. C5 iRNA is semdisilane; the antibody or antigen-binding fragment is pozelimab; The viscosity reducing agent is L-arginine; the buffer is a histidine-based buffer; The stabilizer is sucrose; The non-ionic surfactant is polysorbate 80; The pH is about 6.

5. The combination according to any one of claims 1 to 41.

43. the C5 iRNA is conjugated to a ligand containing one or more terminal N-acetylgalactosamine (GalNAc) or N-acetylglucosamine (GlcNAc) residues; the pH is in the range of about 6 to about 0.5 or higher; and / or - pH is about 6.5; The combination according to any one of claims 1 to 42.

44. - Contains beta-hexosaminidase; - including antibodies of antigen-binding fragments thereof expressed and isolated from mammalian host cells containing beta-hexosaminidase; - antibodies expressed and isolated from Chinese hamster ovary cells, including antigen-binding fragments thereof; Contains at most about 1% of the total semdisilane impurity 1; - Contains about 80% or more of semdisilane based on total semdisilane after 2 years of storage at 2-8°C; - before storage (at t=0) has about 91% semdisilane; - has about 80% or more of its semudisilane content after 1 year, 1 1 / 2 years, 2 years, 2 1 / 2 years, or 3 years of storage at 2-8°C; - having about 80% to about 91% semdisilane; dIPRP shows a semdisilane purity (%) of approximately 90.5% at t=0; 91.1% after 1 month of storage at 2-8°C; 90.8% after 3 months of storage at 2-8°C; 90% after 6 months of storage at 2-8°C; 88.8% after 9 months of storage at 2-8°C; 88.7% after 12 months of storage at 2-8°C; 89% after 18 months of storage at 2-8°C; and / or 89.4% after 24 months of storage at 2-8°C; dIPRP shows semdisilane purity (%) of approximately 90.8% at t=0, 90.6% after 1 month of storage at 2-8°C; 90.5% after 3 months of storage at 2-8°C; 89.4% after 6 months of storage at 2-8°C; 88.3% after 9 months of storage at 2-8°C; 87.8% after 12 months of storage at 2-8°C; 87.8% after 18 months of storage at 2-8°C; and / or 89.4% after 24 months of storage at 2-8°C; - dIPRP shows semdisilane single chain purity (%) of approximately 90.5% at t=0; 90.2% after 1 month storage at 25°C and 60% RH; 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; and 85.8% after 3 months storage at 40°C and 75% RH; dIPRP shows semdisilane purity (%) of approximately 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; and 82.3% after 3 months storage at 40°C and 75% RH; exhibiting a semdisilane purity (%) by dIPRP 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; exhibiting a semdisilane purity (%) by dIPRP 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; exhibiting a semdisilane purity (%) by dIPRP of about 90.5% at t=0; about 89.9% after 1 month of storage at 25°C and 60% RH; about 90.8% after 3 months of storage at 25°C and 60% RH; about 90.4% after 6 months of storage at 25°C and 60% RH; about 90.1% after 0.5 months of storage at 40°C and 75% RH; about 89.6% after 1 month of storage at 40°C and 75% RH; and / or about 89.9% after 3 months of storage at 40°C and 75% RH; and / or exhibiting a semdisilane purity (%) by dIPRP 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; The combination according to any one of claims 1 to 43.

45. a molar ratio of at most about 2.1 parts per million (ppm) beta-hexosaminidase to antibody or antigen-binding fragment; - contains at most about 0.170 micrograms / ml of beta-hexosaminidase; contains at most about 0.04 micrograms / ml of beta-hexosaminidase; and / or or 0.17 micrograms / ml of beta-hexosaminidase; or at most any such concentration The combination according to any one of claims 1 to 44, comprising:

46. 46. ​​A method for administering the combination of any one of claims 1 to 45 to a subject, the method comprising introducing the combination into the body of the subject.

47. 47. The method of claim 46, wherein the combination is administered by injection into the subject's body.

48. 48. The method of claim 47, wherein the combination is administered by intramuscular, subcutaneous, intravenous, intraocular and / or intravitreal injection.

49. 49. A method for treating or preventing a C5-related disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the combination of any one of claims 1 to 48.

50. The disease or disorder is: Disorders of inappropriate or unwanted complement activation; hemodialysis complications; pulmonary disease or disorders; neurological disorders; parasitic diseases; ischemic reperfusion states; proteinuric kidney disease; renal disorders; adult respiratory distress syndrome; adult respiratory distress syndrome (ARDS); age-related macular degeneration (AMD); allergies; Alport syndrome; Alzheimer's disease; autoimmune diseases or; immune complex disorders; inflammatory disorders; eye diseases; organoconiosis; blood disorders (thrombosis and protein-losing enteropathy); asthma; atherosclerosis; bronchoconstriction; bullous Bullous pemphigoid; C3 glomerulopathy; Capillary leak syndrome; CHAPLE disease (CD55 deficiency with complement hyperactivation); chemical injury due to irritant gases and / or chemicals; chronic obstructive pulmonary disease (COPD); complement activation due to burns; 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; dry AMD; dyspnea; emphysema; epilepsy; fibrosing pneumoconiosis; geographic atrophy (GA); glomerulonephritis somatic disease; Goodpasture's syndrome; Guillain-Barré syndrome; hemolytic anemia; hemoptysis; hereditary angioedema; hyperacute allograft rejection; hypersensitivity pneumonitis; immune complex-associated inflammation; inflammatory diseases; autoimmune inflammation; hereditary CD59 deficiency; injury due to inert dust and / or minerals; 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; ocular neovascularization; 50. The method of claim 49, wherein the condition is Parkinson's disease; pneumonia; progressive renal failure; psoriasis; pulmonary embolism and infarction; pulmonary fibrosis; pulmonary vasculitis; renal ischemia; renal ischemia-reperfusion injury; rheumatoid arthritis; schizophrenia; SLE nephritis; smoke poisoning; stroke; systemic inflammatory response in post-pump syndrome due to cardiopulmonary or renal bypass surgery; systemic lupus erythematosus (SLE); burns; traumatic brain injury; uveitis; vasculitis; exudative AMD; paroxysmal nocturnal hemoglobinuria (PNH); and / or xenograft rejection.

51. 51. The method of any one of claims 46 to 50, wherein the subject is administered one or more additional therapeutic agents.

52. 52. The method of claim 51 , wherein the additional chemotherapeutic agent is an androgen, an anticoagulant, an anti-inflammatory agent, an antihypertensive agent, an immunosuppressant, a fibrinolytic agent, a lipid-lowering agent, an anti-CD20 agent, an anti-TNF agent, a C3 inhibitor, an antithrombotic agent, a corticosteroid, a nonsteroidal anti-inflammatory drug, an angiotensin-converting enzyme inhibitor, an inhibitor of hydroxymethylglutaryl CoA reductase and / or an anticonvulsant.

53. 53. The method of claim 52, wherein the additional chemotherapeutic agent is warfarin, aspirin, heparin, phenindione, fondaparinux, idraparinux; and thrombin inhibitors such as argatroban, lepirudin, bivalirudin, dabigatran, vincristine, cyclosporin A, methotrexate, ancrod, ε-aminocaproic acid, antiplasmin-a1, prostacyclin, defibrotide, rituximab, infliximab, and / or magnesium sulfate.

54. an RNA conjugated to a ligand comprising one or more terminal N-acetylgalactosamine (GalNAc) and / or N-acetylglucosamine (GlcNAc) residues; beta-hexosaminidase and 1. A method for increasing RNA stability or reducing beta-hexosaminidase activity in a composition comprising: (i) adding GalNAc and / or GlcNAc to the composition, and / or (ii) increasing or decreasing the pH of the composition from about 6. A method comprising:

55. The composition comprises: - an RNA that is a C5 iRNA; an anti-C5 antibody or antigen-binding fragment thereof expressed and isolated from a mammalian host cell containing beta-hexosaminidase; Depending on the situation, - buffering agents; - viscosity reducers; - stabilizers; and - Nonionic surfactants 55. The method of claim 54, comprising:

56. 56. The method of any one of claims 54-55, wherein the composition comprises an antibody expressed in Chinese Hamster Ovary (CHO) cells.

57. 57. The method of any one of claims 54 to 56, wherein the RNA is double-stranded RNA optionally comprising an overhang of 1 or 2 nucleotides at one or both ends.

58. 58. The method of any one of claims 54 to 57, wherein the RNA is chemically synthesized.

59. A method for preparing the combination according to any one of claims 1 to 45, comprising: combining RNAi with an anti-C5 antibody or antigen-binding fragment; (i) adding GalNAc to the combination; and / or (ii) adjusting the pH of the combination to about 6 or less. A method comprising:

60. 60. A combination product of the method of claim 59.

61. A method for administering to a subject an antibody that specifically binds to C5 (anti-C5) or its antigen-binding fragment in combination with C5 iRNA, the method comprising introducing the antibody or fragment and iRNA into the body of the subject.

62. The antibody or fragment and the iRNA are Subcutaneous injection or intravenous infusion of a combination containing both the antibody or fragment and the iRNA; or Subcutaneous injection or intravenous infusion of separate formulations, each containing either the antibody or fragment or the iRNA.

62. The method of claim 61 , wherein the nucleotide sequence is introduced by:

63. A method for treating or preventing a C5-related disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to C5 in combination with a C5 iRNA, either in a single combination or in separate formulations.

64. 64. The method of any one of claims 61 to 63, further comprising one or more initial intravenous or subcutaneous loading doses of antibody or antigen-binding fragment and / or iRNA.

65. (1) approximately 400 mg of an anti-C5 antibody or antigen-binding fragment; and (2) C5 iRNA approximately 200mg 65. The method of any one of claims 61 to 64, comprising administering one or more doses of both:

66. about 400 mg of the anti-C5 antibody or antigen-binding fragment is administered about every 2, 3, or 4 weeks (± 3 days); Approximately 200 mg of C5 iRNA is administered approximately every 4 weeks (± 3 days).

66. The method according to any one of claims 61 to 65.

67. Targeted at: (i) about 400 mg of an anti-C5 antibody or antigen-binding fragment subcutaneously about every 2 weeks (± 3, 4, 5, 6, or 7 days) and about 200 mg of C5 iRNA subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days); (ii) about 400 mg of an anti-C5 antibody or antigen-binding fragment subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days) and about 200 mg of C5 iRNA subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days); (iii) an intravenous loading dose of an anti-C5 antibody or antigen-binding fragment, about 400 mg of the anti-C5 antibody or antigen-binding fragment subcutaneously, and about 200 mg of C5 iRNA subcutaneously; then, about every 4 weeks (± 3, 4, 5, 6, or 7 days) thereafter, about 400 mg of the anti-C5 antibody or antigen-binding fragment subcutaneously, and about 200 mg of C5 iRNA subcutaneously; (iv) an intravenous loading dose of about 30 or 60 mg / kg of anti-C5 antibody or antigen-binding fragment, about 400 mg of anti-C5 antibody or antigen-binding fragment subcutaneously, and about 200 mg of C5 iRNA subcutaneously; then, about every 4 weeks (± 3, 4, 5, 6, or 7 days) thereafter, about 400 mg of anti-C5 antibody or antigen-binding fragment subcutaneously and about 200 mg of C5 iRNA subcutaneously; (v) an intravenous loading dose of about 30 or 60 mg / kg of anti-C5 antibody or antigen-binding fragment, followed by one or more weekly subcutaneous doses of about 800 mg of anti-C5 antibody or antigen-binding fragment, then, after an optional one-week period, about 400 mg of anti-C5 antibody or antigen-binding fragment subcutaneously and about 200 mg of C5 iRNA subcutaneously; then about every four weeks (± 3, 4, 5, 6, or 7 days) thereafter, about 400 mg of anti-C5 antibody or antigen-binding fragment subcutaneously and about 200 mg of C5 iRNA subcutaneously; (vi) (a) a dose of eculizumab intravenously and about 200 mg of C5 iRNA subcutaneously; (b) a dose of eculizumab up to about 14 days (± 3, 4, 5, 6, or 7 days) later; and (c) about 14 or 15 days later (± 3, 4, 5, 6, or 7 days), an anti-C5 antibody or antigen-binding fragment dose of 30 or 60 mg / kg body weight intravenously, about 400 mg of anti-C5 antibody or antigen-binding fragment subcutaneously, and about 200 mg of C5 iRNA intravenously, and (d) about every 4 weeks (± 3, 4, 5, 6, or 7 days) thereafter, a dose of about 400 mg of anti-C5 antibody or antigen-binding fragment subcutaneously and about 200 mg of C5 iRNA subcutaneously; or (vii) (a) about a 200 mg SC dose of C5 iRNA; (b) about 28 days (± 3, 4, 5, 6, or 7 days) later, a 30 or 60 mg / kg IV loading dose of an anti-C5 antibody or antigen-binding fragment, a 400 mg SC dose of an anti-C5 antibody or antigen-binding fragment, and a 200 mg SC dose of C5 iRNA; and (c) about 29 days (± 3, 4, 5, 6, or 7 days) later and about every 4 weeks (± 3, 4, 5, 6, or 7 days) thereafter, about a 400 mg SC dose of an anti-C5 antibody or antigen-binding fragment and about a 200 mg SC dose of C5 iRNA; or (viii) (a) about 4 weeks (± 3, 4, 5, 6, or 7 days) after administration of ravulizumab, a 200 mg SC dose of C5 iRNA; (b) about 28 days (± 3, 4, 5, 6, or 7 days) later, an IV loading dose of 30 or 60 mg / kg of anti-C5 antibody or antigen-binding fragment, a 400 mg SC dose of anti-C5 antibody or antigen-binding fragment, and a 200 mg SC dose of C5 iRNA; and (c) about 29 days (± 3, 4, 5, 6, or 7 days) later and about every 4 weeks (± 3, 4, 5, 6, or 7 days) thereafter, a 400 mg SC dose of anti-C5 antibody or antigen-binding fragment and a 200 mg SC dose of C5 iRNA.

67. The method of any one of claims 61 to 66, wherein

68. the anti-C5 antibody or antigen-binding fragment and the C5 iRNA are administered subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days) as a single injection of a combination comprising the anti-C5 antibody or antigen-binding fragment and the C5 iRNA; Approximately every 4 weeks (± 3, 4, 5, 6, or 7 days), an additional injection of the anti-C5 antibody or antigen-binding fragment is administered subcutaneously.

68. The method of any one of claims 61 to 67.

69. the anti-C5 antibody or antigen-binding fragment and the C5 iRNA are administered subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days) in separate injections of separate formulations, one containing the anti-C5 antibody or antigen-binding fragment and the other containing the C5 iRNA; Approximately every 4 weeks (± 3, 4, 5, 6, or 7 days), an additional injection of the anti-C5 antibody or antigen-binding fragment is administered subcutaneously.

68. The method of any one of claims 61 to 67.

70. the anti-C5 antibody or antigen-binding fragment and the C5 iRNA are administered subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days) as a single injection of a combination comprising the anti-C5 antibody or antigen-binding fragment and the C5 iRNA; Approximately every two weeks (± 3, 4, 5, 6, or 7 days), an additional injection of the anti-C5 antibody or antigen-binding fragment is administered subcutaneously.

68. The method of any one of claims 61 to 67.

71. the anti-C5 antibody or antigen-binding fragment and the C5 iRNA are administered subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days) in separate injections of separate formulations, one containing the anti-C5 antibody or antigen-binding fragment and the other containing the C5 iRNA; Approximately every two weeks (± 3, 4, 5, 6, or 7 days), an additional injection of the anti-C5 antibody or antigen-binding fragment is administered subcutaneously.

68. The method of any one of claims 61 to 67.

72. 71. The method of any one of claims 61-70, wherein the subject has previously received ravulizumab and / or eculizumab therapy.

73. 73. The method of claim 72, wherein the administration of ravulizumab is intravenous or subcutaneous.

74. 73. The method of claim 72, wherein the administration of eculizumab is about 900 mg intravenously.

75. 75. The method of any one of claims 61-74, wherein the subject has previously received pozelimb monotherapy.

76. 72. The method of any one of claims 61 to 71, wherein the subject is complement inhibitor naive.

77. administering to a subject a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA, wherein the subject has previously received eculizumab, and administering to the subject: (i) a dose of eculizumab intravenously and 200 mg of C5 iRNA subcutaneously; (ii) a dose of eculizumab by about 14 days (± 3, 4, 5, 6, or 7 days) later (about day 15); (iii) about 14 or 15 days (± 3, 4, 5, 6, or 7 days) later (about day 29), an anti-C5 antibody or antigen-binding fragment at a dose of about 30 or 60 mg / kg body weight intravenously, about 400 mg of an anti-C5 antibody or antigen-binding fragment subcutaneously, and about 200 mg of C5 iRNA subcutaneously; and (iv) about 28 days (± 3, 4, 5, 6, or 7 days) later (about day 57), and about every 28 days (± 3, 4, 5, 6, or 7 days) thereafter, about 400 mg of an anti-C5 antibody or antigen-binding fragment subcutaneously and about 200 mg of a C5 iRNA subcutaneously 75. The method of any one of claims 61 to 72 and 74 for treating or preventing a C5-related disease or disorder in a subject in need thereof, wherein

78. administering to a subject a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA, wherein the subject has previously received ravulizumab, and administering to the subject: (i) about a 200 mg SC dose of C5 iRNA about 28 days (± 3, 4, 5, 6, or 7 days) after the last dose of ravulizumab; (ii) about 28 days (± 3, 4, 5, 6, or 7 days) later (about day 29), about a 30 or 60 mg / kg IV dose of an anti-C5 antibody or antigen-binding fragment, about a 400 mg SC dose of an anti-C5 antibody or antigen-binding fragment, and about a 200 mg SC dose of a C5 iRNA; (iii) about 28 days (± 3, 4, 5, 6, or 7 days) later (about day 57), and about every 28 days (± 3, 4, 5, 6, or 7 days) thereafter, about a 400 mg SC dose of an anti-C5 antibody or antigen-binding fragment and about a 200 mg SC dose of a C5 iRNA.

74. The method of any one of claims 61 to 73, for treating or preventing a C5-related disease or disorder in a subject in need thereof, wherein

79. administering to a subject a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA, wherein the subject has not previously received or has not recently received complement inhibitor treatment, and administering to the subject: (i) on about day 1, an intravenous dose of about 30 or 60 mg / kg of an anti-C5 antibody or antigen-binding fragment, an about 400 mg subcutaneous (SC) dose of the antibody or fragment, and an about 200 mg SC dose of C5 iRNA; and (ii) about 400 mg SC of an anti-C5 antibody or antigen-binding fragment and about 200 mg SC of a C5 iRNA, starting about 28 days later (± 3, 4, 5, 6, or 7 days), and about every 4 weeks (± 3, 4, 5, 6, or 7 days) thereafter.

77. The method of any one of claims 61 to 71 and 76 for treating or preventing a C5-related disease or disorder in a subject in need thereof, wherein

80. The subject has previously received anti-C5 antibody or antigen-binding fragment monotherapy, and the subject is administered a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA: (i) about a 400 mg SC dose of the anti-C5 antibody or antigen-binding fragment and about a 200 mg SC dose of the C5 iRNA, starting about 7-8 (± 3 days) days after the last dose of anti-C5 antibody or antigen-binding fragment monotherapy or when the next dose of monotherapy is scheduled, and about every 4 weeks (± 3, 4, 5, 6, or 7 days) thereafter; or (ii) about 7-8 days (± 3 days) after the last dose of anti-C5 antibody or antigen-binding fragment monotherapy or beginning when the next dose of monotherapy is scheduled: about a 400 mg SC dose of anti-C5 antibody or antigen-binding fragment, followed by another dose about every 2 weeks (± 3, 4, 5, 6, or 7 days); and about a 200 mg SC dose of C5 iRNA, followed by another dose about every 4 weeks (± 3, 4, 5, 6, or 7 days).

80. The method of any one of claims 61 to 71 and 75 for treating or preventing a C5-related disease or disorder in a subject in need thereof, comprising administering

81. 1. A method for treating or preventing a C5-related disease or disorder in a subject in need thereof, wherein the subject has received one or more doses of a non-competitive anti-C5 antibody or antigen-binding fragment, comprising administering to the subject a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment thereof in combination with a C5 iRNA: (1) a dose of C5 iRNA after a dose of N / C Ab but before the first dose of pozeliman; or (1) a dose of C5 iRNA after a dose of N / C Ab but before the first dose of pozeliman; then (2) an intravenous loading dose of pozelimb, which is the initial dose of pozelimb; or (1) an intravenous loading dose of pozelimb 400 mg SC Q4W and semdisirane 200 mg SC Q4W; then (2) approximately 4 weeks later (and continued every 4 weeks thereafter): pozelimab 400 mg SC Q4W and semdisiran 200 mg SC Q4W; or (1) a dose of C5 iRNA along with a dose of pozeliman 400 mg SC Q4W and semdisirane 200 mg SC Q4W after completing the dose of N / C Ab and approximately 4 weeks prior to the intravenous loading dose of pozeliman; then (2) approximately 4 weeks later (and continued every 4 weeks thereafter): pozelimab 400 mg SC Q4W and semdisiran 200 mg SC Q4W; or (1) a dose of C5 iRNA and a non-competing antibody or fragment (N / C Ab) on the day the N / C Ab dose is scheduled; (2) the next dose of N / C Ab, on the day such dose is scheduled; (3) pozelimbab 30 or 60 mg / kg IV loading dose, and pozelimbab 400 mg SC and semdisirane 200 mg SC after approximately 1-2 half-lives of N / C Ab or when the next dose of N / C Ab is scheduled; (4) starting 4 weeks later (and continuing every 4 weeks thereafter), pozelimab 400 mg SC Q4W and semdisiran 200 mg SC Q4W; or (1) a dose of C5 iRNA about 1-2 half-lives after the last dose of N / C Ab; or on the day the next dose of N / C is scheduled; or after half the inter-dose interval has elapsed since the last dose of N / C Ab; (2) After approximately 1-2 additional half-lives of N / C Ab, a 30 or 60 mg / kg IV loading dose of pozeliman, 400 mg SC of pozeliman, and 200 mg SC of semdisirane; and (3) starting 4 weeks later (and continuing every 4 weeks thereafter), pozelimab 400 mg SC Q4W and semdisiran 200 mg SC Q4W Administering

82. The dose of C5 iRNA is administered 2, 3, 4, 5, 6, 7, or 8 weeks after the dose of N / C Ab, but 1, 2, 3, or 4 weeks before the first dose of pozeliman; C5 iRNA is semdisilane; C5 iRNA is semdisilane, dose is 200 mg SC; The anti-C5 antibody or antigen-binding fragment thereof is pozelimb; The intravenous loading dose of pozelimb is 30 or 60 mg / kg; The non-competitive anti-C5 antibody or antigen-binding fragment is eculizumab; The non-competitive anti-C5 antibody or antigen-binding fragment is eculizumab and doses are scheduled every 1, 2, 3, or 4 weeks; The non-competitive anti-C5 antibody or antigen-binding fragment is ravulizumab; The non-competitive anti-C5 antibody or antigen-binding fragment is ravulizumab, and doses are scheduled every 4 or 8 weeks; The half-life of the non-competing antibody is about 11 days; and / or The half-life of a non-competing antibody is approximately 32 days.

82. The method of claim 81.

83. During the procedure, subjects: -Hemoglobin stabilization; - Not receiving red blood cell transfusions; - Not having a decrease in hemoglobin of ≥ 2 g / dL; - not experiencing breakthrough hemolysis; CH50 levels in the blood are completely suppressed compared to baseline (at 0 kIU / L) before treatment and / or during any breakthrough hemolytic event; - Absence of treatment-emergent adverse events; -Improvement in fatigue compared to before treatment; >5-point improvement in FACIT-Fatigue score compared to pretreatment; -Improved physical function scores in Europeans; - Organization for Cancer Research and Treatment: Quality of Life Questionnaire; Core 30 items (EORTC QLQ-C30), compared with before treatment; - Improvement in GHS / QoL (General Health Status / Quality of Life Scale (GHS)) compared to before treatment; - A decrease in lactate dehydrogenase (LDH) levels compared to before treatment; Achievement of LDH ≤ 1.5 x upper limit of normal (ULN) compared to before treatment Achieving and maintaining LDH ≤ 1.0 x ULN; - A decrease in blood bilirubin levels compared to before the procedure; - A reduction in reticulocyte count compared to before treatment; - A decrease in the alternative pathway hemolytic activity assay (AH50) compared to before treatment; - Reduction of PNH red blood cells and / or granulocytes compared to before treatment; - Improvement compared to before treatment in fatigue, shortness of breath, muscle weakness, headache, abdominal pain, back / leg pain, chest discomfort, difficulty sleeping, difficulty thinking clearly, and / or difficulty swallowing; - Improved renal function compared to before treatment as measured by estimated glomerular filtration rate (eGFR); - Reduction of free hemoglobin in the blood compared to before treatment; - A decrease in total C5 blood levels compared to before treatment; - a reduction in PNH clone size compared to before treatment; and / or - Increased haptoglobin levels compared to before treatment 83. The method of any one of claims 46 to 53 and 61 to 82, wherein the method achieves, or achieves and maintains, one or more of:

84. C5-related diseases or disorders include disorders of inappropriate or unwanted complement activation; hemodialysis complications; pulmonary diseases or disorders; neurological disorders; parasitic diseases; post-ischemic reperfusion states; proteinuric kidney disease; renal disorders; adult respiratory distress syndrome; adult respiratory distress syndrome (ARDS); age-related macular degeneration (AMD); allergies; Alport syndrome; Alzheimer's disease; autoimmune diseases or disorders; immune complex disorders; inflammatory disorders; eye diseases; organoconiosis; blood disorders (thrombosis and protein-losing enteropathy); asthma; atherosclerosis; tracheal Transcriptional contractions; bullous pemphigoid; C3 glomerulopathy; capillary leak syndrome; CHAPLE disease (CD55 deficiency with excessive complement activation); chemical injury due to irritant gases and / or chemicals; chronic obstructive pulmonary disease (COPD); complement activation due to burns; 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; dry AMD; dyspnea; emphysema; epilepsy; fibrosing pneumoconiosis; geographic atrophy (GA); Glomerulopathy; Goodpasture's syndrome; Guillain-Barré syndrome; hemolytic anemia; hemoptysis; hereditary angioedema; hyperacute allograft rejection; hypersensitivity pneumonitis; immune complex-associated inflammation; inflammatory diseases; autoimmune inflammation; hereditary CD59 deficiency; injury due to inert dust and / or minerals; 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; ocular neovascularization; Parkinson's disease 84. The method of any one of claims 61 to 83, wherein the condition is Son's disease; pneumonia; progressive renal failure; psoriasis; pulmonary embolism and infarction; pulmonary fibrosis; pulmonary vasculitis; renal ischemia; renal ischemia-reperfusion injury; rheumatoid arthritis; schizophrenia; SLE nephritis; smoke poisoning; stroke; systemic inflammatory response in post-pump syndrome due to cardiopulmonary or renal bypass surgery; systemic lupus erythematosus (SLE); burns; traumatic brain injury; uveitis; vasculitis; exudative AMD; paroxysmal nocturnal hemoglobinuria (PNH); and / or xenograft rejection.

85. 85. The method of any one of claims 46-53 and 61-84, wherein the C5 iRNA and the anti-C5 antibody or antigen-binding fragment are combined into a combination drug, and both the antibody or fragment and the C5 iRNA are administered by a single injection of the combination drug.

86. 86. The method of claim 85, wherein the combination has a pH of about 6.

5.

87. 87. The method of any one of claims 46-53 and 61-86, wherein the C5 iRNA and the anti-C5 antibody or antigen-binding fragment are combined into a combination comprising 100 mg / ml semdisirane and 100 mg / ml pozeliimab; or 50 mg / ml semdisirane and 100 mg / ml pozeliimab.

88. The combination drug is At a pH of about 6.5, With semdisilane; Pozelimab expressed and isolated from a mammalian host cell containing beta-hexosaminidase; a buffer; a viscosity reducing agent; a stabilizer; Nonionic surfactants and The method of any one of claims 46 to 53 and 61 to 87, comprising:

89. 89. The method of any one of claims 46 to 53 and 61 to 88, wherein the subcutaneous injection is performed with a pre-filled syringe.

90. The method of any one of claims 46 to 53 and 61 to 89, wherein the subject is suffering from aplastic anemia and / or myelodysplastic syndrome.

91. The subject has previously received subcutaneous pozelimab 400 mg and subcutaneous cemdisirane 200 mg, or the method comprises administering to the subject prior to (optionally any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days prior to), after, or during these administrations: - one or more doses of subcutaneous or intravenous pozelimb; - one or more 400 mg subcutaneous doses of pozelimab; - one or more doses of subcutaneous or intravenous anti-C5 antibody or antigen-binding fragment; - one or more doses of subcutaneous or intravenous eculizumab; - one or more doses of subcutaneous or intravenous ravulizumab; - one or more doses of subcutaneous or intravenous cemdisirane; - one or more doses of subcutaneous or intravenous C5 iRNA; - one or more subcutaneous doses of pozelimab 800 mg; one or more subcutaneous doses of 800 mg of anti-C5 antibody or antigen-binding fragment; - one or more intravenous doses of pozelimab 30 mg / kg body weight; one or more intravenous doses of 30 mg / kg body weight of anti-C5 antibody or antigen-binding fragment; - one or more intravenous doses of about 60 mg / kg of body weight of pozelimab; one or more intravenous doses of about 60 mg / kg body weight of an anti-C5 antibody or antigen-binding fragment; - one or more subcutaneous doses of about 800 mg of pozelimab; one or more subcutaneous doses of about 800 mg of an anti-C5 antibody or antigen-binding fragment; one intravenous dose of about 60 mg / kg of body weight of pozelimbab, followed by one or more subcutaneous doses of about 800 mg of pozelimbab; one intravenous dose of about 60 mg / kg body weight of the anti-C5 antibody or antigen-binding fragment, followed by one or more subcutaneous doses of about 800 mg of the anti-C5 antibody or antigen-binding fragment; - one or more doses of eculizumab ≥ 300, ≥ 600, ≥ 900 or ≥ 1200 mg intravenously; - one or more doses of semdisirane 200 mg subcutaneously; and / or One or more doses of 200 mg of C5 iRNA subcutaneously 91. The method of any one of claims 46-53 and 61-90, further comprising administering

92. - the intravenous administration of the anti-C5 antibody or antigen-binding fragment is separated from the subcutaneous administration of the anti-C5 antibody or antigen-binding fragment or C5 iRNA by approximately 30 minutes; subcutaneous administration of an anti-C5 antibody or antigen-binding fragment and a C5 iRNA followed by an observation period of about 30 minutes, 1 hour, or 2 hours; and / or Subcutaneous administration of C5 iRNA is followed by an observation period of about 30 minutes, 1 hour, or 2 hours; 92. The method of any one of claims 46 to 53 and 61 to 91.

93. The subject is the criteria: Breakthrough hemolysis not due to a complement activation state; and / or - LDH increase of ≥ 2xULN due to complement activation state When indicating one or more of the The subject receives a consolidation treatment further comprising one or more 30 mg / kg IV doses of an anti-C5 antibody or antigen-binding fragment.

93. The method of any one of claims 46 to 53 and 61 to 92.

94. The subject is the criteria: Breakthrough hemolysis not due to a complement activation state; and / or - LDH increase of ≥ 2xULN due to complement activation state When indicating one or more of the Subject undergoes augmentation procedures: (1) if the subject received a treatment regimen comprising about 400 mg of an anti-C5 antibody or antigen-binding fragment administered subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days) and about 200 mg of a C5 iRNA administered subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days); administering a single 30 mg / kg IV dose of anti-C5 antibody or antigen-binding fragment on the day of consolidation, and administering a consolidation regimen beginning on the day of consolidation of about 400 mg of anti-C5 antibody or antigen-binding fragment administered subcutaneously about every 2 weeks (± 3, 4, 5, 6, or 7 days) and about 200 mg of C5 iRNA administered subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days); or (2) if the subject received a treatment regimen comprising about 400 mg of an anti-C5 antibody or antigen-binding fragment administered subcutaneously about every 2 weeks (± 3, 4, 5, 6, or 7 days) and about 200 mg of a C5 iRNA administered subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days); administering a single 30 mg / kg IV dose of anti-C5 antibody or antigen-binding fragment on the day of consolidation, and beginning again on the day of consolidation, a treatment regimen comprising about 400 mg of anti-C5 antibody or antigen-binding fragment administered subcutaneously about every 2 weeks (± 3, 4, 5, 6, or 7 days) and about 200 mg of C5 iRNA administered subcutaneously about every 4 weeks (± 3, 4, 5, 6, or 7 days); The method according to any one of claims 46 to 53 and 61 to 94.

95. The method of any one of claims 46 to 53 and 61 to 94, wherein the anti-C5 antibody or antigen-binding fragment or pozelimab is expressed in a mammalian host cell, and the iRNA or semdisirane is chemically synthesized.

96. 96. The method of claim 95, wherein the host cell is a Chinese hamster ovary cell.

97. The anti-C5 antibody or antigen-binding fragment and the C5 iRNA are a molar ratio of at most about 2.1 parts per million (ppm) beta-hexosaminidase to antibody or antigen-binding fragment; - contains at most about 0.170 micrograms / ml of beta-hexosaminidase; contains at most about 0.04 micrograms / ml of beta-hexosaminidase; and / or 0.15; 0.1525; 0.166; or 0.17 micrograms / ml of beta-hexosaminidase; or at most any such concentration The method according to any one of claims 46 to 53 and 61 to 96, wherein the composition is combined into a combination comprising:

98. The antibody or antigen-binding fragment may be (1) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence shown in SEQ ID NO: 2, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence shown in SEQ ID NO: 10; (2) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 18, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 26; (3) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 34, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 42; (4) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 50, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 58; (5) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 66, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 74; (6) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 82, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 90; (7) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 98, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 106; (8) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 98, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 114; (9) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 122, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 106; (10) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 98, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 130; (11) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 138, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 106; (12) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 146, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 106; (13) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 122, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 130; (14) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 146, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 114; (15) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 146, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 130; (16) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 138, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 130; (17) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 154, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 162; (18) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 170; and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 178; (19) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 186, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 194; (20) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 202, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 210; (21) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 218, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 226; (22) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 234, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO: 242; (23) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 250; and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 258; (24) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 266, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 258; (25) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 274, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 282; (26) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 290; and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 298; (27) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 306, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 314; (28) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 322, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 330; and / or (29) A heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence represented by SEQ ID NO: 338, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence represented by SEQ ID NO:

346. The method according to any one of claims 61 to 97, wherein

99. C5 iRNA is a C5 gene sense strand DNA sequence AAGCAAGATATTTTTATTA 99. The method of any one of claims 46-53 and 61-98, comprising an RNA strand that is complementary to an mRNA transcribed from ATA (nucleotides 782-802 of SEQ ID NO: 360).

100. C5 iRNA is Double-stranded ribonucleic acid (dsRNA) agents comprising a sense strand and an antisense strand and the antisense strand comprises a region of complementarity comprising at least 17 contiguous nucleotides that differ by at most 3 nucleotides from the nucleotide sequence 5'-UAUUAUAAAAUAUCUUGCUUUU-3' (SEQ ID NO: 364); The dsRNA agent comprises at least one modified nucleotide.

100. The method of any one of claims 46 to 53 and 61 to 99.

101. C5 iRNA is a double-stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3' (SEQ ID NO:406) and the antisense strand comprises 5'-usAfsUfuAfuaAfaAfauaUfcUfuGfcuusususudTdT-3' (SEQ ID NO:369); In the array formula: a, g, c, and u are 2'-O-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; The sense strand has a ligand at the 3' end. 【Chemistry 2】 is conjugated to The method of any one of claims 46 to 53 and 61 to 100.

102. The method according to any one of claims 61 to 101, wherein the C5 iRNA and the antibody or antigen-binding fragment thereof that specifically binds to C5 are contained in a combination according to any one of claims 1 to 45.

103. The method of any one of claims 46 to 53 and 61 to 102, wherein the C5 iRNA and the anti-C5 antibody or antigen-binding fragment thereof are in a single combination, and the single combination, when administered subcutaneously, is administered in one or more injections of the combination.

104. 104. The method of any one of claims 46-53 and 61-103, wherein the C5 iRNA and the anti-C5 antibody or antigen-binding fragment are in a single combination, and the single combination, when administered subcutaneously, is administered in two injections of the combination.

105. The method of any one of claims 46 to 104, wherein the C5 iRNA is semdisilane.

106. Semdisilane is Na ＋ 106. The method of claim 105, in a salt form.

107. The method of any one of claims 46 to 106, wherein the anti-C5 antibody or antigen-binding fragment thereof is pozelimb.

108. 108. The method of any one of claims 46-107, wherein the 30 mg / kg or 60 mg / kg IV dose of pozelimbab or an anti-C5 antibody or antigen-binding fragment thereof is a 30 mg / kg IV dose.

109. 108. The method of any one of claims 46-107, wherein the 30 mg / kg or 60 mg / kg IV dose of pozelimbab or an anti-C5 antibody or antigen-binding fragment thereof is a 60 mg / kg IV dose.

110. Pozelimab or an anti-C5 antibody or antigen-binding fragment thereof The amino acid sequence: QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNYNPSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWGQ GTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGP PCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLSGK; and a heavy chain comprising: Amino acid sequence: AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPSRFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC and a light chain comprising 110. The method or combination according to any one of claims 1 to 109, comprising:

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