High-concentration c5 Anti-

Abstract

Pharmaceutical formulations comprising anti- C5 antigen binding proteins and a pharmaceutically acceptable carrier are provided.SOLUTION: The present invention includes high-concentration, low-viscosity pharmaceutical formulations comprising anti- C5 antibodies or antigen-binding fragments thereof and arginine. Such formulations may be provided in conjunction with an RNAi molecule such as semdisilane. Also provided are methods of treating C5 associated diseases such as PNH and aHUS.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 888,086, filed August 16, 2019, which is incorporated by reference herein in its entirety for all purposes.

[0002] The Sequence Listing of the present application has been submitted electronically as an ASCII sequence listing with the file name "10643seqlist", a creation date of August 11, 2020, and a size of 136 Kb. The submitted Sequence Listing is a part of the present specification and is incorporated herein by reference in its entirety.

[0003] The field of the disclosure relates to pharmaceutical formulations comprising antibodies and antigen-binding fragments thereof and methods of treatment using such formulations. [Background technology]

[0004] Pharmaceutical formulations for delivering high doses of antibodies or other polypeptides in moderate volumes pose challenges due to the resulting high viscosity. As the antibody concentration increases, the viscosity of the formulation typically increases exponentially. See Non-Patent Document 1. For example, Cimzia contains PEGylated Fab' fragments at a concentration of 200 mg / ml and a viscosity of approximately 80 cP (relatively high viscosity). See Non-Patent Document 2.

[0005] Viscous solutions require high ejection forces through a needle to administer the drug, which can require long injection times. The pain and discomfort experienced by patients during long injection times can negatively impact compliance and adherence to drug therapy. Furthermore, the potential for product loss, which can result from highly viscous solutions adhering to contact surfaces of primary packaging, can also be an issue. When drug delivery is by autoinjector, the challenge is to ensure that the device can generate the forces required to function properly throughout its shelf life, thus requiring extensive modeling and accelerated aging to simulate the high pressures exerted on the device.

[0006] Acceptable subcutaneous (SQ or SC) anti-C5 therapeutic antibody formulations have been particularly challenging to develop. Because plasma C5 concentrations are relatively high (approximately 80 μg / mL), large doses of antibody are typically required to achieve therapeutic blockade. (Non-Patent Document 3) Subcutaneous administration is typically preferred for patient convenience. While SQ injections can usually be administered by the patient themselves, intravenous (IV) administration must be performed by a physician / in a clinic. For example, eculizumab has been approved for the treatment of various C5-mediated diseases. Patients receive large doses (900–1200 mg) of eculizumab every two weeks, and this enormous dosage requires IV administration. (Non-Patent Document 3) Another approved therapeutic anti-C5 antibody, ravulizumab (sold as Ultomoris), is administered IV at even higher levels, 2400–3000 mg. SQ Ultomoris is administered weekly at 700 mg from a 100 mg / ml formulation (7 ml dosing volume given in two separate injections). Non-Patent Document 4. As discussed, the high SQ dosing volume poses problems, for example, because it takes a long time to inject the entire dose. With a device capable of an infusion rate of 1 ml / min, this requires 7 minutes. During this time, errors can occur during the infusion, such as interruptions to the infusion. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Yadav et al., J Pharm Sci. 99(12)4812-29(2010) [Non-patent document 2] “Innovative Drug Delivery Technology to Meet Evolving Need of Biologics & Small Molecules”, ONdrugDelivery Magazine, Issue 56 (March 2015), pp. 4-6 [Non-patent document 3] Holers, Annu Rev Immunol 32:433~459 (2014) [Non-patent document 4] Alexion Pharmaceuticals, Inc., Investor Day presentation (March 20, 2019) Summary of the Invention [Means for solving the problem]

[0008] The present invention provides antigen-binding proteins (e.g., antibodies or antigen-binding fragments thereof) that specifically bind to C5 (H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9 ;H4H12166P10;H4H12167P;H4Hl2168P;H4Hl2169P;H4H12170P;H4H12171P;H4H12175P;H4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N;H2M11695N;ravulizumab;crovalimab, eculizumab;tesidolumab or mubodina) approximately 150 or 200 mg / ml or more; and a buffer (e.g., phosphate buffer, acetate buffer, citrate buffer, histidine buffer, or imidazole buffer); arginine (e.g., L-arginine HCl, e.g., 50 to 100 mM, e.g., 100 mM); water; and optionally, an oligosaccharide (e.g., sucrose, mannitol, dextrose, glycerin, TMAO (trimethylamine-N-oxide), trehalose, ethylene glycol, glycerin ... and optionally a pharmaceutically acceptable carrier comprising a non-ionic surfactant (e.g., a polyoxyethylene-based surfactant or a glycoside compound-based surfactant, polysorbate-20, polysorbate-80, or Tween-20), a pH of up to about 6.1, e.g., 5-6, e.g., 5.8; and a viscosity of about 14 cP, 14.3 cP, or 15 cP (20°C) or less. In an embodiment of the present invention, the anti-C5 antigen-binding protein is pozeliman. In an embodiment of the present invention, the formulation comprises about 200 mg / ml of an antibody (e.g., pozeliman) that specifically binds to human C5; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% sucrose; about 0.15% polysorbate-80; and water, pH 5.8±0.2. In an embodiment of the invention, the pharmaceutical formulation is aqueous (e.g., suitable for intravenous and / or subcutaneous administration) and comprises H4H12166P (e.g., about 200 mg / mL), histidine (e.g., histidine-HCl; e.g., about 20 mM), pH about 5.8, arginine (e.g., about 100 mM; e.g., L-arginine or L-arginine hydrochloride), a polyol such as sucrose (e.g., about 2% (w / v)), and a non-ionic surfactant such as polysorbate (e.g., polysorbate 80; e.g., about 0.15% (w / v)).In an embodiment of the invention, the pharmaceutical formulation is aqueous (e.g., suitable for intravenous and / or subcutaneous administration) and contains H4H12166P (e.g., about 200 mg / mL, 200 mg / mL ± 20 mg / mL, or 180-210 mg / mL), histidine (e.g., histidine-HCl; e.g., about 10-20 or 10-24 mM), pH about 5.5 ± 0.6, and arginine (e.g., about 100 mM ± 20 mM; e.g., L-arginine, L-arginine HCl, or L-arginine monohydrochloride). and optionally a non-ionic surfactant such as a polysorbate (e.g., polysorbate 80; e.g., about 0.15% (w / v)).In an embodiment of the invention, the pharmaceutical formulation is aqueous (e.g., suitable for intravenous and / or subcutaneous administration) and comprises an antibody that specifically binds to C5, having the amino acid sequence: QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNYNPSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNW YVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 368); and the amino acid sequence: AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPSRFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD About 200 mg / mL or 274 mg / mL of an antibody comprising a light chain immunoglobulin comprising NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 369), about 20 mM histidine (e.g., histidine-HCl), about pH 5.8, about 100 mM L-arginine (e.g., L-arginine HCl, or L-arginine monohydrochloride), about 2% (w / v) sucrose, and about 0.15% (w / v) polysorbate 80 (PS-80).In an embodiment of the invention, the formulation comprises one or more additional therapeutic agents, such as an RNA interfering agent that binds to an mRNA sequence partially or completely encoding C5, for example, an RNA strand comprising the ribonucleotide sequence 5'-UAUUAUAAAAAUAUCUUGCUUUU-3' (SEQ ID NO: 358); and an RNA interfering agent comprising an RNA strand comprising the ribonucleotide sequence 5'-AAGCAAGAUAUUUUUAUAAUA-3' (SEQ ID NO: 359). In an embodiment of the invention, the additional therapeutic agent is cemdisiran. In embodiments of the invention, the additional therapeutic agent is an anticoagulant, warfarin, aspirin, heparin, phenindione, fondaparinux, idraparinux, a thrombin inhibitor, argatroban, lepirudin, bivalirudin, dabigatran, an anti-inflammatory agent, a corticosteroid, a nonsteroidal anti-inflammatory drug (NSAID), an antihypertensive agent, angiotensin-converting enzyme inhibitor, an immunosuppressant, vincristine, cyclosporin A or methotrexate, the thrombolytic agent ancrod, E-aminocaproic acid, an antiplasmin-a1, prostacyclin, defibrotide, an antihyperlipidemic agent, a hydroxymethylglutaryl-CoA reductase inhibitor, an anti-CD20 agent, rituximab, an anti-TNFα agent, infliximab, an antiepileptic agent, magnesium sulfate, a C3 inhibitor, and / or an antithrombotic agent.

[0009] The invention also provides methods for making the pharmaceutical formulations of the invention, which methods comprise the step of mixing the antigen-binding protein with a carrier component. The pharmaceutical formulations that are the products of such methods also form part of the invention.

[0010] The invention also provides a pharmaceutical formulation of the invention, including a container or injection device, such as a vial, syringe, pre-filled syringe, or autoinjector, that contains the pharmaceutical formulation of the invention.

[0011] The present invention also provides anti-C5 antigen binding proteins (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H and intravenous formulations (e.g., sterile intravenous formulations) comprising an aqueous solution for intravenous administration (e.g., 0.9% saline, lactated Ringer's solution, dextrose 5% in water or 0.45% saline). For example, in embodiments of the present invention, the intravenous aqueous solution has a volume of about 250 ml, 500 ml, 750 ml, or 1000 ml. Such intravenous formulations may include any one or more of NaCl, dextrose, potassium salts, potassium chloride, calcium salts, calcium chloride, sodium lactate, and / or lactate salts. Plastic bags or glass bottles for intravenous injection containing the intravenous formulation also form part of the present invention. Such intravenous formulations can be configured to achieve a dose of about 30 mg / kg body weight when administered to a subject. A method for making such an intravenous formulation, comprising the step of introducing a pharmaceutical formulation described herein into an intravenous aqueous solution, is also part of the present invention, along with the intravenous formulation that is the product of such a method.

[0012] The invention also provides a method for reducing the viscosity of an aqueous composition comprising water and about 150 mg / ml or more (e.g., about 200 mg / ml) of an anti-C5 antigen-binding protein (e.g., an anti-C5 antibody or antigen-binding fragment thereof, e.g., about 150 mg / ml, 175 mg / ml, 200 mg / ml, 211 mg / ml, 220 mg / ml, 242 mg / ml, or 274 mg / ml, e.g., 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), comprising combining the water and antigen-binding protein with arginine (e.g., 50 mM or 100 mM) and, optionally, one or more additional carrier components (e.g., a buffer, a non-ionic surfactant, and / or an oligosaccharide). In an embodiment of the invention, the antigen binding protein comprises H2M11683N;H2M11686N;H4H12159P;H4H12161P;H4H12163P;H4H12164P;H4H12166P;H4H12166P2;H4H12166P3;H4H12166P4;H4H12166P5;H4H12166P6;H4H12166P7;H4H12166P8;H4H12166P9;H4H H4H12166P10; H4H12167P; H4H12168P; H4H1212169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab; eculizumab; crovalimab, tesidolumab, or mubodina. In embodiments of the invention, the viscosity of the formulation is reduced by about 30% or about 30-42%, for example, where viscosity is in cP when measured at 20°C.

[0013] The present invention also provides a method for administering a pharmaceutical formulation of the present invention to a subject (e.g., a human), comprising introducing the formulation into the body (e.g., parenterally, e.g., intravenously, intramuscularly, or subcutaneously) of the subject (e.g., the subject is suffering from a C5-related disease).

[0014] The present invention also provides methods for treating or preventing a C5-related disease (e.g., atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), or CHAPLE disease) in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a therapeutically effective amount of an antigen-binding protein (e.g., an antibody or antigen-binding fragment thereof) that specifically binds to C5 (e.g., human C5) in a pharmaceutical formulation of the present invention. In embodiments of the present invention, the C5-related disease is selected from the group consisting of adult respiratory distress syndrome; age-related macular degeneration (AMD); allergy; Alport syndrome; Alzheimer's disease; antiphospholipid syndrome (APS); asthma; atherosclerosis; atypical hemolytic uremic syndrome (aHUS); autoimmune diseases; autoimmune hemolytic anemia (AIHA); balloon angioplasty; bronchoconstriction; pemphigoid; burns; C3 glomerulopathy; capillary leak syndrome; cardiovascular disorders; fulminant antiphospholipid syndrome (CAP). S); cerebrovascular disease; CHAPLE disease; chemical injury; chronic obstructive pulmonary disease (COPD); cold agglutinin disease (CAD); corneal and / or retinal tissue; Crohn's disease; Degos disease; dense deposit disease (DDD); dermatomyositis; diabetes; diabetic angiopathy; diabetic macular edema (DME); diabetic nephropathy; diabetic retinopathy; dilated cardiomyopathy; inappropriate or unwanted complement activation disorders; respiratory distress; emphysema; epidermolysis bullosa; epilepsy; fibrogenic dust disease; frostbite; geographic atrophy (GA); glomerulonephritis; glomerulopathy; Goodpa Schuur syndrome; Graves' disease; Guillain-Barré syndrome; Hashimoto's thyroiditis; hemodialysis complications; hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; hemolytic anemia; hemoptysis; Henoch-Schönlein purpura nephritis; hereditary angioedema; hyperacute allograft rejection; hypersensitivity pneumonitis; idiopathic thrombocytopenic purpura (ITP); IgA nephropathy; immune complex disorders; immune complex vasculitis; immune complex-associated inflammation; infectious diseases; inflammation caused by autoimmune diseases; inflammatory disorders; hereditary CD59 deficiency; inert dust and / or mineral injury; interleukin-2-induced toxicity during IL-2 therapy; ischemia-reperfusion injury; Kawasaki disease; pulmonary disease or injury; lupus nephritis; membranous proliferation vascular disease; membranoproliferative glomerulonephritis; mesenteric artery reperfusion after aortic reconstruction; mesenteric / intestinal vasculopathy; multifocal motor neuropathy (MMN); multiple sclerosis; myasthenia gravis; myocardial infarction; myocarditis; neurological disorders; neuromyelitis optica; obesity; intraocular angiogenesis; intraocular neovascularization affecting the choroid; organic dust disease; parasitic diseases; Parkinson's disease; paroxysmal nocturnal hemoglobinuria (PNH); pauci-immune vasculitis; pemphigus; percutaneous transluminal coronary angioplasty (PTCA); peripheral vascular disorders; pneumonia; post-ischemic reperfusion state; post-pump syndrome in cardiopulmonary bypass surgery syndrome); post-pump syndrome in renal bypass surgery; progressive renal failure; proliferative nephritis; proteinuric kidney disease; psoriasis; pulmonary embolism; pulmonary fibrosis; pulmonary infarction; pulmonary vasculitis; habitual abortion; renal damage; renal ischemia; renal ischemia-reperfusion injury; renal vascular damage; restenosis after stent placement; rheumatoid arthritis; rotational atherectomy; schizophrenia; sepsis; septic shock; SLE nephritis; smoke poisoning; spinal cord injury; spontaneous abortion; stroke; systemic inflammatory response to sepsis; systemic lupus erythematosus (SLE); systemic lupus erythematosus-associated vasculitis; Takayasu's disease; burns; thrombotic thrombocytopenic purpura (TTP); traumatic brain injury; type 1 diabetes; typical hemolytic uremic syndrome; uveitis; vasculitis; vasculitis associated with rheumatoid arthritis; venous gas embolism (VGE); and xenograft rejection.

[0015] The present invention also provides a method for reducing complement activity in the body of a subject (e.g., a human) in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-C5 antigen-binding protein (e.g., an antibody or antigen-binding fragment thereof) in a pharmaceutical formulation of the present invention. [Brief explanation of the drawings]

[0016] [Figure 1] Figure 1 shows a DSC thermogram of 1 mg / mL H4H12166P determined by VP-DSC. Tm2, ​​shown in the inset, represents a slight curvature observed at the onset of the larger endotherm. This is not a well-defined endotherm, and therefore, only two Tms are reported for this profile in Tables 1-3, as represented by the two major endotherms. [Figure 2] FIG. 1 shows the DSC thermogram of 150 mg / mL H4H12166P determined by TA-DSC. [Figure 3] FIG. 1 shows the DSC thermogram of 200 mg / mL formulated H4H12166P as determined by TA-DSC. [Figure 4A] Graphs showing the effect of pH, temperature, and container headspace on various quality attributes (Δ% high molecular weight (HMW) species; Δ% native species; Δ% low molecular weight (LMW) species; Δ% acidic species; Δ% major species; Δ% basic species; Δ protein concentration; Δ pH; and Δ optical density). [Figure 4B] 1 is a graph showing the effect of pH, temperature, and container headspace on protein concentration of 150 mg / mL H4H12166P. [Figure 5A] Figure 1 shows the rate of formation of molecular size variants (HMW species) at various temperatures in 150 mg / mL H4H12166P, 20 mM histidine, pH 5.8. The rate was estimated as a function of incubation temperature using the transfer function from the DoE study (SE-UPLC results shown in Figure 4). [Figure 5B]Figure 1 shows the rate of formation of molecular size variants (major monomer species) at various temperatures in 150 mg / mL H4H12166P, 20 mM histidine, pH 5.8. The rate was estimated as a function of incubation temperature using the transfer function from the DoE study (SE-UPLC results shown in Figure 4). [Figure 5C] Figure 1 shows the rate of formation of molecular size variants (LMW species) at various temperatures in 150 mg / mL H4H12166P, 20 mM histidine, pH 5.8. The rate was estimated as a function of incubation temperature using the transfer function from the DoE study (SE-UPLC results shown in Figure 4). [Figure 6A] Figure 1 shows the rate of charge variant (acidic species) formation in 150 mg / mL H4H12166P, 20 mM histidine, pH 5.8 at various temperatures. The transfer function from the DoE study (CEX-UPLC results shown in Figure 4) was used to estimate the rate as a function of incubation temperature. [Figure 6B] Figure 1 shows the rate of charge variant (major peak) formation in 150 mg / mL H4H12166P, 20 mM histidine, pH 5.8 at various temperatures. The transfer function from the DoE study (CEX-UPLC results shown in Figure 4) was used to estimate the rate as a function of incubation temperature. [Figure 6C] Figure 1 shows the rate of charge variant (basic species) formation in 150 mg / mL H4H12166P, 20 mM histidine, pH 5.8 at various temperatures. The transfer function from the DoE study (CEX-UPLC results shown in Figure 4) was used to estimate the rate as a function of incubation temperature. [Figure 7] FIG. 1 shows high molecular weight (HMW) species formed in 150 mg / mL H4H12166P after agitation and freeze / thaw (F / T) stress. [Figure 8] FIG. 1 shows acidic charge variant species in 150 mg / mL H4H12166P after agitation and freeze / thaw (F / T) stress. [Figure 9] FIG. 1 shows the relative % peak area of ​​oxidized species at 150 mg / mL H4H12166P determined by HIC-HPLC after incubation with 500 ppm H2O2 at 37° C. for up to 24 hours. [Figure 10] FIG. 1 shows the total % oxidation level in 150 mg / mL H4H12166P as determined by HIC-HPLC after forced oxidation with different concentrations of hydrogen peroxide at 37° C. for up to 24 hours. [Figure 11] FIG. 1 shows acidic charge variants in 150 mg / mL H4H12166P determined by CEX-UPLC after incubation with different concentrations of hydrogen peroxide at 37° C. for up to 24 hours. [Figure 12] FIG. 1 shows basic charge variants in 150 mg / mL H4H12166P determined by CEX-UPLC after incubation with different concentrations of hydrogen peroxide at 37° C. for up to 24 hours. [Figure 13] FIG. 1 shows high molecular weight (HMW) species in 150 mg / mL H4H12166P determined by SE-UPLC after incubation with different concentrations of hydrogen peroxide at 37° C. for up to 24 hours. [Figure 14] FIG. 1 illustrates an exemplary formulation of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0017] The pharmaceutical formulations of the present invention are characterized by several particularly advantageous properties. The formulations have both a high protein concentration and a low viscosity. The particularly low viscosity of the formulations contrasts with that of some commercially available anti-C5 antibody products. The low viscosity of the formulations of the present invention facilitates the delivery of large amounts of anti-C5 antibody in a small volume. Furthermore, the pharmaceutical formulations of the present invention exhibit a high degree of stability—resistance to significant increases in high molecular weight (HMW) species under highly oxidative conditions, and only minimal increases in HMW species after several hours of stirring.

[0018] As used herein, for example, with reference to a pharmaceutical formulation containing a given anti-C5 antibody or antigen-binding fragment thereof, "high molecular weight" (HMW) species refers to any species of antibody or antigen-binding fragment thereof in the formulation that elutes from a size exclusion column (e.g., SE-UPLC) earlier than (e.g., has a higher molecular weight than) a single species of such antibody (a tetrameric complex having two heavy chains and two light chains) or antigen-binding fragment thereof. The percentage of HMW species refers to the percentage of such species relative to the total amount of antibody or antigen-binding fragment thereof in the formulation, e.g., by SE-UPLC analysis.

[0019] As used herein, for example, with reference to a pharmaceutical formulation containing a given anti-C5 antibody or antigen-binding fragment thereof, "low molecular weight" (LMW) species refers to any species of antibody or antigen-binding fragment thereof in a formulation that elutes later (e.g., has a lower molecular weight) from a size exclusion column (e.g., SE-UPLC) than that of a single species of such antibody (a tetrameric complex having two heavy chains and two light chains) or antigen-binding fragment thereof. The percentage of LMW species refers to the percentage of such species relative to the total amount of antibody or antigen-binding fragment thereof in the formulation, e.g., by SE-UPLC analysis.

[0020] The concentrations of excipients in the formulations of the present invention are expressed as percentages (%) in weight / volume (w / v) units, where w / v refers to the mass of the ingredient / volume of the solution x 100.

[0021] The term "C5," also known as "complement component 5" or "complement factor 5," refers to a serum protein of the complement cascade. The C5 protein is a 1,676 amino acid protein containing two chains, α and β. The protein represents the convergence point for three complement activation pathways: the classical pathway, the alternative pathway, and the mannose-binding lectin pathway. The amino acid sequence of the full-length C5 protein is exemplified by the amino acid sequence provided in GenBank under accession number NP001726.2.

[0022] In accordance with the present invention, conventional molecular biology, microbiology, and recombinant DNA techniques may be employed that are within the capabilities of one of ordinary skill in the art. Such techniques are fully explained in the literature. See, for example, Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, 2nd ed. (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (herein "Sambrook et al., 1989"); DNA Cloning: A Practical Approach, Vols. I and II (D.N. Glover, ed., 1985); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Nucleic Acids and Biotechnology, vol. 1, pp. 111-114, 1984; and The Journal of Nucleic Acids, vol. 1, pp. 111-114, 1984. id Hybridization (edited by BDHames & SJHiggins (1985));Transcription And Translation (edited by BDHames & SJHiggins (1984));Animal Cell Culture (edited by RIFreshney (1986));Immobilized Cells And Enzymes (IRL Press (1986));B.Perbal, A Practical Guide To Molecular Cloning (1984); FMAusubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley & See Sons, Inc. (1994).

[0023] Anti-C5 antigen-binding protein The present invention provides pharmaceutical formulations comprising anti-C5 antigen-binding proteins (eg, antibodies and antigen-binding fragments thereof) and a pharmaceutically acceptable carrier.

[0024] In embodiments of the invention, the anti-C5 antigen binding protein binds to the beta chain or the alpha chain, or both, of C5, e.g., at residues 591-599 and / or 775-794, e.g., NMATGMDSW (SEQ ID NO: 353) and / or WEVHLVPRRKQLQFALPDSL (SEQ ID NO: 354). In embodiments of the invention, the anti-C5 antigen binding protein does not bind to C5a.

[0025] In an embodiment of the invention, the anti-C5 antigen binding protein binds C5 at residues KDMQLGRLHMKTLLPVSK (SEQ ID NO: 355).

[0026] In embodiments of the invention, the anti-C5 antigen binding protein binds to the β chain of C5, for example, at residues 332-398, 332-378, 332-364, 332-348, 350-420, 369-409, 379-398, and / or 386-392.

[0027] In an embodiment of the invention, the anti-C5 antigen binding protein binds to C5a, for example, at residues NDETCEQRA (SEQ ID NO: 356) and / or SHKDMQL (SEQ ID NO: 357).

[0028] In embodiments of the invention, the anti-C5 antigen binding protein binds to the β chain of C5, e.g., residues 19 to 180. In embodiments of the invention, binding to C5 is reduced by E48A, D51A, and / or K109A C5 mutations.

[0029] The immunoglobulin polypeptides in the anti-C5 antigen-binding proteins (e.g., antibodies and antigen-binding fragments thereof) of the pharmaceutical formulations of the invention are set forth in Table A. See International Patent Application Publication No. WO 2017 / 218515.

[0030] [Table 1]

[0031] [Table 2]

[0032] In an embodiment of the invention, the anti-C5 antigen binding protein is eculizumab (sold as Soliris), crovalimab, ravulizumab (ALXN1210; sold as Ultomiris), tesidolumab (see US8241628; WO2010 / 015608; or WO2017 / 212375), or mubodina (see US7999081). In an embodiment of the invention, the anti-C5 antigen binding protein is the pozeliimab (REGN3918; H4H12166P) antibody. The pozeliimab (REGN3918; H4H12166P) antibody has the amino acid sequence: QVQLQESGPG LVKPSETLSL TCTVSGDSVS SSYWTWIRQP PGKGLEWIGY IYYSGSSNYN PSLKSRATIS VDTSKNQFSL KLSSVTAADT AVYYCAR EGN VDTTMIFDYW GQGTLVTVSS ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTKT YTCNVDHKPS NTKVDKRVES KYGPPCPPCP APEFLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSQED PEVQFNWYVD GVEVHNAKTK PREEQFNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKGLPS SIEKTISKAK GQPREPQVYT LPPSQEEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSRL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLGK (SEQ ID NO: 368) heavy chain immunoglobulins, including; and the amino acid sequence: AIQMTQSPSS LSASVGDRVT ITCRASQGIR NDLGWYQQKP GKAPKLLIYA ASSLQSGVPS RFAGRGSGTD FTLTISSLQP EDFATYYCLQ DFNYPWTFGQ GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 369) See WO2017 / 218515.

[0033] In an embodiment of the invention, the anti-C5 antigen binding protein has the amino acid sequence: QVQLVESGGGLVQPGRSLRLSCAASGFTVHSSYYMAWVRQAPGKGLEWVGAIFTGSGAEY KAEWAKGRVTISKDTSKNQVVLTMTMNMDPVDTATYYCASDAGYDYPTHAMHYWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEL RRGPKVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPS REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVLHEALHAHYTRKELSLSP (SEQ ID NO: 370), or its HCDR1, HCDR2, and HCDR3; or its V H (or variants thereof); and the amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQGISSSLAWYQQKPGKAPKLLIYGASETESGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQNTKVGSSYGNTFGGGTKVEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSS TLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 371), or its LCDR1, LCDR2, and LCDR3; or its V L (or a variant thereof).

[0034] The present invention includes pharmaceutical formulations comprising antibodies and antigen-binding fragments thereof that comprise the variable regions and CDRs specifically discussed herein, as well as variable regions and CDRs that are variants thereof, as discussed herein.

[0035] Immunoglobulin chains (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H1216 7P;H4Hl2168P;H4Hl2169P;H4H12170P;H4H12171P;H4H12175P;H4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N;H2M11695N; ravulizumab, eculizumab, crovalimab, tesidormab, or mubodina, or a V thereof comprising the amino acid sequences specifically set forth herein. H , V LThe comparison is performed using algorithm parameters selected to give the largest match between each sequence relative to the full length of each reference sequence (e.g., expectation threshold: 10; word size: 3; maximum matches in query range: 0; BLOSUM 62 matrix; gap cost: presence 11, extension 11). 1; conditional composition score matrix adjustment), when implemented by the BLAST algorithm, the reference amino acid sequences set forth herein (e.g., SEQ ID NOs: 2; 4; 6; 8; 10; 12; 14; 16; 18; 20; 22; 24; 26; 28; 30; 32; 34; 36; 38; 40; 42; 44; 46; 48; 50; 52; 54; 56; 58; 60; 62; 64; 66; 68; 70; 72; 74; 76; 78; 80; 82; 84; 86; 88; 90; 92; 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; 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 4;96;98;98;98;100;100;100;102;102;102;104;104;104;106;106;106;106;108;108;108;108;110;110;110;112;112;112;112;114;114;116;116;118;118;120;120;122;122;124;124;126;126;128;128;130;130;130;130;132;132;132; 132;134;134;134;134;136;136;136;136;138;138;140;140;142;142;144;144;146;146;146;148;148;148;150;150;150;152;152;152;154;156;158;160;162;164;166;168;170;172;174;176;178;180;182;184;186;188;190;192;194;196;19 8;200;202;204;206;208;210;212;214;216;218;220;222;224;226;228;230;232;234;236;238;240;242;244;246;248;250;252;254;256;258;258;260;260;262;262;264;264;266;268;270;272;274;276;278;280;282;284;286;288;290;292;294;296;298;300;302;304;306;308;310;312;314;316;318;320;322;324;326;328;330;332;334;336;338;340;342;344;346;348;350, 352, 353, 354, 355, 356, 357, 362, 363 , 364, 365, 366, 367, 368 and / or 369), e.g., see Table A; and at least about 70-99.9% (e.g., at least 70%, 72%, 74%, 75%, 76%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,; 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%) identical or similar to a polypeptide.

[0036] Additionally, immunoglobulin chains (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H121 66P10;H4H12167P;H4Hl2168P;H4Hl2169P;H4H12170P;H4H12171P;H4H12175P;H4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N;H2M11695N;ravulizumab, eculizumab, crovalimab, tesidormab, or mubodina, its V H , V LA variant of a polypeptide such as a V, HC, or LC, or CDR, can comprise the amino acid sequence of a reference polypeptide specifically set forth herein, but for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) mutations, e.g., one or more missense mutations (e.g., conservative substitutions), nonsense mutations, deletions, or insertions. For example, the present invention provides an immunoglobulin light chain (or V) comprising the amino acid sequence set forth in SEQ ID NO: 106, except for having one or more such mutations. L ) variant, and / or an immunoglobulin heavy chain (or V) comprising the amino acid sequence set forth in SEQ ID NO: 98, except having one or more of such mutations. H In embodiments of the invention, the anti-C5 antigen binding protein comprises an immunoglobulin light chain variant comprising CDR-L1, CDR-L2, and CDR-L3, in which one or more (e.g., one, two, or three) of the CDRs have one or more of such mutations (e.g., conservative substitutions), and / or an immunoglobulin heavy chain variant comprising CDR-H1, CDR-H2, and CDR-H3, in which one or more (e.g., one, two, or three) of the CDRs have one or more of such mutations (e.g., conservative substitutions).

[0037] The following references relate to the BLAST algorithm, which is often used for sequence analysis: BLAST algorithm: Altschul et al. (2005) FEBS J. 272(20): 5101-5109; Altschul, S. F. et al. (1990) J. Mol. Biol. 215: 403-410; Gish, W. et al. (1993) Nature Genet. 3: 266-272; Madden, T. L. et al. (1996) Meth. Enzymol. 266: 131-141; Altschul, S. F. et al. (1997) Nucleic Acids Res. 25: 3389-3402; Zhang, J. et al. (1997) Genome Res. 7:649-656; Wootton, JC et al., (1993) Comput. Chem. 17:149-163; Hancock, JM et al., (1994) Comput. Appl. Biosci. 10:67-70; Alignment scoring system: Dayhoff, MO et al., "A "A model of evolutionary change in proteins." Atlas of Protein Sequence and Structure, (1978) Vol. 5, suppl. 3. M O Dayhoff (ed.), pp. 345-352, Natl. Biomed. Res. Found., Washington, DC; Schwartz, RM et al., "Matrices for detecting distant relationships." Atlas of Protein Sequence and Structure, (1978) Vol. 5, suppl. 3. M O Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, DC; Altschul, SF, (1991) J. Mol. Biol. 219:555-565; States, DJ et al., (1991) Methods 3:66-70; Henikoff, S. et al., (1992) Proc. Natl. Acad. Sci. USA 89:10915-10919; Altschul, S. F. et al., (1993) J. Mol. Evol. 36:290-300; alignment statistics: Karlin, S. et al., (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268; Karlin, S. et al., (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877; Dembo, A. et al., (1994) Ann. Prob. 22:2022-2039; and Altschul, S. F. "Evaluating the statistical significance of multiple distinct local 'Theoretical and Computational Methods in Genome Research (ed. S. Suhai), (1997) pp. 1-14, Plenum, NY.

[0038] Unless otherwise specified, "H2M11683N"; "H2M11686N"; "H4H12159P"; "H4H12161P"; "H4H12163P"; "H4H12164P"; "H4H12166P"; "H4H12166P2"; "H4H12166P3"; "H4H12166P4"; "H4H12166P5"; "H4H12166P6"; "H4H12166P7"; "H4H12166P8"; "H4H12166P9"; "H4H12166P10"; "H4H12167P"; "H4Hl2168P"; "H4Hl2169P"; "H4H12170P"; "H4H12171P"; "H4H12175P"; "H4H12176P2"; "H4H12177P2"; "H4H12183P2"; "H2M11682N"; "H2M11684N"; "H2M11694N" or "H2M11695N" refer to an anti-C5 antigen binding protein, e.g., a C5-binding protein, as described herein. H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166 an immunoglobulin heavy chain or variable region thereof (V) comprising an amino acid sequence as specifically set forth herein corresponding to H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; or H2M11695N; 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 a variant thereof), and / or H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2 ... an immunoglobulin light chain or variable region thereof (V) comprising an amino acid sequence as specifically set forth herein corresponding to H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H1212169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; or H2M11695N; L ) (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), and / or a heavy chain or a V comprising 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 light chain or a V containing 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 invention, V refers to an antibody or antigen-binding fragment thereof that specifically binds to C5, comprising: His 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 light chain domain.

[0039] In an embodiment of the invention, the antigen binding protein, H2M11683N, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO:2 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO:10 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0040] In an embodiment of the invention, the antigen binding protein, H2M11686N, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 18 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 26 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0041] In an embodiment of the invention, the antigen binding protein, H4H12159P, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 34 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 42 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0042] In an embodiment of the invention, the antigen binding protein, H4H12161P, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 50 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 58 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0043] In an embodiment of the invention, the antigen binding protein, H4H12163P, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 66 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 74 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0044] In an embodiment of the invention, the antigen binding protein, H4H12164P, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 82 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 90 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0045] In an embodiment of the invention, the antigen binding protein, H4H12166P, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 98 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 106 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0046] In an embodiment of the invention, the antigen binding protein, H4H12166P2, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 98 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 114 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0047] In an embodiment of the invention, the antigen binding protein, H4H12166P3, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 122 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 106 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0048] In an embodiment of the invention, the antigen binding protein, H4H12166P4, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 98 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 130 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0049] In an embodiment of the invention, the antigen binding protein, H4H12166P5, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 138 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 106 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0050] In an embodiment of the invention, the antigen binding protein, H4H12166P6, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 146 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 106 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0051] In an embodiment of the invention, the antigen binding protein, H4H12166P7, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 122 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 130 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0052] In an embodiment of the invention, the antigen binding protein, H4H12166P8, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 146 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 114 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0053] In an embodiment of the invention, the antigen binding protein, H4H12166P9, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 146 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 130 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0054] In an embodiment of the invention, the antigen binding protein, H4H12166P10, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 138 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 130 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0055] In an embodiment of the invention, the antigen binding protein, H4H12167P, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 154 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 162 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0056] In an embodiment of the invention, the antigen binding protein, H4H12168P, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 170 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 178 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0057] In an embodiment of the invention, the antigen binding protein, H4H12169P, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 186 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 194 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0058] In an embodiment of the invention, the antigen binding protein, H4H12170P, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 202 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 210 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0059] In an embodiment of the invention, the antigen binding protein, H4H12171P, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 218 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 226 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0060] In an embodiment of the invention, the antigen binding protein, H4H12175P, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 234 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 242 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0061] In an embodiment of the invention, the antigen binding protein, H4H12176P2, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 250 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 258 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0062] In an embodiment of the invention, the antigen binding protein, H4H12177P2, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 266 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 258 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0063] In an embodiment of the invention, the antigen binding protein, H4H12183P2, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 274 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 282 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0064] In an embodiment of the invention, the antigen binding protein, H2M11682N, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 290 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 298 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0065] In an embodiment of the invention, the antigen binding protein, H2M11684N, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 306 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 314 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0066] In an embodiment of the invention, the antigen binding protein, H2M11694N, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 322 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 330 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0067] In an embodiment of the invention, the antigen binding protein, H2M11695N, comprises an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 338 and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 346 (e.g., when the antigen binding protein is an antibody or antigen-binding fragment thereof).

[0068] In embodiments of the invention, anti-C5 antigen-binding proteins, e.g., antibodies and antigen-binding fragments, comprise a heavy chain constant domain, e.g., of type IgA (e.g., IgA1 or IgA2), IgD, IgE, IgG (e.g., IgG1, IgG2, IgG3, and IgG4 (e.g., containing the S228P mutation)), or IgM. Silva et al., J Biol Chem. 290(9):5462-9 (2015). In embodiments of the invention, antigen-binding proteins, e.g., antibodies and antigen-binding fragments, comprise a light chain constant domain, e.g., of type kappa or lambda. The present invention relates to variable domains as set forth herein and in the art (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12166P11; H4H12166P12; H4H12166P13; H4H12166P14; H4H12166P15; H4H12166P16; H4H12166P17; H4H12166P18; H4H12166P19; H4H12166P20; H4H12166P21; H4H12166P31; H4H12166P18; H4H12166P19; H4H12166P22; H4H12166P23; H4H12166P24; H4H12166P25; H4H12166P26; H4H12166P27; H4H12166P28; H4H12166P29; H4H12166P31; H4H12166P32; H4H12166P33; H4H12166P34; H4H1216 H4H12166P9; H4H12166P10; H4H12167P; H4Hl2168P; H4Hl2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; and pharmaceutical formulations comprising antigen binding proteins including ravulizumab, eculizumab, crovalimab, tesidolumab, mubodina, IFX-1 (see, e.g., US2017 / 0137499), orendalizumab).

[0069] As used herein, the term "antibody" refers to an immunoglobulin molecule (i.e., a "full antibody molecule") comprising four polypeptide chains, two heavy chains (HC) comprising three H-CDRs and two light chains (LC) comprising three L-CDRs, interconnected by disulfide bonds (e.g., IgG4), e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4 H12166P3;H4H12166P4;H4H12166P5;H4H12166P6;H4H12166P7;H4H12166P8;H4H12166P9;H4H12166P10;H4H12167P;H4Hl2168P;H4Hl2169P;H4H12170P;H4H12171P;H4H12175P;H4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N;H2M11695N. In an embodiment of the present invention, the assignment of amino acids to each CDR domain in an immunoglobulin chain is in accordance with 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 invention provides a method for the identification of V H CDR and V L and antibodies and antigen-binding fragments comprising the CDRs of V H and V L comprises the amino acid sequence as set forth herein (or a variant thereof), and the CDRs are as defined by Kabat and / or Chothia.

[0070] As used herein, the term "antigen-binding portion" or "antigen-binding portion" of an antibody or antigen-binding protein "Antigen-binding fragment," and the like, includes any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments (heavy chain portions of Fab fragments cleaved with papain); (iv) Fv fragments (V H or V L and (v) single-chain Fv (scFv) molecules; consisting of amino acid residues that mimic a hypervariable region of an antibody (e.g., an isolated complementarity-determining region (CDR) such as a CDR3 peptide) or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, and small modular immunopharmaceuticals (SMIPs) are also used herein. In the present case, the expression "antigen-binding fragment" is encompassed within the phrase "antigen-binding fragment". In an embodiment of the invention, the antigen-binding fragment is H2M11683N;H2M11686N;H4H12159P;H4H12161P;H4H12163P;H4H12164P;H4H12166P;H4H12166P2;H4H12166P3;H4H12166P4;H4H12166P5;H4H12166P6;H4H12166P7;H4H12166P8;H4H12166P9;H4H12166P10;H4H12167P; and / or CDR-L1, CDR-L2, and CDR-L3) of H4Hl2168P; H4Hl2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N.

[0071] The term "recombinant" antigen-binding protein, e.g., antibody or antigen-binding fragment thereof, refers to such molecules that are produced, expressed, isolated, or obtained by technologies or methods known in the art, such as recombinant DNA technology, including DNA splicing and transgenic expression. The term includes antibodies expressed in a non-human mammal (including a transgenic non-human mammal, e.g., a transgenic mouse) or host cell (e.g., a Chinese hamster ovary (CHO) cell) or cellular expression system, or antibodies isolated from a recombinant combinatorial human antibody library. The present invention provides recombinant antigen binding proteins as set forth herein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4Hl2168P; H4Hl2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; or H2M11695N).

[0072] The present invention includes formulations comprising monoclonal anti-C5 antigen-binding proteins (e.g., antibodies and antigen-binding fragments thereof). As used herein, the term "monoclonal antibody" or "mAb" refers to an antibody from a population of substantially homogeneous antibodies (i.e., the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts). The modifier "monoclonal" is not to be construed as requiring production of the antibody by any particular method. Monoclonal antibodies may be made by the hybridoma method of Kohler et al. (1975) Nature 256:495, or by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567).

[0073] "Isolated" antigen binding proteins (e.g., antibodies and antigen-binding fragments thereof), polypeptides, polynucleotides, and vectors are at least partially free from other biological molecules derived from the cell or cell culture in which they are produced. Such biological molecules 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 from expression system components such as biological molecules derived from the host cell or its growth medium. In general, the term "isolated" is not intended to be limited to the complete absence of such biological molecules (e.g., trace or insignificant amounts of impurities may remain), the absence of water, buffers, or salts, or the components of a pharmaceutical formulation that includes the antigen binding protein (e.g., antibody or antigen-binding fragment).

[0074] An "anti-C5" antigen binding protein specifically binds to C5. The term "specifically binds" refers to an antibody that specifically binds to C5 with an affinity of at least about 10, as measured, for example, at 25°C or 37°C, by a real-time, label-free biolayer interference assay, e.g., Octet® HTX biosensor, or by surface plasmon resonance, e.g., BIACORE™, or by solution affinity ELISA. -9 M or less (lower number) (e.g., about 10 -10 M, about 10 -11 M, or about 10 -12 M)'s, K D The term "antigen binding protein" refers to an antigen binding protein (e.g., a mAb) that has binding affinity for an antigen such as human C5 protein at 25° C., expressed as a function of affinity. In some embodiments of the invention, the anti-C5 antigen binding protein also binds to variants of C5, for example, including mutations such as R885H or R885C.

[0075] Pharmaceutical preparations The present invention provides a method for the preparation of a C5 si-RNA, such as semdisilane, comprising administering to a subject a C5 si-RNA containing an anti-C5 antigen binding protein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H1 H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, eculizumab, crovalimab, tesidolumab, or mubodina). For example, the invention includes a pharmaceutical formulation comprising, consisting of, or consisting essentially of: 200 mg / ml pozelimab; 20 mM histidine buffer; 100 mM L-arginine hydrochloride; 2% (w / v) sucrose; 0.15% (w / v) polysorbate-80; and water, pH 5.8.

[0076] As used herein, a pharmaceutical formulation or pharmaceutical composition refers to a formulation / composition comprising an anti-C5 antigen-binding protein and a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier comprises one or more excipients. In an embodiment of the present invention, the pharmaceutical formulation of the present invention is aqueous, i.e., comprises water.

[0077] Pharmaceutical formulations containing anti-C5 antigen binding proteins are prepared by mixing the antigen binding protein with one or more excipients (see, e.g., Hardman et al. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science ce 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; Dosage Forms: Disperse Systems, Marcel Dekker, NY; see Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, NY).

[0078] In an embodiment of the invention, the pharmaceutical formulation of the invention comprises: ≥150 mg / ml, ≥200 mg / ml, ≥250 mg / ml, ≥274 mg / ml, or ≥275 mg / ml of anti-C5 antigen-binding protein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8;H4H12166P9;H4H12166P10;H4H12167P;H4Hl2168P;H4Hl2169P;H4H12170P;H4H12171P;H4H12175P;H4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N;H2M11695N;ravolizumab, eculizumab, crovalimab, tesidormab, or mubodina) buffer (e.g., about 20 mM); · amino acids (e.g., about 100 mM); Optionally, sugar (e.g., about 2%); optionally, a non-ionic surfactant (e.g., about 0.15%); and ·water; pH about 5-6 (e.g., about pH 5.8).

[0079] In an embodiment of the invention, the pharmaceutical formulation of the invention is aqueous (e.g., suitable for intravenous and / or subcutaneous administration) and contains an anti-C5 antibody or antigen-binding fragment thereof (e.g., pozelimab) (e.g., about 200 mg / mL or about 180-210 mg / mL), histidine (e.g., histidine-HCl; e.g., about 20 mM, or 20 mM ± 4 mM), pH about 5.8, or 5.8 ± 0.3, arginine (e.g., about 100 mM, or 100 mM ± 20 mM; e.g., L-arginine, L-arginine HCl, or L-arginine monohydrochloride), a polyol such as sucrose (e.g., about 2%, or 2% ± 0.4% (w / v)), and a non-ionic surfactant such as a polysorbate (e.g., polysorbate 80; e.g., about 0.15%, or 0.15% ± 0.075% (w / v)), e.g., 200mg / ml pozelimab; 20mM histidine buffer; 100mM L-arginine hydrochloride; 2% (w / v) sucrose; 0.15% (w / v) polysorbate-80; and water pH 5.8 Includes:

[0080] "Arginine" or "L-arginine" includes any pharmaceutically acceptable salt form thereof, for example, L-arginine hydrochloride.

[0081] The buffer regulates the pH of the formulation and, in some cases, contributes to the overall stability of the protein product. In embodiments of the invention, the buffer is a phosphate buffer, acetate buffer, citrate buffer, histidine buffer, or imidazole buffer.

[0082] The amino acid can be any one of the 20 essential amino acids. In an embodiment of the invention, the amino acid is glycine, arginine, aspartic acid, glutamic acid, lysine, asparagine, glutamine, proline, or histidine.

[0083] In an embodiment of the invention, the oligosaccharide is sucrose, mannitol, dextrose, glycerin, TMAO (trimethylamine N-oxide), trehalose, ethylene glycol, glycine betaine, xylitol, or sorbitol.

[0084] Nonionic surfactants contain molecules with uncharged head groups. In an embodiment of the present invention, the nonionic surfactant is polyoxyethylene-based or glycoside compound-based. In an embodiment of the present invention, the nonionic surfactant is polysorbate-20 (PS20), polysorbate-80 (PS80), or tween-20.

[0085] In an embodiment of the present invention, the pharmaceutical formulations of the invention (e.g., comprising H4H12166P) have a viscosity of about 8, 9, 10, 11, 12, 13, 14, 14.3, 15, 16, 17, 18, 19, or 20, or 8-20 cP at about 20°C (e.g., at a concentration of about 200 mg / ml antibody); the pharmaceutical formulation comprises a viscosity as set forth in Table 8-1 herein (e.g., ±10%) when measured at the indicated temperature, e.g., when the antibody is at a concentration as set forth in that table (e.g., ±1% or 3% or 5% or 10%), e.g., when the antibody is H4H12166P, and when the antibody is formulated in about 20 mM histidine, pH about 5.8, about 100 mM arginine, about 2% sucrose, and about 0.15% polysorbate (e.g., polysorbate 80); - a pharmaceutical formulation of the invention (e.g., comprising H4H12166P) has a viscosity of about 50 cP at 20°C (e.g., at a concentration of about 274 mg / ml antibody); The pharmaceutical formulation of the present invention (e.g., containing H4H12166P) has an osmolality of about 267 to 404 mmol / kg; the pharmaceutical formulation of the invention (e.g., comprising H4H12166P) contains about 1.1-2.1 (as measured by SE-UPLC) or 0.1 (as measured by MCE-SDS) % high molecular weight species at t=0 (i.e., before any significant period of storage or incubation); The pharmaceutical formulation of the present invention (e.g., containing H4H12166P) contains about 0.4 to 0.5 (as measured by SE-UPLC) or 3.2 (as measured by non-reducing microchip capillary electrophoresis (MCE)-SDS (sodium dodecyl sulfate)) % low molecular weight species at t=0; The pharmaceutical formulation of the present invention (e.g., comprising H4H12166P) contains about 98.5 (as measured by SE-UPLC) or 96.7 (as measured by MCE-SDS) % major species at t=0; The pharmaceutical formulation of the present invention (e.g., comprising H4H12166P) may be soluble in water for about 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, or 48 hours after stirring, e.g., at 250 rpm. For example, a pharmaceutical formulation of the invention (e.g., comprising H4H12166P) (e.g., at an antibody concentration of about 274 mg / ml) exhibits an increase in high molecular weight (HMW) species of about 0% (e.g., after up to about 7 days of stirring at 250 rpm), about 0.2% (e.g., after about 6 months of stirring at 250 rpm), or about 0.3% (e.g., after about 15.5 months of stirring at 250 rpm), as measured by SE-UPLC; the pharmaceutical formulations of the invention (e.g., comprising H4H12166P) exhibit an increase in high molecular weight (HMW) species of about 0.0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, about 0.6%, or about 0.7% after about 24 or 48 hours of stirring, e.g., at 250 rpm; - the pharmaceutical formulations of the invention (e.g., comprising H4H12166P) exhibit about 0% (or less than 0.1%) increase in high molecular weight (HMW) species after two freeze (at -30°C)-thaw (at room temperature) cycles, e.g., in a 1.5 ml volume in a 5 ml container, as measured, e.g., by SE-UPLC; - the pharmaceutical formulation of the invention (e.g., comprising H4H12166P) exhibits about 0% or 0.1% increase in high molecular weight (HMW) or low molecular weight (LMW) species after four freeze (at -30°C)-thaw (at room temperature) cycles, e.g., in a 1.5 ml volume in a 5 ml container, as measured by, e.g., SE-UPLC; - the pharmaceutical formulation of the invention (e.g., comprising H4H12166P) exhibits an increase in high molecular weight (HMW) species of about 0.1% after 8 freeze (at -30°C)-thaw (at room temperature) cycles, e.g., in a 1.5 ml volume in a 5 ml container, as measured by, e.g., SE-UPLC; - the pharmaceutical formulations of the invention (e.g., comprising H4H12166P) exhibit about 0% (or less than about 0.1%) increase in low molecular weight (LMW) species after 2, 4, or 8 freeze (at -30°C)-thaw (at room temperature) cycles, e.g., in a 1.5 ml volume in a 5 ml container, as measured by, e.g., SE-UPLC; The anti-C5 antigen-binding protein (e.g., an antibody or antigen-binding fragment thereof (e.g., H4H12166P)) in the pharmaceutical formulation of the invention has a Tm1 (onset) of about 58.0°C; Tm1 is about 61.7°C; and Tm2 is about 73.2°C (e.g., as measured using differential scanning calorimetry (DSC)); one or more methionines (e.g., heavy chain Met105, Met252, Met428 and / or light chain Met4 of H4H12166P) in an anti-C5 antigen-binding protein (e.g., an antibody or antigen-binding fragment thereof (e.g., H4H12166P)) in a pharmaceutical formulation of the invention are oxidized to a level of, e.g., about 6% or less, or about 5% or less, about 4% or less, about 3% or less, about 2% or less, or about 1% or less when incubated at 37°C in the presence of HO or 1 parts per million (ppm) for about 24 hours, e.g., the oxidized methionine is methionine sulfoxide or methionine sulfone; In a pharmaceutical formulation of the invention, heavy chain CDR methionine 105 (e.g., of H4H12166P) is oxidized (e.g., to methionine sulfoxide or methionine sulfone) at about 4.2% or 4.3% when incubated at 37°C in the presence of 20 or 1 parts per million (ppm) of H2O for about 24 hours. In the pharmaceutical formulations of the invention, when incubated at 37°C with 1 ppm H2O2 for 24 hours, the level of oxidized heavy chain Met105, Met252, Met428, and / or light chain Met4, for example, of H4H12166P, increases by no more than about 0.1% or 0.2% compared to the level incubated without H2O2 or the level without incubation after 24 hours of incubation at 37°C; The pharmaceutical formulations of the invention (e.g., containing H4H12166P) contain an endotoxin content of about 0.1 EU / mg or less; - the pharmaceutical formulations of the invention (e.g., comprising H4H12166P) contain, e.g., prior to storage or incubation for a significant period of time, about 0.9% (or less) high molecular weight (HMW) species (e.g., as measured by size-exclusion ultra-performance liquid chromatography (SE-UPLC)); - the pharmaceutical formulations of the invention (e.g., comprising H4H12166P) contain, e.g., prior to storage or incubation for a significant period of time, about 0.2% (or less) low molecular weight (LMW) species (e.g., as measured by size-exclusion ultra-performance liquid chromatography (SE-UPLC)); The pharmaceutical formulations of the invention (e.g., comprising H4H12166P) contain, e.g., about 98.9%, 99%, or 100% of the major species (e.g., as measured by size-exclusion ultra-performance liquid chromatography (SE-UPLC)) before storage or incubation for a significant period of time; the pharmaceutical formulations of the invention (e.g., comprising H4H12166P) contain about 0.9%, less than about 1.0%, about 1.0%, about 1.1%, or about 1.2%, or about 0.9-1.2% high molecular weight (HMW) species (e.g., as measured by size-exclusion ultra-performance liquid chromatography (SE-UPLC)) after about 1 month, about 3 months, or about 6 months, or about 9 months, or about 12 months of storage at about 5°C, e.g., the percentage of HMW species increases by about 0.1% or less, or 0.2% or less, or 0.3% or less after about 1 month, about 3 months, or about 6 months, or about 9 months, or about 12 months of storage at about 5°C; the pharmaceutical formulations of the invention (e.g., comprising H4H12166P) contain about 2%, 2.1%, 2.2%, 2.3%, or 2.4% high molecular weight (HMW) species (e.g., as measured by size-exclusion ultra-performance liquid chromatography (SE-UPLC)) after about 2 days, 7 days, 6 months, or 15.5 months of storage at about 5°C, e.g., the percentage of HMW species increases by about 0.1% or less, or 0.2% or less, or 0.3% or less after about 6 months or 15.5 months of storage at about 5°C; the pharmaceutical formulations of the invention (e.g., comprising H4H12166P) contain about 1.1%, about 1.2%, about 1.3%, about 1.4%, or about 1.5%, or about 1.1-1.5% high molecular weight (HMW) species (e.g., as measured by size-exclusion ultra-performance liquid chromatography (SE-UPLC)) after about 0.5 months, about 1 month, about 3 months, or about 6 months of storage at about 25°C, e.g., at about 60% relative humidity, e.g., the % HMW species increases by about 0.6% or less after about 6 months of incubation; the pharmaceutical formulations of the invention (e.g., comprising H4H12166P) contain about 1.3%, about 1.4%, about 1.9%, about 3.8%, or about 5.8%, or about 1.3-5.8% high molecular weight (HMW) species (e.g., as measured by size-exclusion ultra-performance liquid chromatography (SE-UPLC)) after about 0.25 months, about 0.5 months, about 1 month, about 2 months, or about 3 months of storage at about 40°C and about 75% relative humidity, e.g., the % HMW species increases by about 4.5% or less after about 3 months of incubation; the pharmaceutical formulations of the invention (e.g., comprising H4H12166P) contain about 0.2%, about 0.3%, about 0.4%, about 0.5%, or about 0.4-0.6% or 0.2-0.4% low molecular weight (LMW) species (e.g., as measured by size-exclusion ultra-performance liquid chromatography (SE-UPLC)) after about 1 month, about 3 months, about 6 months, about 9 months, or about 12 months of storage at about 5°C, e.g., the percentage of LMW species increases by about 0.1% or less, or 0.2% or less, or 0.3% or less, or 0.4% or less after about 1 month, about 3 months, about 6 months, about 9 months, or about 12 months of storage at about 5°C; The pharmaceutical formulations of the present invention (e.g., containing H4H12166P) have a low molecular weight (LMW) species content of about 0.2%, about 0.3%, or about 0.4%, or about 0.2-0.4%, for example, after storage at about 25°C under about 60% relative humidity for about 0.5 months, about 1 month, about 3 months, or about 6 months (e.g., by size exclusion ultra-performance liquid chromatography (SE-UPL)). C), e.g., the percentage of LMW species increases by about 0.1% or less after about 0.5 months, about 1 month, about 3 months, or about 6 months of storage at about 5°C; a pharmaceutical formulation of the invention (e.g., comprising H4H12166P) comprises about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, or about 0.3-0.8% low molecular weight (LMW) species (e.g., as measured by size-exclusion ultra-performance liquid chromatography (SE-UPLC)) after about 0.25 months, about 0.5 months, about 1 month, about 2 months, or about 3 months of storage at about 40°C, e.g., at about 75% relative humidity; e.g., the percentage of LMW species increases by about 0.1% or less, 0.2% or less, 0.3% or less, 0.4% or less, or 0.5% or less after about 0.25 months, about 0.5 months, about 1 month, about 2 months, or about 3 months of storage at about 5°C; the pharmaceutical formulations of the invention (e.g., comprising H4H12166P) comprise about 98%, about 98.3%, about 98.7%, about 98.8%, about 99%, or about 98-99% of the major species (e.g., as measured by size-exclusion ultra-performance liquid chromatography (SE-UPLC)) after about 1 month, about 3 months, about 6 months, about 9 months, or about 12 months of storage at about 5°C, e.g., the percentage of the major species does not decrease by about 0.1% or less, 0.2% or less, 0.3% or less, 0.4% or less, 0.5% or less, or more than 0.6% after about 1 month, about 3 months, about 6 months, about 9 months, or about 12 months of storage at about 5°C; the pharmaceutical formulations of the invention (e.g., comprising H4H12166P) comprise about 98%, about 98.6%, about 98.4%, about 98.7%, about 98.8%, about 98.1%, about 99%, or about 98-99% of the major species (e.g., as measured by size-exclusion ultra-performance liquid chromatography (SE-UPLC)) after about 0.5 months, about 1 month, about 3 months, or about 6 months of storage at about 25°C, e.g., at about 60% relative humidity, e.g., the percentage of the major species does not decrease by about 0.1% or less, 0.2% or less, 0.3% or less, 0.4% or less, 0.5% or less, 0.6% or less, 0.7% or less, or more than 0.8% after about 1 month, about 3 months, or about 6 months of storage at about 25°C; the pharmaceutical formulations of the invention (e.g., comprising H4H12166P) comprise about 98.3%, about 98.4%, about 97.6%, about 95.5%, about 93.4%, or about 93.4-98.4% or about 93-98% of the major species (e.g., as measured by size-exclusion ultra-performance liquid chromatography (SE-UPLC)) after about 0.25 months, about 0.5 months, about 1 month, about 2 months, or about 6 months of storage at about 40°C, e.g., at about 75% relative humidity, wherein the percentage of the major species does not decrease by about 1% or less, 2% or less, 3% or less, 4% or less, 5% or less, or more than 5.5% after about 0.25 months, about 0.5 months, about 1 month, about 2 months, or about 3 months of storage at about 40°C; the pharmaceutical formulations of the invention (e.g., comprising H4H12166P) comprise, e.g., before storage or incubation for a significant period of time, about 29% acidic charge variants, about 11% basic charge variants, and / or about 60% major species, as measured, e.g., by imaging capillary isoelectric focusing (iCIEF); the pharmaceutical formulations of the invention (e.g., comprising H4H12166P) comprise about 30%, 31%, or 32% acidic charge variants, about 14%, 13%, 12%, or 11% basic charge variants, and / or about 56% or 57% major species, as measured by, e.g., imaging capillary isoelectric focusing (iCIEF), e.g., after about 6, 9, or 12 months of storage at about 5°C; and / or do not show an increase in acidic charge variants of more than about 3.0% or 3.1% after 12 months of storage at 5°C, and / or do not show an increase in major species of more than about 3.0% or 3.1% after 12 months of storage at 5°C, and / or do not show an increase in basic charge variants of more than about 0.1% or 0% after 12 months of storage at 5°C; a pharmaceutical formulation of the invention (e.g., comprising H4H12166P), e.g., after about 6 months of storage at about 25°C, comprises about 33% acidic charge variants, about 20% basic charge variants, and / or about 47% major species, as measured by, e.g., imaging capillary isoelectric focusing (iCIEF); a pharmaceutical formulation of the invention (e.g., comprising H4H12166P), e.g., after about 3 months of storage at about 40°C, comprises about 45% acidic charge variants, about 36% basic charge variants, and / or about 20% major species, as measured by, e.g., imaging capillary isoelectric focusing (iCIEF); when a pharmaceutical formulation of the invention (e.g., comprising H4H12166P) is stored at about 37°C, it forms HMW species at a rate of about 0.6% per month and / or forms acidic variants at a rate of about 0.6% per month; when a pharmaceutical formulation of the invention (e.g., comprising H4H12166P) is stored at about 40°C, it forms HMW species at a rate of about 1.2% per month and / or forms acidic variants at a rate of about 3.1% per month; and / or when a pharmaceutical formulation of the present invention (e.g., comprising H4H12166P) is stored at about 45°C, it forms HMW species at a rate of about 2.6% per month and / or forms acidic variants at a rate of about 8.8% per month; In this case, for example, the formulation contains a buffer, L-arginine, water, optionally an oligosaccharide, optionally a non-ionic surfactant, and has a pH of about 5.8 (e.g., with a viscosity of about 14.3 or about 14 or about 15 at 20°C).

[0086] The present invention includes embodiments in which any one or more selected from the foregoing features any of the anti-C5 antigen binding proteins described herein.

[0087] In an embodiment of the invention, the formulation comprises: For example, having a viscosity (e.g., at 20°C) of about 13.2 to 16.7 cP, or 14 cP, or about 14.3 cP, or about 15 cP. about 150 mg / ml, 175 mg / ml, 200 mg / ml, 211 mg / ml, 220 mg / ml, 242 mg / ml, or 274 mg / ml of an anti-C5 antibody or antigen-binding fragment thereof (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H 12166P10;H4H12167P;H4Hl2168P;H4Hl2169P;H4H12170P;H4H12171P;H4H12175P;H4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N;H2M11695N;ravolizumab, eculizumab, crovalimab, tesidormab, or mubodina) histidine buffer (e.g., about 20 mM), L-arginine (e.g., L-arginine HCl) (e.g., about 100 mM) optionally, sucrose (e.g., about 2% (w / v)); optionally, polysorbate-80 (PS-80) (e.g., about 0.15% (w / v)); and ·water; pH approx. 5.8.

[0088] The present invention provides a pharmaceutical composition comprising about 200 mg / ml H2M11683N; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80 (PS-80), and water, pH 5.8±0.2. Includes pharmaceutical preparations.

[0089] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H2M11686N; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0090] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12159P; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0091] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12161P; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0092] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12163P; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0093] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12164P; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0094] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12166P; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0095] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12166P2; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0096] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12166P3; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0097] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12166P4; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0098] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12166P5; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2. nothing.

[0099] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12166P6; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0100] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12166P7; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0101] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12166P8; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0102] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12166P9; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0103] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12167P; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0104] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12168P; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0105] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12169P; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0106] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12170P; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0107] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12171P; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0108] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12175P; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2. .

[0109] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12176P2; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0110] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12177P2; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0111] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12183P2; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0112] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H2M11682N; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0113] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H2M11684N; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0114] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H2M11694N; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0115] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H2M11695N; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0116] The invention includes a pharmaceutical formulation comprising about 200 mg / ml ravulizumab; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0117] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml crovalimab; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0118] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml eculizumab; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0119] The present invention provides a pharmaceutical composition comprising about 200 mg / ml tesidolumab; about 20 mM histidine buffer; The pharmaceutical formulation comprises about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0120] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml mubodina; about 20 mM histidine buffer; about 100 mM L-arginine; about 2% (w / v) sucrose; about 0.15% (w / v) polysorbate-80, and water, pH 5.8±0.2.

[0121] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12166P, about 5 mM histidine, about 2.5% (w / v) proline, about 5% (w / v) sucrose, about 150 mM L-arginine-HCl, about 0.2% (w / v) PS-80, and water, pH about 5.7.

[0122] The present invention includes a pharmaceutical formulation comprising about 135 mg / ml H4H12166P, about 20 mM histidine, about 5% (w / v) proline, about 10% (w / v) sucrose, about 150 mM L-arginine-HCl, about 0.02% (w / v) PS-80, and water, pH about 5.7.

[0123] The present invention includes a pharmaceutical formulation comprising about 160 mg / ml H4H12166P, about 5 mM histidine, about 5% (w / v) sucrose, about 75 mM L-arginine-HCl, about 0.02% (w / v) PS-80, and water, pH about 6.2.

[0124] The present invention includes a pharmaceutical formulation comprising about 120 mg / ml H4H12166P, about 40 mM histidine, about 5% (w / v) proline, about 0.02% (w / v) PS-80, and water, pH about 6.8.

[0125] The present invention includes a pharmaceutical formulation comprising about 120 mg / ml H4H12166P, about 40 mM histidine, about 0.02% (w / v) PS-80, and water, pH about 5.7.

[0126] The present invention includes a pharmaceutical formulation comprising about 160 mg / ml H4H12166P, about 5 mM histidine, about 2.5% (w / v) proline, about 10% (w / v) sucrose, about 0.2% (w / v) PS-80, and water, pH about 6.8.

[0127] The present invention includes a pharmaceutical formulation comprising about 120 mg / ml H4H12166P, about 40 mM histidine, about 5% (w / v) proline, about 150 mM L-arginine-HCl, about 0.02% (w / v) PS-80, and water, pH about 5.7.

[0128] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12166P, about 5 mM histidine, about 0.2% (w / v) PS-80, and water, pH about 5.7.

[0129] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12166P, about 20 mM histidine, about 5% (w / v) proline, about 10% (w / v) sucrose, about 0.2% (w / v) PS-80, and water, pH about 6.2.

[0130] The present invention includes a pharmaceutical formulation comprising about 120 mg / ml H4H12166P, about 40 mM histidine, about 150 mM L-arginine-HCl, about 0.02% (w / v) PS-80, and water, pH about 6.8.

[0131] The present invention relates to a composition containing about 200 mg / ml H4H12166P, about 5 mM histidine, about 5% (w / v) proline, about 150 mM L-arginine-HCl, about 0.2% (w / v) A pharmaceutical formulation comprising PS-80, and water, pH about 6.2.

[0132] The present invention includes a pharmaceutical formulation comprising about 120 mg / ml H4H12166P, about 20 mM histidine, about 5% (w / v) proline, about 5% (w / v) sucrose, about 150 mM L-arginine-HCl, about 0.2% (w / v) PS-80, and water, pH about 6.8.

[0133] The present invention includes a pharmaceutical formulation comprising about 120 mg / ml H4H12166P, about 5 mM histidine, about 10% (w / v) sucrose, about 0.2% (w / v) PS-80, and water, pH about 5.7.

[0134] The present invention includes a pharmaceutical formulation comprising about 120 mg / ml H4H12166P, about 5 mM histidine, about 0.2% (w / v) PS-80, and water, pH about 6.8.

[0135] The present invention includes a pharmaceutical formulation comprising about 120 mg / ml H4H12166P, about 5 mM histidine, about 150 mM L-arginine-HCl, about 0.2% (w / v) PS-80, and water, pH about 5.7.

[0136] The present invention includes a pharmaceutical formulation comprising about 175 mg / ml H4H12166P, about 40 mM histidine, about 5% (w / v) proline, about 0.2% (w / v) PS-80, and water, pH about 5.7.

[0137] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12166P, about 5 mM histidine, about 10% (w / v) sucrose, about 150 mM L-arginine-HCl, about 0.2% (w / v) PS-80, and water, pH about 6.8.

[0138] The present invention includes a pharmaceutical formulation comprising about 185 mg / ml H4H12166P, about 40 mM histidine, about 10% (w / v) sucrose, about 0.02% (w / v) PS-80, and water, pH about 5.7.

[0139] The present invention includes a pharmaceutical formulation comprising about 120 mg / ml H4H12166P, about 40 mM histidine, about 10% (w / v) sucrose, about 150 mM L-arginine-HCl, about 0.2% (w / v) PS-80, and water, pH about 5.7.

[0140] The present invention includes a pharmaceutical formulation comprising about 120 mg / ml H4H12166P, about 40 mM histidine, about 10% (w / v) sucrose, about 0.02% (w / v) PS-80, and water, pH about 6.8.

[0141] The present invention includes a pharmaceutical formulation comprising about 120 mg / ml H4H12166P, about 5 mM histidine, about 5% (w / v) proline, about 0.02% (w / v) PS-80, and water, pH about 5.7.

[0142] The present invention includes a pharmaceutical formulation comprising about 170 mg / ml H4H12166P, about 40 mM histidine, about 5% (w / v) proline, about 10% (w / v) sucrose, about 150 mM L-arginine-HCl, about 0.02% (w / v) PS-80, and water, pH about 6.8.

[0143] The present invention includes a pharmaceutical formulation comprising about 120 mg / ml H4H12166P, about 40 mM histidine, about 5% (w / v) proline, about 10% (w / v) sucrose, about 0.02% (w / v) PS-80, and water, pH about 5.7.

[0144] The present invention includes a pharmaceutical formulation comprising about 120 mg / ml H4H12166P, about 5 mM histidine, about 2.5% (w / v) proline, about 10% (w / v) sucrose, about 150 mM L-arginine-HCl, about 0.02% (w / v) PS-80, and water, pH about 6.2.

[0145] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12166P, about 5 mM histidine, about 5% (w / v) proline, about 10% (w / v) sucrose, about 75 mM L-arginine-HCl, about 0.2% (w / v) PS-80, and water, pH about 5.7.

[0146] The present invention includes a pharmaceutical formulation comprising about 120 mg / ml H4H12166P, about 5 mM histidine, about 5% (w / v) proline, about 10% (w / v) sucrose, about 75 mM L-arginine-HCl, about 0.2% (w / v) PS-80, and water, pH about 6.8.

[0147] The present invention relates to a composition containing about 160 mg / ml H4H12166P, about 5 mM histidine, about 5% (w / v) proline, about 150 mM L-arginine-HCl, about 0.2% (w / v) A pharmaceutical formulation comprising PS-80, and water, pH about 6.8.

[0148] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12166P, about 20 mM histidine, about 2.5% (w / v) proline, about 75 mM L-arginine-HCl, about 0.02% (w / v) PS-80, and water, pH about 6.8.

[0149] The present invention includes a pharmaceutical formulation comprising about 170 mg / ml H4H12166P, about 35 mM histidine, about 150 mM L-arginine-HCl, about 0.02% (w / v) PS-80, and water, pH about 5.7.

[0150] The present invention includes a pharmaceutical formulation comprising about 183 mg / ml H4H12166P, about 40 mM histidine, about 0.2% (w / v) PS-80, and water, pH about 6.8.

[0151] The present invention includes a pharmaceutical formulation comprising about 200 mg / ml H4H12166P, about 5 mM histidine, about 5% (w / v) proline, about 5% (w / v) sucrose, about 0.02% (w / v) PS-80, and water, pH about 6.8.

[0152] The present invention includes a pharmaceutical formulation comprising about 160 mg / ml H4H12166P, about 40 mM histidine, about 2.5% (w / v) proline, about 5% (w / v) sucrose, about 75 mM L-arginine-HCl, about 0.2% (w / v) PS-80, and water, pH about 6.2.

[0153] The present invention includes a pharmaceutical formulation comprising about 187 mg / ml H4H12166P, about 40 mM histidine, about 0.02% (w / v) PS-80, and water, pH about 5.7.

[0154] See, for example, Figure 14. The present invention includes any of the pharmaceutical formulations depicted in Figure 14.

[0155] The present invention provides anti-C5 antigen binding proteins, e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H1212169P; H4H12170P; H4H1217 1P;H4H12175P;H4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N;H2M11695N;A container (e.g., a plastic or glass vial with, for example, a cap, or a chromatography column, hollow needle, or syringe cylinder) containing a pharmaceutical formulation of the invention comprising ravulizumab, eculizumab, crovalimab, tesidolumab, or mubodina is provided.

[0156] The present invention also provides anti-C5 antigen binding proteins, e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4 H12167P;H4H12168P;H4H12169P;H4H12170P;H4H12171P;H4H12175P;H4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N;H2M11695N;An injection device containing a pharmaceutical formulation of the present invention comprising ravulizumab, eculizumab, crovalimab, tesidolumab, or mubodina is provided.The injection device is included in a kit.The injection device is a device for introducing a substance into a subject's body via a parenteral route, for example, intraocularly, intravitreally, intramuscularly, subcutaneously, or intravenously. For example, the injection device can be a syringe or autoinjector (e.g., pre-filled with a pharmaceutical formulation) that includes a cylinder or barrel for holding the liquid to be injected (e.g., containing an antibody or fragment thereof or a pharmaceutical formulation), a needle for piercing the skin, blood vessel, or other tissue for injection of the liquid, and a plunger for pushing the liquid out of the cylinder, through the needle bore, and into the body of the subject.

[0157] The present invention also provides (a) anti-C5 antigen binding proteins, e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4 ;H4H12166P5;H4H12166P6;H4H12166P7;H4H12166P8;H4H12166P9;H4H12166 P10;H4H12167P;H4Hl2168P;H4Hl2169P;H4H12170P;H4H12171P;H4H12175P;H 4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N;H2M11695N;A pharmaceutical formulation of the invention comprising ravulizumab, eculizumab, crovalimab, tesidolumab, or mubodina; and (b) an oligonucleotide, e.g., semdisirane, or a pharmaceutical formulation thereof comprising a pharmaceutically acceptable carrier, and optionally, a kit comprising one or more additional materials, e.g., written materials (e.g., instructions for use).

[0158] For producing the pharmaceutical formulations of the invention, anti-C5 antigen-binding proteins, such as antibodies or antigen-binding fragments thereof (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P 10;H4H12167P;H4Hl2168P;H4Hl2169P;H4H12170P;H4H12171P;H4H12175P;H4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N;H2M11695N; ravulizumab, eculizumab, crovalimab, tesidormab, or mubodina) with the required excipients (e.g., histidine, arginine, sucrose, PS-80, and water). ), and optionally, an additional therapeutic agent. Optionally, the pharmaceutical composition is then lyophilized. Such methods, and the pharmaceutical formulations that are the products of such methods, are also part of the present invention.

[0159] In an embodiment of the invention, the pharmaceutical formulation of the invention comprises only one anti-C5 antigen binding protein. In an embodiment of the invention, the pharmaceutical formulation of the invention comprises more than one, for example two or three, anti-C5 antigen binding proteins. In an embodiment of the invention, when two or more anti-C5 antigen binding proteins are present in a pharmaceutical formulation of the invention, two or more of the antigen binding proteins (e.g., H4H12176P2 + H4H12177P2; H4H12166P8 + H4H12170P; H4H12166P + H4H12170P; H4H12166P + H4H12161P; H4H12166P + H4H12171P; H4H12166P + H4H12175P; H4H12166P + H4H12176P2, or H4H12166P + H4H12177P2) do not compete for binding to C5. In an embodiment of the invention, when two or more anti-C5 antigen binding proteins are present, they compete for binding to C5.

[0160] combination The present invention provides a method for the treatment of C5-related diseases, comprising administering to a patient a therapeutically effective amount of an anti-C5 antigen binding protein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, eculizumab, crovalimab, tesidolumab, or mubodina), as well as methods of use thereof and methods of making such compositions.

[0161] In an embodiment of the invention, the additional therapeutic agent is an oligonucleotide (e.g., a duplex of DNA or RNA, or both) that binds, for example, to DNA or mRNA encoding C5. In an embodiment of the invention, the oligonucleotide is up to about 23 nucleotides in length, about 19-22 nucleotides in length, about 19-23 nucleotides in length, or about 19 nucleotides in length, about 20 nucleotides in length, about 21 nucleotides in length, about 22 nucleotides in length, or about 23 nucleotides in length (e.g., a 19-23 nucleotide RNA molecule). In an embodiment of the invention, the oligonucleotide is single-stranded (e.g., in the antisense orientation) or double-stranded. A double-stranded oligonucleotide comprises a strand in the sense orientation and a strand in the antisense orientation. In an embodiment of the invention, the double-stranded oligonucleotide (e.g., RNA) has a 3' overhang and / or a 5' overhang, e.g., of at least two nucleotides. In an embodiment of the invention, the oligonucleotide is naked; in another embodiment, the oligonucleotide is chemically modified.

[0162] In an embodiment of the present invention, the additional therapeutic agent is an RNAi agent that binds with the RNA that codes for C5 or a part thereof.RNAi agent refers to the agent that contains RNA and mediates the targeted cleavage of RNA transcripts through the RNA-induced silencing complex (RISC) pathway.RNAi leads to the sequence-specific degradation of mRNA through the process known as RNA interference.RNAi regulates, for example, inhibits, the expression of C5 in cells, for example, the cells in subjects such as mammalian subjects.

[0163] In one embodiment of the present invention, the RNAi agent of the present invention comprises a single-stranded RNA that interacts with a target RNA sequence, e.g., a C5 target mRNA sequence, to direct cleavage of the target RNA. Without intending to be bound by theory, it is believed that long double-stranded RNAs introduced into cells are degraded into siRNAs by a type III endonuclease known as Dicer (Sharp et al. (2001) Genes Dev. 15:485). Dicer, an RNase 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 its 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 in the RISC cleave the target, inducing silencing (Elbashir et al., (2001) Genes Dev. 15:188). Thus, in one aspect, the present invention relates to intracellularly generated single-stranded RNA (siRNA), which promotes the formation of a RISC complex, resulting in the silencing of the target gene, i.e., the C5 gene. Thus, the term "siRNA" is also used herein to refer to RNAi as described herein.

[0164] In another embodiment, the RNAi agent can be a single-stranded siRNA introduced into a cell or organism to inhibit target mRNA. In an embodiment of the present invention, the single-stranded RNAi agent binds to the RISC endonuclease, Argonaute 2, which then cleaves the target mRNA. In an embodiment of the present invention, the single-stranded siRNA is 15-30 nucleotides 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 incorporated herein 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.

[0165] In another embodiment of the present invention, RNAi agent is double-stranded RNA (dsRNA).dsRNA refers to the complex of ribonucleic acid molecules, which has a double-stranded structure and comprises two antiparallel and substantially complementary nucleic acid strands, and is said to have " sense " and " antisense " orientation with respect to target RNA, i.e., C5 gene.In some embodiments of the present invention, double-stranded RNA (dsRNA) causes the degradation of target RNA, for example, mRNA, through the post-transcriptional gene silencing mechanism known as RNA interference.

[0166] In an embodiment of the invention, an oligonucleotide (e.g., an RNAi) is conjugated to another molecule, such as a sugar, e.g., an N-acetylgalactosamine (GalNAc) derivative, such as: [ka]

[0167] In an embodiment of the invention, an oligonucleotide (e.g., an RNAi) is conjugated to another molecule, as shown in the following schematic diagram: [ka] wherein X is O or S.

[0168] In an embodiment of the invention, the additional therapeutic agent is semdisilane. In an embodiment of the invention, the additional therapeutic agent is the antisense strand nucleotide sequence: 5'-UAUUAUAAAAAUAUCUUGCUUUU-3' (SEQ ID NO: 358) and / or the sense strand nucleotide sequence: 5'-AAGCAAGAUAUUUUUAUAAUA-3' (SEQ ID NO: 359) It is a double-stranded RNA containing

[0169] In an embodiment of the invention, the additional therapeutic agent is a double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5, said dsRNA agent comprising a sense strand and an antisense strand. The sense strand contains 5'-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3' (SEQ ID NO: 360) and the antisense strand comprises 5'-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3' (SEQ ID NO: 361) 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 deoxythymine nucleotide; and s is a phosphorothioate linkage; and the sense strand is conjugated at the 3' end with the following ligand: [ka] See U.S. Patent No. 9,249,415.

[0170] In an embodiment of the present invention, RNAi is in a pharmaceutical preparation that comprises lipid nanoparticles (LNP).LNP is a vesicle that comprises a lipid layer that encapsulates pharmaceutically active molecules such as RNAi.LNP is described in, for example, United States Patent No. 6,858,225, No. 6,815,432, No. 8,158,601 and No. 8,058,069, the entire contents of which are incorporated herein by reference.

[0171] In embodiments of the invention, the additional therapeutic agent is an anticoagulant, warfarin, aspirin, heparin, phenindione, fondaparinux, idraparinux, a thrombin inhibitor, argatroban, lepirudin, bivalirudin, dabigatran, an anti-inflammatory agent, a corticosteroid, a nonsteroidal anti-inflammatory drug (NSAID), an antihypertensive agent, angiotensin-converting enzyme inhibitor, an immunosuppressant, vincristine, cyclosporin A, or methotrexate, a fibrinolytic agent ancrod, E-aminocaproic acid, an antiplasmin-a1, prostacyclin, defibrotide, an antihyperlipidemic agent, a hydroxymethylglutaryl-CoA reductase inhibitor, an anti-CD20 agent, rituximab, an anti-TNFα agent, infliximab, an anticonvulsant, magnesium sulfate, a C3 inhibitor, and / or an antithrombotic agent.

[0172] The term "in combination with" refers to the components of a pharmaceutical formulation: (1) an anti-C5 antigen binding protein and a pharmaceutical The term "component" indicates that the components of the environmentally acceptable carrier can be formulated together with one or more additional therapeutic agents, such as (2) semdisilane, for example, for simultaneous delivery, into a single composition, or can be formulated separately into two or more compositions (e.g., a kit containing each component, e.g., with the additional therapeutic agent in a separate formulation). Components administered together can be administered to a subject at the same time or at different times than the other components are administered; for example, each administration can be given simultaneously (e.g., together in a single composition or essentially simultaneously during the same administration session) or non-simultaneously at one or more intervals over a predetermined period of time. Furthermore, separate components administered together can be administered to a subject by the same or different routes.

[0173] Administration and Treatment The pharmaceutical formulations of the present invention are useful for treating or preventing C5-related diseases and / or for alleviating at least one sign or symptom associated with such C5-related diseases.

[0174] The term "C5-associated disease" refers to a disease, disorder, condition, or syndrome that is caused, maintained, or aggravated, or whose signs and / or symptoms are caused, maintained, or aggravated, directly or indirectly, by complement system activity, and that can be reduced, stabilized, or eliminated by inhibiting C5 activity. Such C5 activity can be inhibited, for example, by preventing cleavage of the C5 precursor into C5a and C5b chains and / or formation of the membrane attack complex (MAC).

[0175] Treating a C5-related disease refers to the reduction, stabilization, or elimination of the disease and / or one or more of its signs and / or symptoms.

[0176] Subjective evidence of a disease, disorder, condition, or syndrome is a symptom. A sign is objective evidence of a disease, disorder, condition, or syndrome. For example, blood flowing from the nostrils is a sign insofar as it is apparent to the patient, doctor, etc. Anxiety, back pain, and fatigue are symptoms insofar as only the patient can perceive them.

[0177] The term "subject" includes mammals such as humans, mice, goats, rabbits, rats, dogs, non-human primates, or monkeys. In embodiments of the invention, the amino acid arginine 885 is mutated to another amino acid at C5 of the subject, e.g., R885H or R885C.

[0178] The pharmaceutical formulations of the present invention are useful for treating or preventing C5-related diseases, which are one or more of the following: ·Adult respiratory distress syndrome Age-related macular degeneration (AMD) ·allergy Alport syndrome Alzheimer's disease Antiphospholipid syndrome (APS) ·asthma Atherosclerosis ·Atypical hemolytic uremic syndrome (aHUS) ·Autoimmune diseases ·Autoimmune hemolytic anemia (AIHA) Balloon angioplasty Bronchoconstriction Pemphigoid ·burn C3 glomerulopathy ·Capillary leak syndrome Cardiovascular disorders Fulminant antiphospholipid syndrome (CAPS) Cerebrovascular disorders CHAPLE disease (CD55 deficiency with hyperactivation of complement, vasculopathic thrombosis, and protein-losing enteropathy) ·Chemical damage ·Chronic obstructive pulmonary disease (COPD) ·Cold agglutinin disease (CAD); Corneal and / or retinal tissue Crohn's disease Degos disease Dense deposit disease (DDD) ·Dermatomyositis ·Diabetes Diabetic vascular disease ·Diabetic macular edema (DME) ·Diabetic nephropathy ·Diabetic retinopathy Dilated cardiomyopathy Impairment of inappropriate or undesired complement activation ·Difficulty breathing Emphysema ·Epidermolysis bullosa Epilepsy Fibrinogenic dust disease ·frostbite Geographic atrophy (GA) Glomerulonephritis Glomerulopathy Goodpasture's syndrome Graves' disease Guillain-Barré syndrome Hashimoto's thyroiditis ·Hemodialysis complications Hemolysis, elevated liver enzymes, and thrombocytopenia (HELLP) syndrome ·Hemolytic anemia Hemoptysis Henoch-Schönlein purpura nephritis Hereditary angioedema Hyperacute allograft rejection ·Hypersensitivity pneumonitis Idiopathic thrombocytopenic purpura (ITP) IgA nephropathy Immune complex disorders ·Immune complex vasculitis Immune complex-related inflammation ·Infectious diseases Inflammation caused by autoimmune diseases Inflammatory disorders Hereditary CD59 deficiency Injuries caused by inert dust and / or minerals Interleukin-2-induced toxicity during IL-2 treatment ·Ischemia-reperfusion injury Kawasaki disease Lung disease or disorder Lupus nephritis Membranoproliferative glomerulonephritis Membranoproliferative nephritis Mesenteric artery reperfusion after aortic reconstruction Mesenteric / intestinal vascular disorders Multifocal motor neuropathy (MMN) Multiple sclerosis ·Myasthenia gravis Myocardial infarction Myocarditis Neurological disorders Neuromyelitis optica ·obesity ·Intraocular angiogenesis Intraocular neovascularization affecting the choroid ·Organic dust disease Parasitic diseases Parkinson's disease Paroxysmal nocturnal hemoglobinuria (PNH) ·Microimmune vasculitis ·Pemphigus Percutaneous transluminal coronary angioplasty (PTCA) Peripheral (e.g., musculoskeletal) circulatory disorders ·pneumonia Post-ischemic reperfusion state Post-pump syndrome in cardiopulmonary bypass surgery Post-pump syndrome in renal bypass surgery ·Progressive renal failure Proliferative nephritis Proteinuric kidney disease ·psoriasis Pulmonary embolism Pulmonary fibrosis ·Pulmonary infarction ·Pulmonary vasculitis Habitual miscarriage Kidney damage ·renal ischemia ·Renal ischemia-reperfusion injury Renal vascular disorders Restenosis after stent placement Rheumatoid arthritis (RA) Rotational atherectomy Schizophrenia ·Sepsis Septic shock ·SLE nephritis Smoke damage Spinal cord injury Spontaneous abortion ·stroke ·Systemic inflammatory response to sepsis Systemic lupus erythematosus (SLE) Systemic lupus erythematosus-associated vasculitis ·Takayasu disease Burns Thrombotic thrombocytopenic purpura (TTP) Traumatic brain injury ·Type I diabetes ·Typical hemolytic uremic syndrome (tHUS) Uveitis ·Vasculitis Rheumatoid arthritis-associated vasculitis Venous gas embolism (VGE); and / or xenograft rejection

[0179] Accordingly, the present invention provides a method for treating or preventing a C5-related disease (e.g., PNH, aHUS, or CHAPLE) in a subject in need thereof, e.g., in a subject suffering from a C5-related disease, comprising administering to a subject an anti-C5 antigen binding protein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12166P11; H4H12166P12; H4H12166P13; H4H12166P14; H4H12166P15; H4H12166P16; H4H12166P17; H4H12166P18; H4H12166P19; H4H12166P20; H4H12166P21; H4H12166P32; H4H12166P42; H4H12166P19; H4H12166P19; H4H12166P10; H4H12166P11; H4H12166P12; H4H12166P13; H4H12166P14; H4H12166P15; H4H12166P H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, crovalimab, or eculizumab), optionally in combination with an additional therapeutic agent (e.g., semdisirane) to a subject. In an embodiment of the invention, the subject has previously received a different anti-C5 antigen binding protein, for example, ravulizumab, crovalimab, or eculizumab.

[0180] Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening disease of the blood. The disease is characterized by the destruction of red blood cells (hemolytic anemia), blood clots (thrombosis), and bone marrow dysfunction (not producing enough of the three blood components). Signs and symptoms of PNH can include significant fatigue or weakness, easy bruising or bleeding, shortness of breath, recurrent infections and / or flu-like symptoms, difficulty controlling bleeding even from very small wounds, the appearance of small red dots on the skin indicating bleeding under the skin, severe headache, fever due to infection, and blood clots (thrombosis). Accordingly, the present invention provides a method for treating or preventing PNH in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of the ... Anti-C5 antigen binding proteins (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H1216 The present invention provides methods for reducing, stabilizing, and / or eliminating one or more signs and / or symptoms of PNH (e.g., hemolytic anemia) in a subject suffering from PNH and said signs and / or symptoms, comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation of the present invention comprising an anti-C5 antigen binding protein.

[0181] Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by low levels of circulating red blood cells due to the destruction of red blood cells (hemolytic anemia), low platelet counts due to platelet consumption (thrombocytopenia), and the inability of the kidneys to process waste products from the blood and excrete them in the urine (acute renal failure), a condition known as uremia. Signs and symptoms of aHUS can include, for example, feeling sick, fatigue, irritability, and lethargy, anemia, thrombocytopenia, acute renal failure, high blood pressure, and organ damage. Accordingly, the present invention provides a method for treating or preventing aHUS in a subject in need thereof, comprising administering to a subject an anti-C5 antigen binding protein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12166P11; H4H12166P12; H4H12166P13; H4H12166P14; H4H12166P15; H4H12166P16; H4H12166P17; H4H12166P18; H4H12166P19; H4H12166P20; H4H12166P30; H4H12166P40; H4H12166P50; H4H12166P19; H4H12166P10; H4H12166P11; H4H12166P12; H4H12166P13; H4H12166P14; H4H12166P15; H4H12166P16; H4H12166P17; H4H12166P18; H4H12166P19; H4H12166P20 H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, crovalimab, or eculizumab) to a subject. The present invention includes methods for reducing, stabilizing, and / or eliminating one or more signs and / or symptoms of aHUS (e.g., hemolytic anemia) in a subject suffering from aHUS and said signs and / or symptoms, comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation of the present invention comprising an anti-C5 antigen binding protein.

[0182] CHAPLE disease is an autosomal recessive genetic disorder caused by loss-of-function mutations in CD55 (also known as decay-accelerating factor, DAF). Signs and symptoms of CHAPLE include hypoproteinemia (low serum levels of albumin and immunoglobulins) leading to facial and extremity edema and recurrent infections, malabsorption syndrome (chronic diarrhea, failure to thrive, anemia, and micronutrient deficiencies), complement hyperactivation, intestinal lymphangiectasia (IL) and intestinal inflammation, and / or increased susceptibility to visceral thrombosis. Accordingly, the present invention provides a method for treating or preventing CHAPLE disease in a subject in need thereof, comprising administering to a subject an anti-C5 antigen binding protein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12166P11; H4H12167P; H4H12168P; H4H12166P12; H4H12168P; H4H12166P13; H4H12168P; H4H12169 ... The present invention provides methods for reducing, stabilizing, and / or eliminating one or more signs and / or symptoms of CHAPLE (e.g., hypoproteinemia) in a subject suffering from CHAPLE and said signs and / or symptoms, comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation of the present invention comprising an anti-C5 antigen binding protein.

[0183] Antiphospholipid syndrome (APS) is an autoimmune disease characterized by arterial and venous thrombosis due to antiphospholipid antibodies. The disorder is called primary if it occurs in the absence of another autoimmune disease. Secondary APS occurs in association with an autoimmune disorder such as systemic lupus erythematosus. Fulminant APS (CAPS) is a rare, life-threatening form of APS in which widespread intravascular thrombosis results in multiple organ ischemia and failure. Accordingly, the present invention provides a method for treating or preventing APS (e.g., primary or secondary or CAPS) in a subject in need thereof, comprising administering to a subject an anti-C5 antigen binding protein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H1212169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, crovalimab, or eculizumab) to a subject. The present invention includes methods for reducing, stabilizing, and / or eliminating one or more signs and / or symptoms of APS (e.g., primary, secondary, or CAPS) in a subject suffering from APS and said signs and / or symptoms, comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation of the present invention comprising an anti-C5 antigen binding protein.

[0184] Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease that causes weakness of the skeletal muscles responsible for breathing and movement of the body, including the arms and legs. Accordingly, the present invention provides a method for treating or preventing myasthenia gravis in a subject in need thereof, comprising administering to a subject an anti-C5 antigen binding protein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H1212169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, crovalimab, or eculizumab) to a subject. The present invention includes methods for reducing, stabilizing, and / or eliminating one or more signs and / or symptoms of MG in a subject suffering from MG and said signs and / or symptoms, comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation of the present invention comprising an anti-C5 antigen binding protein.

[0185] Typical hemolytic uremic syndrome (tHUS) can occur after gastrointestinal infection with Shiga toxin-producing Escherichia coli (STEC). Typical HUS (STEC-HUS; STEC-HUS) is initiated when Shiga toxin (or Shiga-like toxin), a known potent cytotoxin, binds to the cell membrane glycolipid Gb3 (via domain B). Domain A is internalized, subsequently halting protein synthesis and inducing apoptosis of affected cells. Shiga toxin has several additional effects on endothelial cells, one of which is the enhancement of functional tissue factor expression, which may contribute to microvascular thrombosis. The toxin causes damage or activation of the endothelium, red blood cells, and platelets. Accordingly, the present invention provides a method for treating or preventing tHUS in a subject in need thereof, comprising administering to a subject an anti-C5 antigen binding protein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12166P11; H4H12166P12; H4H12166P13; H4H12166P14; H4H12166P15; H4H12166P16; H4H12166P17; H4H12166P18; H4H12166P19; H4H12166P20; H4H12166P30; H4H12166P40; H4H12166P50; H4H12166P60; H4H12166P19; H4H12166P10; H4H12166P11; H4H12166P12; H4H12166P13; H4H12166P14; H4H12166P15; H4H12166P16; H4H12166P17; H4H12166P18; H4H12166P1 H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, crovalimab, or eculizumab) to a subject. The present invention includes a method for reducing, stabilizing, and / or eliminating one or more signs and / or symptoms of tHUS in a subject suffering from tHUS and said signs and / or symptoms, comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation of the present invention comprising an anti-C5 antigen binding protein.

[0186] The present invention also relates to a method for switching therapeutic regimens for treating or preventing C5-related disease, comprising discontinuing administration of an initial such therapeutic regimen and administering to the patient a therapeutically effective amount of H2M11683N;H2M11686N;H4H12159P;H4H12161P;H4H12163P;H4H12164P;H4H12166P;H4H12166P2;H4H12166P3;H4H12166P4;H4H12166P5;H4H12166P6;H4H121 and H2M11695N.

[0187] Certain standard treatments for C5-related diseases are cumbersome and pose significant risks due to complications. The present invention also provides a method for avoiding such standard treatments and their complications by treating the underlying C5-related disease (e.g., PNH or aHUS) with the pharmaceutical formulations of the present invention as provided herein. For example, the standard treatments include blood transfusion, bone marrow transplantation (BMT), kidney transplantation, hemodialysis, and / or balloon angioplasty.

[0188] Complications of blood transfusion include, for example, allergic reactions, fever, acute immune hemolytic reactions, and blood-borne infections (e.g., human immunodeficiency virus (HIV), hepatitis C, hepatitis B, and / or West Nile virus). Accordingly, the present invention provides a method for avoiding blood transfusion and / or one or more complications of blood transfusion (e.g., allergic reactions, fever, acute immune hemolytic reactions, and blood-borne infections) in a subject with a C5-related disease (e.g., PNH or aHUS) by treating the underlying C5-related disease (e.g., PNH or aHUS) with a pharmaceutical formulation of the present invention as provided herein. The present invention also includes methods, wherein treatment comprises administering to a subject a therapeutically effective amount of an anti-C5 antigen binding protein in a pharmaceutical formulation of the present invention.

[0189] Complications of bone marrow transplantation include, for example, graft-versus-host disease, stem cell (graft) failure, organ damage, infection, cataracts, infertility, and death. Accordingly, the present invention includes methods for avoiding bone marrow transplantation and / or one or more complications of bone marrow transplantation (e.g., graft-versus-host disease, stem cell (graft) failure, organ damage, infection, cataracts, infertility, and death) in a subject with a C5-related disease (e.g., PNH or aHUS) by treating the underlying C5-related disease (e.g., PNH or aHUS) with a pharmaceutical formulation of the present invention as provided herein, wherein the treatment comprises administering to the subject a therapeutically effective amount of an anti-C5 antigen-binding protein in the pharmaceutical formulation of the present invention.

[0190] Complications of hemodialysis include, for example, infection, sepsis, hypotension, muscle cramps, itching, sleep disorders, sleep apnea, anemia, hypertension, fluid overload, pericarditis, hyperkalemia, amyloidosis, or depression. Accordingly, the present invention includes methods for avoiding hemodialysis and / or one or more complications of hemodialysis (e.g., infection, sepsis, hypotension, muscle cramps, itching, sleep disorders, sleep apnea, anemia, hypertension, fluid overload, pericarditis, hyperkalemia, amyloidosis, or depression) in a subject with a C5-related disease (e.g., PNH or aHUS) by treating the underlying C5-related disease (e.g., PNH or aHUS) with a pharmaceutical formulation of the present invention as provided herein, wherein the treatment comprises administering to the subject a therapeutically effective amount of an anti-C5 antigen-binding protein in the pharmaceutical formulation of the present invention.

[0191] Complications of kidney transplantation include, for example, blood clots, bleeding, ureteral leakage or blockage, infection, kidney failure, kidney rejection, death, heart attack, and stroke. Accordingly, the present invention includes methods for avoiding kidney transplantation and / or one or more complications of kidney transplantation (e.g., blood clots, bleeding, ureteral leakage or blockage, infection, kidney failure, kidney rejection, death, heart attack, and stroke) in a subject with a C5-related disease (e.g., PNH or aHUS) by treating the underlying C5-related disease (e.g., PNH or aHUS) with a pharmaceutical formulation of the present invention as provided herein, wherein the treatment comprises administering to the subject a therapeutically effective amount of an anti-C5 antigen binding protein in the pharmaceutical formulation of the present invention.

[0192] The pharmaceutical formulations of the present invention are used to treat or prevent C5-associated ophthalmological diseases, such as age-related macular degeneration (AMD; e.g., wet or dry), diabetic retinopathy (DR), non-infectious uveitis, geographic atrophy, Stargardt's macular dystrophy, or optic neuritis.

[0193] AMD is a progressive degeneration of the macula (the central part of the retina), typically in people over the age of 55. Various complement components, including C3, C5b-9, CFB, and CFH, have been detected in both drusen and AMD lesions. In addition, increased plasma levels of C3a, C3d, Bb, and C5a have been observed in AMD patients. These results suggest increased local and systemic complement activation in AMD.

[0194] DR is a progressive degeneration of retinal vasculature and nerve cells as a result of diabetes. The choriocapillaris of DR eyes contain significant levels of C3d and C5b-9 complexes. C5b-9 deposition can also be detected in the retinal blood vessels of patients with type 2 diabetes for more than 9 years, and increased C5a has been detected in the vitreous of patients with proliferative DR, suggesting that complement activation is involved in retinal vascular damage in DR.

[0195] Non-infectious uveitis is inflammation in one or both eyes that is not caused by an infection. Heat, redness, pain, and swelling.

[0196] Geographic atrophy (GA) is a chronic, progressive degeneration of the macula, part of late-stage age-related macular degeneration (AMD). The disease is characterized by localized, sharply circumscribed atrophy of the outer retinal tissue, the retinal pigment epithelium, and the choriocapillaris. It typically begins in the perifoveal region and spreads over time to involve the fovea, resulting in a central scotoma and permanent loss of vision, usually in both eyes.

[0197] Autosomal recessive Stargardt macular dystrophy (STGD1) is a dystrophy caused by mutations in the ABCA4 (ABCR) gene. Mutations in ABCA4 also cause cone-rod dystrophy. The age of onset in juvenile and early adult STGD1 is usually between 8 and 25 years of age, but it can also occur in older adults (late adult-onset STGD1). The hallmark of the disease is the premature accumulation of lipofuscin (a yellowish-brown autofluorescent pigment associated with aging) in the retinal pigment epithelium (RPE) of the eye, which causes a pattern of yellowish spots extending outward from the macula.

[0198] Optic neuritis is an inflammation that damages the optic nerve. Pain and temporary vision loss in one eye are common symptoms of optic neuritis.

[0199] Accordingly, the present invention includes methods for treating or preventing a C5-associated ophthalmological disease, such as age-related macular degeneration (AMD; e.g., wet or dry), diabetic retinopathy (DR), non-infectious uveitis, geographic atrophy, Stargardt's macular dystrophy, or optic neuritis, in a subject in need thereof, comprising administering to the subject, e.g., by intraocular or intravitreal injection, a therapeutically effective amount of an anti-C5 antigen binding protein in a pharmaceutical formulation of the present invention.

[0200] The anti-C5 antigen-binding proteins of the present invention also reduce complement activity (e.g., C5-mediated complement activity) in the subject's body. For example, in an embodiment of the present invention, complement activity is complement-mediated hemolysis (e.g., classical pathway-mediated or alternative pathway-mediated) or C5 activity (e.g., binding of C5a to C5aR1, generation of C5a and / or C5b from C5 precursors; or formation or deposition of membrane attack complex (MAC) in cells, such as endothelial cells). In an embodiment of the present invention, complement activity is the ability of serum collected from the subject's body to lyse sheep red blood cells coated with anti-sheep antibody. Accordingly, the present invention provides a method for reducing complement activity in the body of a subject, comprising administering to a subject an anti-C5 antigen binding protein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P) in a pharmaceutical formulation of the present invention. 8;H4H12166P9;H4H12166P10;H4H12167P;H4H12168P;H4H12169P;H4H12170P;H4H12171P;H4H12175P;H4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N;H2M11695N;ravolizumab, crovalimab, or eculizumab), for example, a therapeutically effective amount thereof, is provided.

[0201] In certain embodiments, a therapeutically effective amount of an anti-C5 antigen binding protein in a pharmaceutical formulation of the present invention is administered to a subject with a C5-related disease. The therapeutically effective amount of an anti-C5 antigen binding protein in a pharmaceutical formulation of the present invention may vary depending on the age and size of the subject to be administered, the target disease, condition, route of administration, and the like. In this context, the therapeutically effective amount of the anti-C5 antigen-binding protein in the pharmaceutical formulation of the present invention is about 0.1 to about 100 mg / kg body weight, about 5 to about 80 mg, about 10 to about 70 mg, or about 20 to about 50 mg / kg body weight (e.g., single or multiple doses thereof). In an embodiment of the present invention, the therapeutically effective amount of the anti-C5 antigen-binding protein in the pharmaceutical formulation of the present invention is about 0.1 mg to about 1000 mg, about 1 to about 600 mg, about 5 to about 500 mg, or about 10 to about 400 mg. Depending on the severity of the condition, the frequency and duration of treatment can be adjusted. In certain embodiments, an initial dose is followed by administration of a second or multiple subsequent doses of the antigen-binding protein in an amount that may be approximately the same as or less than the initial dose, with the subsequent doses being separated by at least 1 day to 3 days; at least 1 week; at least 2 weeks; at least 3 weeks, or at least 4 weeks.

[0202] In an embodiment of the invention, the therapeutically effective amount of the anti-C5 antigen binding protein (e.g., pozeliimab) in the pharmaceutical formulation of the invention is about 30 mg / kg body weight administered intravenously (IV) one or more times; optionally further comprising one or more doses of the formulation administered subcutaneously.

[0203] In an embodiment of the present invention, the therapeutically effective amount of an additional therapeutic agent that is an RNAi (e.g., semdisirane) is about 0.001 to about 200.0 milligrams per kg of recipient body weight per day, generally in the range of about 1 to 50 mg per kg of body weight per day. For example, the therapeutically effective amount of an RNAi, e.g., dsRNA (e.g., semdisirane), is about 0.01 mg / kg, about 0.05 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 3 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, or about 50 mg / kg per single dose.

[0204] In a further embodiment of the invention, an additional therapeutic agent is administered to a subject in conjunction with the pharmaceutical formulation of the invention. In an embodiment of the invention, the additional therapeutic agent is administered in a dosage according to the Physicians' Desk Reference 2003 (Thomson Healthcare; 57th Edition (November 1, 2002)).

[0205] The present invention further provides anti-C5 antigen binding proteins, e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168 P;H4H12169P;H4H12170P;H4H12171P;H4H12175P;H4H12176P2;H4H12177P2;H4H12183P2;H2M11682N;H2M11684N;H2M11694N;H2M11695N;Provided is a method for administering to a subject a pharmaceutical formulation of the present invention comprising ravulizumab, crovalimab, or eculizumab, the method comprising introducing the pharmaceutical formulation into the body of a subject (e.g., a human) for example, parenterally.For example, the method comprises piercing the body of the subject with a syringe needle and injecting the pharmaceutical formulation into the body of the subject, for example, into the subject's vein, artery, eye, muscle tissue, or subcutaneous tissue.

[0206] The pharmaceutical formulations of the present invention may be administered in a variety of ways, including parenteral, non-parenteral, oral, rectal, transmucosal, intestinal, parenteral, intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, intraocular, inhalation, insufflation, topical, dermal, intraocular, intravitreal, transdermal, or intra-arterial.

[0207] Intravenous administration The anti-C5 antigen binding proteins discussed herein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H121 66P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; ravulizumab, crovalimab, or eculizumab) can be administered to a subject via intravenous (IV) route. Thus, the present invention includes intravenous formulations, including aqueous solutions for intravenous administration (e.g., NS) and pharmaceutical formulations provided herein. An intravenous formulation can be prepared by adding a pharmaceutical formulation provided herein (e.g., about 200 mg / ml pozeliimab; 20±4 mM histidine buffer; 100±20 mM L-arginine; 2±0.4% (w / v) sucrose; 0.15±0.075% (w / v) polysorbate-80; and water, pH 5.8±0.3) to an aqueous solution for intravenous administration (e.g., NS). The pharmaceutical formulation can be added to the aqueous solution for intravenous administration, for example, by injection through a medication port in a container (e.g., a bag) holding the solution. The resulting intravenous formulation can then be administered to a subject. The intravenous formulation resulting from such a method, along with methods for its use as provided herein, form part of the present invention.

[0208] Aqueous solutions for intravenous administration into which the pharmaceutical preparation can be incorporated to form a formulation for intravenous administration include, for example, 0.9% normal saline (NS, 0.9NaCl, or NSS), lactated Ringers (LR, Ringers Lactate), or RL), dextrose 5% in water (D5 or D5W, intravenous sugar solution); 0.45% Normal saline (half normal saline, 0.45% NaCl, 45% NS); 0.33% NaCl; 0.225% NaCl; dextrose 2.5% in water (D 2.5 W; 3% NaCl; 5% NaCl; 0.45% NaCl in dextrose 5% (D5 1 / 2 NS); 5% dextrose and 0.45% NaCl; dextrose 5% in 0.9% NaCl (D5NS); dextrose 5% in lactated Ringer's solution (D5LR); LR containing 0.6% NaCl; dextrose 10% in water (D 10 W); dextrose in water 20% (D 20 W); or dextrose 50% in water (D 50 W). These solutions are well known in the art and are commercially available.

[0209] Containers and other devices which contain such intravenous preparations (eg, sterile plastic or glass intravenous bottles or intravenous plastic bags) also form part of the invention.

[0210] Intravenous formulations can be administered into a subject's veins by any of several methods known in the art. For example, intravenous formulations can be administered through a peripheral intravenous (PIV) line or a central IV line. A PIV introduces intravenous formulations into a subject's peripheral veins (typically veins in the arms, hands, legs, and feet). A central IV line has a catheter that runs through the vein and drains into a large central vein (a vein in the torso), usually the superior vena cava, the inferior vena cava, or even the right atrium of the heart.

[0211] Accordingly, the present invention provides a method for intravenously administering to a subject an intravenous formulation of the present invention comprising a pharmaceutical formulation provided herein (e.g., about 200 mg / ml pozeliimab; 20±4 mM histidine buffer; 100±20 mM L-arginine; 2±0.4% (w / v) sucrose; 0.15±0.075% (w / v) polysorbate-80; and water, pH 5.8±0.3) in an aqueous solution for intravenous administration (e.g., NS), the method comprising administering intravenously to a subject the pharmaceutical formulation of the present invention (e.g., about 200 mg / ml pozeliimab; 20±4 mM histidine buffer; 100±20 mM L-arginine; 2±0.4% (w / v) sucrose; 0.15±0.075% (w / v) polysorbate-80; and water, pH 5.8±0.3), the method comprising administering intravenously to a subject an intravenous formulation of the present invention comprising administering intravenously to a subject an intravenous solution (e.g., NS), the pharmaceutical formulation of the present invention (e.g., about 200 mg / ml pozeliimab; 20±4 mM histidine buffer; 100±20 mM L-arginine; 2±0.4% (w / v) sucrose; 0.15±0.075% (w / v) polysorbate-80; and water, pH 5.8±0.3), the method comprising administering intravenously to a subject an intravenous solution (e.g., NS ... Also provided are methods for administering the intravenous formulations of the present invention into a subject's vein (e.g., a peripheral vein), for example, by IV infusion (e.g., infusion or pump infusion). Also provided are methods for administering the intravenous formulations of the present invention, which may include adding the pharmaceutical formulations described herein (e.g., about 200 mg / ml pozeliman; 20±4 mM histidine buffer; 100±20 mM L-arginine; 2±0.4% (w / v) sucrose; 0.15±0.075% (w / v) polysorbate-80; and water, pH 5.8±0.3) to an aqueous solution for intravenous administration (e.g., NS), and introducing the resulting intravenous formulation into a subject's vein, for example, by IV infusion (e.g., infusion or pump infusion). Such methods optionally further include administering the pharmaceutical formulation by a route other than intravenous, for example, subcutaneously.

[0212] The present invention includes methods for treating or preventing a C5-related disease (e.g., PNH) in a subject by administering an intravenous formulation, the method comprising administering an anti-C5 antigen-binding protein to the subject intravenously (e.g., one or more IV doses of 1 mg / kg, 3 mg / kg, 10 mg / kg, 15 mg / kg, or 30 mg / kg). Optionally, the method further comprises administering a pharmaceutical formulation of the present invention to the subject by a route other than IV, for example subcutaneously, i.e., the pharmaceutical formulation is administered without forming the pharmaceutical formulation into an intravenous formulation. [Example]

[0213] The following examples are provided to further describe the present invention and should not be construed as limiting thereof. The scope of the present invention includes any of the methods and pharmaceutical preparations illustrated in the following examples below. [Example]

[0214] Steric stability of H4H12166P Melting temperature (T m ) was determined by TA differential scanning calorimetry (DSC) and VP-DSC using the parameters shown in Tables 1-1 and 1-2. The determined melting temperatures are summarized in Table 1-3. In addition, the thermal melting profiles of H4H12166P determined by VP-DSC at 1 mg / mL and TA-DSC at 150 mg / mL and 200 mg / mL are shown in Figures 1, 2, and 3, respectively.

[0215] [Table 3]

[0216] [Table 4]

[0217] [Table 5]

[0218] The first transition (T m 1) most likely represents the thermal unfolding of the CH2 domain in the Fc region, while the major transition (larger endotherm) comes from the Fab region domain. T determined for all samples m Although the values ​​are similar (61-62°C), this peak is 150 mg / mL The measured T corresponding to the major transition in the TA-DSC thermogram for H4H12166P is not well defined (Figure 2). m The T value (approximately 76 °C) is higher than the major transition temperatures in the 150 mg / mL (69 °C) and 200 mg / mL (73 °C) H4H12166P samples. m These differences between the two samples may be due to differences in instrumentation and data analysis, as well as the large differences in protein concentration in each sample. A slightly higher T was determined for the 200 mg / mL H4H12166P sample compared to the 150 mg / mL H4H12166P sample. m The 2 values ​​may be due to (1) a difference of 0.3 pH units between the two formulations and (2) the presence of a formulation stabilizer in the 200 mg / mL H4H12166P sample. [Example]

[0219] Effects of pH, temperature, and headspace To characterize the degradation pathways of 150 mg / mL H4H12166P, temperature, pH, and container headspace were evaluated in a design of experiments (DoE) study. A risk assessment was completed. The factors used in this study are listed in Table 2-1.

[0220] [Table 6]

[0221] Results from a study designed to characterize 150 mg / mL H4H12166P in 20 mM histidine buffer over a range of temperatures, pH, and container headspace are shown in Figure 4. The impact of these factors on the evaluated quality attributes of H4H12166P is summarized below: Temperature and pH showed the greatest effect on H4H12166P quality attributes such as molecular size and charge variants, pH, and turbidity. The formation of molecular size variants (HMW species) and acidic charge variants, as determined by SE-UPLC and CEX-UPLC, respectively, increased with temperature, with a corresponding decrease in the % main peak. The formation of basic charge variants gradually increased with decreasing pH at higher temperatures. At higher temperatures, a larger increase in solution pH (up to 0.15 pH units) was observed after 90 days of incubation at pH 5.7 compared to pH 6.7. An increase in turbidity was measured at higher temperatures and pH.

[0222] Transfer functions obtained from analysis of the DoE study results were used to estimate the rates of formation of molecular size and charge variant species in 150 mg / mL H4H12166P, 20 mM histidine, pH 5.8 at temperatures ranging from 25° C. to 45° C. (Table 2-2); these rates are plotted as a function of temperature and as a graphical representation of the decomposition rates at different temperatures in Figures 5 and 6, respectively. A summary of these results is provided below: The formation of high molecular weight species (HMW) and acidic charge variants is the predominant degradation pathway in H4H12166P after heat stress in: 37°C (HMW rate = 0.6% per month and acid rate = 0.6% per month), 40°C (HMW rate = 1.2% per month and acid rate = 3.1% per month), and 45°C (HMW rate = 2.6% per month and acid rate = 8.8% per month). · Minimal fragmentation (LMW species) or formation of basic charge variants was observed under these conditions. At temperatures above 30°C, the rate of decomposition (% HMW and acidity) increases almost linearly up to 45°C. The rate of HMW formation at 30°C was lower compared to 25°C (Table 2-2), but the magnitude of this difference (0.27%) was smaller than the error in the model fit (0.45%) and was not significant. As the temperature increases, a decreasing trend in the rate of change of basic charge variant species is observed (Figure 6), which may be due to their conversion to acidic charge variant species. However, the overall change (<1%) is largely due to the error in the model fit (1.5%). Being smaller, the changes may not be meaningful within the range of parameters evaluated in this study.

[0223] [Table 7]

[0224] The rationale for including headspace as a factor in this characterization study was to assess the effect of different amounts of headspace oxygen on the susceptibility of H4H12166P to methionine oxidation. Methionine oxidation was quantified by peptide mapping (LCMS), but because this is not a high-throughput method, the test was only performed on a 150 mg / mL H4H12166P, 20 mM histidine, pH 6.2 sample filled in a 10 mL glass vial (maximum headspace) at t = 0 and 28 days at 45°C as a worst-case scenario. The results, listed in Tables 2-3, show only a very small increase (1.3%) in oxidation of Met105, located within the CDR of H4H12166P, under these incubation conditions. Other Met residues showed lower and negligible changes in oxidation with thermal incubation. Container headspace showed minimal impact on other monitored quality attributes across the range evaluated (2.5 mL - 11.5 mL) (Figure 4). The lower protein recovery (Δprotein concentration) observed at smaller headspaces was not statistically significant, as indicated by the large confidence intervals and effect test (Figure 4). Therefore, oxidation of H4H12166P due to the presence of headspace oxygen is not considered a degradation pathway.

[0225] [Table 8] [Example]

[0226] Effects of freeze / thaw, agitation, and forced oxidation (hydrogen peroxide spike) Single-factor studies of the sensitivity of 150 mg / mL H4H12166P in 20 mM histidine, pH 6.2, to freeze / thaw, agitation, and oxidative (H2O2 spike) stress. The incubation / stress conditions used to evaluate the stability of H4H12166P are shown in Table 3-1. The concentrations of hydrogen peroxide evaluated in this study are listed in Table 3-2.

[0227] [Table 9]

[0228] [Table 10]

[0229] 14 mL of F1 (control) and 10 mL of each subsequent formulation (F2-F8) listed in Table 3-2 were prepared. Each formulation was filter-sterilized in a laminar flow hood using a syringe and a Millipore Millex GV (PVDF Durapore) 0.2 μM filter. After filter-sterilization, formulations F2-F8 were spiked with H2O2 in a laminar flow hood. The formulations were dispensed as follows: 1. 1 ml of formulation F1 was filled into ten 2 ml glass vials (also used for F / T and agitation tests) 2. 1 mL of each of formulations F2 to F8 was filled into four 2 mL glass vials. The analytical test plans for F / T, agitated, and oxidatively stressed samples are shown in Table 3-4.

[0230] [Table 11]

[0231] After exposure to freeze / thaw and agitation stress, under the conditions described in Table 3-1, 150 mg / mL H4H12166P, 20 mM histidine, pH 6.2 showed increased levels of HMW species (Figure 7). After 4× and 8× freeze / thaw cycles, the HMW species increased by 0.8% and 1.3%, respectively. After 6 hours of stirring, a small increase in HMW species was observed, and after 24 hours of stirring, a >0.5% increase in HMW species was observed.

[0232] No changes in charge variants, as determined by CEX-UPLC, were observed after either freeze / thaw or agitation stress (see Figure 8). The level of methionine oxidation in 150 mg / mL H4H12166P after incubation with different concentrations of hydrogen peroxide at 37 °C for 24 h was determined by peptide mapping (LC-MS). When incubated with 1 ppm hydrogen peroxide, neither an increase in methionine oxidation nor a significant loss of potency was observed in H4H12166P (Tables 3-5). When H4H12166P was incubated with 500 ppm hydrogen peroxide, an approximately 80% increase in Met105 oxidation, an approximately 21% increase in Met252 oxidation, and an approximately 6% increase in Met428 oxidation were observed. After incubation with 500 ppm hydrogen peroxide, a significant loss of potency, as determined by bioassay, was observed.

[0233] [Table 12]

[0234] To quantify the level of methionine oxidation in H4H12166P, a method based on high-throughput hydrophobic interaction chromatography (HIC) HPLC was developed. Although this method is not sensitive enough to allow identification of the specific methionine residue undergoing oxidation, distinct peaks that increased with incubation time were resolved in the chromatogram. The peak areas for the 500 ppm hydrogen peroxide sample, representing the changes in the different oxidized species, are shown in Figure 9. The total % oxidation (calculated from the sum of all peak areas for the oxidized species, excluding the major peak) at different concentrations of hydrogen peroxide after incubation at 37°C for up to 24 hours is shown in Figure 10. These results demonstrate the inability to detect oxidation in H4H12166P when incubated with up to 10 ppm hydrogen peroxide under these conditions. The results for 1 ppm and 500 ppm hydrogen peroxide obtained by peptide mapping (LC-MS) and HIC-HPLC are qualitatively consistent (Tables 3-5 and Figure 10).

[0235] H4H12166P samples incubated with hydrogen peroxide were also analyzed for charge (CEX-UPLC) and molecular size (SE-UPLC) variants. A small (approximately 1%) decrease in acidic charge variants and a comparable increase in basic charge variants was observed only at 100 ppm and 500 ppm hydrogen peroxide (Figures 11 and 12).

[0236] There was no significant increase in the formation of HMW species even at the highest tested concentration of hydrogen peroxide (Figure 13), indicating that even high levels of H4H12166P methionine oxidation do not generate conformational species prone to self-association or aggregation. [Example]

[0237] Comparison of viscosity of H4H12166P and comparative molecules at high concentrations Viscosity was measured using a Rheosense m-VROC viscometer. Prior to analysis, standards and formulations were filtered through a 0.22 μm PVDF spin filter. Prior to unknown sample viscosity analysis, two standards of known viscosity were measured: 2 cP and a glycerin standard. The temperature measurements were carried out at 20°C.

[0238] [Table 13] [Example]

[0239] Long-term and accelerated stability studies of 200mg / ml H4H12166P Stability studies evaluated the stability of the liquid aqueous H4H12166P 200 mg / mL formulation under long-term storage and stress conditions. The following two stability studies were initiated: (1) 0.5 mL fills in 2 mL type 1 borosilicate glass vials, stored upright, and (2) 2.5 mL fill in a 5 mL type 1 borosilicate glass vial, stored inverted

[0240] [Table 14]

[0241] result The properties of an aqueous formulation containing 200 mg / mL H4H12166P, 20 mM histidine, pH 5.8, 100 mM L-arginine hydrochloride, 2% (w / v) sucrose, and 0.15% (w / v) polysorbate 80 after 6 months of long-term (5°C) storage in 2 mL Schott Type 1 borosilicate glass vials (stored upright) are shown in Table 5-2. Tables 5-3 and 5-4 summarize the properties of the liquid aqueous H4H12166P 200 mg / mL formulation after storage at accelerated conditions of 25°C and 60% RH and stress conditions of 40°C and 75% RH, respectively.

[0242] [Table 15]

[0243] [Table 16]

[0244] [Table 17]

[0245] Comparison of results between 2 mL and 5 mL glass vials revealed that factors such as container size (2 mL and 5 mL) and fill volume (0.5 mL and 2.5 mL) did not significantly affect degradation pathways or trends in key quality attributes in the H4H12166P formulation. [Example]

[0246] Agitation and freeze / thaw studies for 200mg / mL H4H12166P The stability study evaluated the stability of a liquid aqueous H4H12166P 200 mg / mL formulation under agitation and freeze / thaw conditions.

[0247] [Table 18]

[0248] result The properties of an aqueous formulation containing 200 mg / mL H4H12166P, 20 mM histidine, pH 5.8, 100 mM L-arginine hydrochloride, 2% (w / v) sucrose, and 0.15% (w / v) polysorbate 80 in 6R Type 1 borosilicate glass vials (stored upright) after vortexing or freeze / thawing are shown in Tables 6-2 and 6-3.

[0249] [Table 19]

[0250] [Table 20]

[0251] No appreciable change in physical or chemical stability after 48 hours of stirring and 4 cycles of freeze / thaw for an aqueous formulation containing 200 mg / mL H4H12166P. [Example]

[0252] Long-term stability study of 274mg / mL H4H12166P The stability study evaluated the stability of liquid aqueous H4H12166P 274 mg / mL under long-term storage (5°C).

[0253] result The properties of an aqueous formulation containing 274 mg / mL H4H12166P, 20 mM histidine, pH 5.8, 100 mM L-arginine hydrochloride, 2% (w / v) sucrose, and 0.15% (w / v) polysorbate 80 after 15.5 months of long-term (5°C) storage in a 5 mL container are shown in Table 7-1. Table 7-2 summarizes the properties of the liquid aqueous H4H12166P 274 mg / mL formulation after freeze / thaw.

[0254] [Table 21]

[0255] [Table 22]

[0256] No appreciable change in physical or chemical stability after 15.5 months at 5°C with 8 freeze / thaw cycles for an aqueous formulation containing 274 mg / mL H4H12166P. [Example]

[0257] Viscosity comparison of H4H12166P Viscosity was measured using a Rheosense Initium automated viscometer. Prior to analysis, standards and formulations were filtered through 0.22 μm PVDF spin filters. Prior to unknown sample viscosity analysis, two standards of known viscosity were measured: 2 cP and a glycerin standard. Viscosity measurements were performed at different temperatures (5°C to 40°C) on aqueous formulations containing 161-274 mg / mL H4H12166P, 20 mM histidine, pH 5.8, 100 mM L-arginine hydrochloride, 2% (w / v) sucrose, and 0.15% (w / v) polysorbate 80. Table 8-1 summarizes the measured viscosities.

[0258] [Table 23]

[0259] All references cited herein are incorporated by reference to the same extent as if each individual publication, database entry (e.g., Genbank sequence or GeneID entry), patent application, or patent was specifically and individually indicated to be incorporated by reference. This incorporation-by-reference statement is intended by applicant to relate to each and every individual publication, database entry (e.g., Genbank sequence or GeneID entry), patent application, or patent, even if such citation is not immediately adjacent to the specific incorporation-by-reference statement. The inclusion of a specific incorporation-by-reference statement within this specification in no way weakens the general incorporation-by-reference statement, if any. The citation of a reference herein is not intended as an admission that the reference is relevant prior art, nor does it constitute any admission as to the content or date of these publications or documents.

Claims

1. 1. An aqueous pharmaceutical formulation for treating a C5-related disease in a subject, comprising 161 to 274 mg / ml of pozelimab and a pharmaceutically acceptable carrier comprising a histidine buffer and 50 to 100 mM L-arginine, wherein the formulation has a pH of 5.5 to 6.1 and a viscosity of 8 to 50 cP at 20°C.

2. 2. The pharmaceutical formulation of claim 1, wherein the concentration of pozeliman is 200 mg / ml.

3. 3. The pharmaceutical formulation according to claim 1, wherein the L-arginine is L-arginine hydrochloride.

4. The pharmaceutical preparation according to any one of claims 1 to 3, wherein the concentration of L-arginine is 100 mM.

5. 5. The pharmaceutical formulation according to any one of claims 1 to 4, comprising an oligosaccharide, wherein the oligosaccharide is sucrose, mannitol, dextrose, glycerin, TMAO (trimethylamine-N-oxide), trehalose, ethylene glycol, glycine betaine, xylitol, or sorbitol.

6. 6. The pharmaceutical formulation according to any one of claims 1 to 5, comprising an oligosaccharide, wherein the oligosaccharide is sucrose.

7. 7. The pharmaceutical formulation according to claim 5 or 6, wherein the concentration of the oligosaccharide is 2% (w / v).

8. The pharmaceutical formulation according to any one of claims 1 to 7, wherein the concentration of the histidine buffer is 20 mM.

9. a nonionic surfactant selected from polyoxyethylene-based surfactants or glycoside compound-based surfactants, polysorbate-20, and polysorbate-80; The pharmaceutical formulation according to any one of claims 1 to 8, further comprising an anti-inflammatory agent.

10. 10. The pharmaceutical formulation of claim 9, wherein the non-ionic surfactant is polysorbate-80.

11. The pharmaceutical formulation according to any one of claims 1 to 10, which comprises a nonionic surfactant, and the concentration of the nonionic surfactant is 0.15% (w / v).

12. At a pH of 5.8±0.3 and a viscosity of 8-50 cP at 20° C. Pozelimab 180-210 mg / ml; 20±4 mM histidine buffer; 100 mM L-arginine; 2±0.4% (w / v) oligosaccharides; 0.15±0.075% (w / v) non-ionic surfactant; and water 10. A pharmaceutical formulation comprising:

13. At a pH of 5.8±0.3 and a viscosity of 8-20 cP at 20° C. Pozelimab 200 mg / ml; 20±4 mM histidine buffer; 100 mM L-arginine; 2±0.4% (w / v) sucrose; 0.15±0.075% (w / v) polysorbate-80; and water 10. A pharmaceutical formulation comprising:

14. The pharmaceutical formulation of any one of claims 1 to 13, administered in combination with a further therapeutic agent.

15. 15. The pharmaceutical formulation of claim 14, which is administered separately from the additional therapeutic agent.

16. 16. The pharmaceutical formulation of claim 14 or 15, wherein the further therapeutic agent is an oligonucleotide, 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 agent, angiotensin-converting enzyme inhibitor, an immunosuppressant, vincristine, cyclosporin A, or methotrexate, the fibrinolytic agent ancrod, E-aminocaproic acid, an antiplasmin-a1, prostacyclin, defibrotide, an antihyperlipidemic agent, hydroxymethylglutaryl-CoA reductase inhibitor, an anti-CD20 agent, rituximab, an anti-TNFα agent, infliximab, an anticonvulsant, magnesium sulfate, a C3 inhibitor, and / or an antithrombotic agent.

17. Further therapeutic agents include DNA oligonucleotides, RNA oligonucleotides, single-stranded DNA oligonucleotides, single-stranded RNA oligonucleotides, a double-stranded DNA oligonucleotide, or double-stranded RNA oligonucleotides; 17. The pharmaceutical formulation of claim 16, wherein the oligonucleotide is

18. 18. The pharmaceutical formulation of claim 17, wherein the oligonucleotide is conjugated to a sugar and the oligonucleotide is formulated separately from the pharmaceutical formulation.

19. The pharmaceutical preparation according to any one of claims 1 to 18, wherein the C5-related disease is selected from the group consisting of geographic atrophy, paroxysmal nocturnal hemoglobinuria (PNH), myasthenia gravis, and CHAPLE disease.

20. C5-related diseases include adult respiratory distress syndrome, age-related macular degeneration (AMD), allergies, Alport syndrome, Alzheimer's disease, antiphospholipid syndrome (APS), asthma, atherosclerosis, atypical hemolytic uremic syndrome (aHUS), autoimmune diseases, autoimmune hemolytic anemia (AIHA), balloon angioplasty, bronchoconstriction, pemphigoid, burns, C3 glomerulopathy, capillary leak syndrome, cardiovascular disorders, fulminant antiphospholipid syndrome (CAPS), cerebrovascular disorders, CHAPLE disease, and chemoradioactivity. Biochemical damage; chronic obstructive pulmonary disease (COPD); cold agglutinin disease (CAD); corneal and / or retinal tissue; Crohn's disease; Degos disease; dense deposit disease (DDD); dermatomyositis; diabetes; diabetic angiopathy; diabetic macular edema (DME); diabetic nephropathy; diabetic retinopathy; dilated cardiomyopathy; disorders of inappropriate or unwanted complement activation; dyspnea; emphysema; epidermolysis bullosa; epilepsy; fibrosing dust disease; frostbite; geographic atrophy (GA); glomerulonephritis; glomerulopathy; Goodpasture's syndrome ; Graves' disease; Guillain-Barré syndrome; Hashimoto's thyroiditis; Hemodialysis complications; Hemolysis, elevated liver enzymes, and thrombocytopenia (HELLP) syndrome; Hemolytic anemia; Hemoptysis; Henoch-Schönlein purpura nephritis; Hereditary angioedema; Hyperacute allograft rejection; Hypersensitivity pneumonitis; Idiopathic thrombocytopenic purpura (ITP); IgA nephropathy; Immune complex disorders; Immune complex vasculitis; Immune complex-associated inflammation; Infectious diseases; Inflammation caused by autoimmune diseases; Inflammatory disorders; Hereditary CD59 deficiency; Inactive Dust and / or mineral injury; interleukin-2 induced toxicity during IL-2 therapy; ischemia-reperfusion injury; Kawasaki disease; pulmonary disease or injury; lupus nephritis; membranoproliferative glomerulonephritis; membranoproliferative nephritis; mesenteric artery reperfusion after aortic reconstruction; mesenteric / intestinal vasculopathy; multifocal motor neuropathy (MMN); multiple sclerosis; myasthenia gravis; myocardial infarction; myocarditis; neurological disorders; neuromyelitis optica; obesity; intraocular angiogenesis; intraocular neovascularization affecting the choroid; organic dust disease; parasitic diseases; Parkinson's disease; Paroxysmal nocturnal hemoglobinuria (PNH); microimmune vasculitis; pemphigus; percutaneous transluminal coronary angioplasty (PTCA); peripheral circulatory disorders; pneumonia; post-ischemic reperfusion state; post-pump syndrome in cardiopulmonary bypass surgery; post-pump syndrome in renal bypass surgery; progressive renal failure; proliferative nephritis; proteinuric kidney disease; psoriasis; pulmonary embolism; pulmonary fibrosis; pulmonary infarction; pulmonary vasculitis; recurrent abortion; renal damage; renal ischemia; renal ischemia-reperfusion injury; renal vascular disorders; restenosis after stent placement; rheumatoid arthritis; 19. The pharmaceutical formulation or intravenous formulation of any one of claims 1 to 18, which is selected from the group consisting of rotational atherectomy; schizophrenia; sepsis; septic shock; SLE nephritis; smoke poisoning; spinal cord injury; spontaneous abortion; stroke; systemic inflammatory response to sepsis; systemic lupus erythematosus (SLE); systemic lupus erythematosus-associated vasculitis; Takayasu's disease; burns; thrombotic thrombocytopenic purpura (TTP); traumatic brain injury; type 1 diabetes; typical hemolytic uremic syndrome; uveitis; vasculitis; vasculitis associated with rheumatoid arthritis; venous gas embolism (VGE); and xenograft rejection.

21. 21. The pharmaceutical formulation of any one of claims 1 to 20, wherein the subject has already received a first therapeutic agent other than pozelimb prior to administration of the pharmaceutical formulation.

22. 22. The pharmaceutical formulation of claim 21, wherein the first therapeutic agent is tesidolumab, crovalimab, eculizumab, or ravulizumab.

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