High concentration of anti-C5 antibody complex

Abstract

We offer a formulation containing high-concentration anti-C5 antibodies. [Solution] This disclosure relates to a stable aqueous solution containing a high concentration of an anti-C5 antibody (e.g., ravulizumab), and a method for preparing the solution. This disclosure also provides a method for treating or preventing complement-related disorders, such as paroxysmal nocturnal hemoglobinuria (PNH) and thrombotic microangiopathy (TMA), including atypical hemolytic uremic syndrome (aHUS), using the solution. A further feature is a therapeutic kit containing one or more of the solutions.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits of U.S. Provisional Patent Application No. 62 / 932,674 filed 8 November 2019 and U.S. Provisional Patent Application No. 62 / 992,319 filed 20 March 2020, both of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Therapeutic antibodies must be formulated to be suitable for administration to patients and to maintain their stability during storage and subsequent use. For example, therapeutic antibodies in aqueous solutions tend to decompose, aggregate, or undergo undesirable chemical modifications unless the solution is properly formulated. The stability of antibodies in liquid formulations depends on the type and amount of excipients used in the formulation, as well as their relative ratios. Furthermore, viscosity and visual quality must also be considered when preparing aqueous antibody formulations. Therefore, when formulating therapeutic antibodies, considerable care must be taken to devise formulations that maintain stability, contain appropriate concentrations of antibodies, have suitable viscosity, and can be conveniently administered to patients.

[0003] Anti-C5 antibodies are known in the art. However, there remains a need in the art for novel pharmaceutical formulations containing anti-C5 antibodies that are sufficiently stable and suitable for administration to patients, for example, those suffering from complement-related disorders such as PNH or aHUS, who are at substantial risk of pathological condition and death. Therefore, the object of the present invention is to provide improved formulations and methods for treating patients suffering from complement-related disorders. [Overview of the project] [Means for solving the problem]

[0004] This specification provides stable, high-concentration aqueous solutions of anti-C5 antibodies, such as ULTOMIRIS® (labulizumab) (also known as "antibody BNJ441" and "ALXN1210"), and methods for producing and using formulations. In particular, this disclosure provides formulation conditions suitable for maintaining the physical and functional stability of labulizumab in high-concentration solutions for a considerable period of time.

[0005] The advantages of a stable, high-concentration anti-C5 antibody aqueous solution (e.g., ravulizumab) are numerous. Firstly, in therapeutic applications where it is necessary to administer a small amount of antibody to the patient, the therapeutic effect often depends on the amount of antibody that can be administered in that small amount.

[0006] Furthermore, the method for producing the aqueous solutions described herein does not require a freeze-drying step, nor does it require a high-concentration aqueous solution that needs to be reconstituted from the characteristic freeze-dried material. The high-concentration antibody solution characterized by the present invention offers several advantages over reconstituted freeze-dried antibody formulations. Firstly, physicians must aseptically reconstitute freeze-dried antibody solutions on-site, which increases the possibility of microbial contamination of the solution before administration. Furthermore, reconstitution requires considerable care to ensure that all solid components contained in the reconstitution container are properly dissolved in the solution. Thus, the high-concentration aqueous solutions provided herein provide physicians, caregivers, and / or patients with a rapid, easy, safe, and efficient means of delivering therapeutic antibodies to patients who require them.

[0007] Other advantages of high-concentration formulations include, for example, reduced manufacturing costs due to less bulk storage space and / or fewer product refills. In addition, the ability to produce products with longer shelf lives ultimately reduces the number of production steps required, thus lowering costs for both manufacturers and consumers of high-concentration therapeutic antibodies.

[0008] Exemplary anti-C5 antibodies are ravulizumab, or its antigen-binding fragments and variants, comprising heavy and light chains having the sequences shown in SEQ ID NOs. 14 and 11, respectively. In other embodiments, the antibody comprises the heavy and light chain complementarity-determining regions (CDRs) or variable regions (VRs) of ravulizumab. Thus, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable (VH) region of ravulizumab having the sequence shown in SEQ ID NOs. 12, and the CDR1, CDR2, and CDR3 domains of the light chain variable (VL) region of ravulizumab having the sequence shown in SEQ ID NOs. 8. In another embodiment, the antibody comprises the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively.

[0009] In another embodiment, the antibody includes VH and VL regions having the amino acid sequences described in SEQ ID NO: 12 and SEQ ID NO: 8, respectively.

[0010] In another embodiment, the antibody includes a heavy chain constant region as described in SEQ ID NO: 13.

[0011] In another embodiment, the antibody comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), where the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434 in the natural human IgG Fc constant region, respectively, in EU numbering.

[0012] In another embodiment, the antibody comprises the CDR1, CDR2, and CDR3 heavy chain sequences described in SEQ ID NOs. 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences described in SEQ ID NOs. 4, 5, and 6, respectively, and a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), where the variant human Fc CH3 constant region includes Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434 in the natural human IgG Fc constant region, respectively, with EU numbering.

[0013] In another embodiment, the antibody competes with the antibody described above for binding to the same epitope on C5 and / or binds to the same epitope on C5. In another embodiment, the antibody has at least about 90% variable region amino acid sequence identity with the antibody described above (e.g., at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% variable region identity with SEQ ID NO: 12 and / or SEQ ID NO: 8).

[0014] In another embodiment, the antibody is 0.1 nM ≤ K at pH 7.4 and 25°C. D affinity dissociation constant (K) in the range ≤ 1 nM D ) binds to human C5. In another embodiment, the antibody is at pH 6.0 and 25°C, K D It binds to human C5 at a concentration of ≥10 nM. In yet another embodiment, the antibody [(K of the antibody or its antigen-binding fragment against human C5 at pH 6.0 and 25°C) D ) / (K of antibody against human C5 or its antigen-binding fragment at pH 7.4 and 25°C) D )] is greater than 25.

[0015] In one embodiment, a stable aqueous solution is provided (e.g., a sterile solution). In another embodiment, the stable aqueous solution comprises one or more additional agents (e.g., stabilizers, buffers, surfactants, and / or preservatives). For example, in one embodiment, the stable aqueous solution comprises a stabilizer. Exemplary stabilizers include, but are not limited to, polyols, sugars (e.g., sucrose or trehalose), amino acids (e.g., arginine), amines, and salting-out salts. In one embodiment, the solution comprises at least one stabilizer at a concentration of 2% to 10%. In another embodiment, the solution comprises at least one stabilizer at a concentration of 10 mM to 50 mM. In another embodiment, the stabilizer is present in the solution at a concentration of at least 20 mM or equal to 20 mM. In another embodiment, the stabilizer is present in the solution at a concentration of at least 25 mM or equal to 25 mM. In another embodiment, the stabilizer is present in the solution at a concentration of at least 50 mM or equal to 50 mM. In another embodiment, the solution comprises 5% sucrose. In another embodiment, the solution contains about 30 mg / mL to 60 mg / mL of sucrose (for example, about 30 mg / mL, 31 mg / mL, 32 mg / mL, 33 mg / mL, 34 mg / mL, 35 mg / mL, 36 mg / mL, 37 mg / mL, 38 mg / mL, 39 mg / mL, 40 mg / mL, 41 mg / mL, 42 mg / mL, 43 mg / mL, 44 mg / mL, 45 mg / mL, 46 mg / mL, 47 mg / mL, 48 mg / mL, 49 mg / mL, 50 mg / mL, 51 mg / mL, 52 mg / mL, 53 mg / mL, 54 mg / mL, 55 mg / mL, 56 mg / mL, 57 mg / mL, 58 mg / mL, 59 mg / mL, or 60 mg / mL). In a particular embodiment, the solution contains 50 mg / mL of sucrose. In another embodiment, the solution contains 20-30 mM arginine (e.g., L-arginine). For example, in one embodiment, the solution contains 20 mM arginine, 21 mM arginine, 22 mM arginine, 23 mM arginine, 24 mM arginine, 25 mM arginine, 26 mM arginine, 27 mM arginine, 28 mM arginine, 29 mM arginine, or 30 mM arginine. In a particular embodiment, the solution contains 25 mM L-arginine.

[0016] In another embodiment, the solution comprises at least one buffer. Non-limiting examples of typical buffers that can be included in the washing solution include Tris (tris(hydroxymethyl)methylamine), bis-Tris, bis-Tris propane, histidine, triethanolamine, diethanolamine, formate, acetate, MES (2-(N-morpholino)ethanesulfonic acid), phosphate, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), citrate, MOPS (3-(N-morpholino)propanesulfonic acid), TAPS (3-{[tris(hydroxymethyl)methyl]amino}propanesulfonic acid), Bicine (N,N-bis(2-hydroxyethyl)glycine), tricine (N-tris(hydroxymethyl)methylglycine), TES (2-{[tris(hydroxymethyl)methyl]amino}ethanesulfonic acid), PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid)), cacodylate (dimethylarsinic acid), SSC (sodium citrate saline), monobasic sodium phosphate, and dibasic sodium phosphate. In another embodiment, the buffer is an amino acid. The amino acid may be, for example, one selected from the group consisting of arginine (e.g., L-arginine), histidine (e.g., L-histidine), serine (e.g., L-serine), and glycine (e.g., L-glycine). In another embodiment, the solution comprises two or more buffers. In a particular embodiment, the buffer is monobasic sodium phosphate. In another particular embodiment, the buffer is dibasic sodium phosphate.

[0017] In another embodiment, the solution contains at least one buffer at a concentration of 10 mM to 300 mM. In another embodiment, the solution contains at least one buffer at a concentration of 10 mM to 200 mM. In another embodiment, the solution contains at least one buffer at a concentration of 10 mM to 100 mM. In another embodiment, the solution contains at least one buffer at a concentration of 10 mM to 50 mM. In another embodiment, the solution contains at least one buffer at a concentration of 20 mM to 50 mM. In another embodiment, the buffer is present in the solution at a concentration of at least 20 mM or equal to 20 mM. In another embodiment, the buffer is present in the solution at a concentration of at least 25 mM or equal to 25 mM. In another embodiment, the buffer is present in the solution at a concentration of at least 50 mM or equal to 50 mM. In a particular embodiment, the buffer is monobasic sodium phosphate at a concentration of about 33.1 mM. In another particular embodiment, the buffer is dibasic sodium phosphate at a concentration of about 16.5 mM.

[0018] In another embodiment, the solution contains a surfactant. In one embodiment, the surfactant in the formulation is a non-ionic surfactant. In certain embodiments, the surfactant in the formulation is a polyoxyethylene sorbitan fatty acid ester, such as polysorbate 20, 40, 60, 80, or a combination of one or more of these. In one embodiment, the surfactant in the formulation is polysorbate 80 (Tween 80). The concentration of the surfactant in the solution may be, for example, 0.001% or more and 0.02% or less. For example, the surfactant may be present in the formulation in an amount of about 0.001% to about 1%, or about 0.001% to about 0.5%, or about 0.01% to about 0.2%. In one embodiment, the aqueous solution contains the surfactant at a concentration of at least, or about, 0.001% (e.g., at least, or about, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, or 0.5% or more). In another embodiment, the aqueous solution contains a pharmaceutically acceptable surfactant at 0.2% or less (e.g., 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13, 0.12, 0.11, 0.10, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, or 0.001% or less). In certain embodiments, the surfactant is 0.05 w / v% polysorbate 80.

[0019] In another embodiment, the solution contains water for injection.

[0020] In another embodiment, the pH is 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, or 7.9. In another embodiment, the pH of the solution is 7.0 to 7.4. In another embodiment, the pH of the solution is 7.2 to 7.8. In another embodiment, the pH of the solution is 7.2 to 7.6. In a particular embodiment, the pH of the solution is 7.4.

[0021] In another embodiment, the solution is in any container suitable for storing drugs and other therapeutic compositions. For example, the solution may be contained in a sealed and sterile vial, ampoule, syringe, cartridge, or plastic or glass container of a predetermined volume. Various types of vials, including, for example, glass or plastic vials, can be used to contain the solution of the present invention. In one embodiment, the vial is a 3 mL single-use vial. In another embodiment, the vial is a 3 mL single-use vial containing 300 mg of ravulizumab. In another embodiment, the vial is an 11 mL single-use vial. In another embodiment, the vial is an 11 mL single-use vial containing 1,100 mg of ravulizumab.

[0022] In another embodiment, the solution is diluted before administration. For example, in one embodiment, the solution is diluted with physiological saline (0.9% sodium chloride) before administration. In another embodiment, the solution is diluted to a concentration of 50 ± 15 mg / mL of ravulizumab (e.g., 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65 mg / mL of ravulizumab) before administration. In a specific embodiment, the solution is diluted to a concentration of approximately 50 mg / mL of ravulizumab before administration. In another embodiment, the solution is stable for up to 24 hours at 2°C to 8°C (36°F to 46°F) after dilution. In another embodiment, the amount of saline solution (e.g., sodium chloride) may be selectively reduced, for example, when administering the solution to a patient on a sodium-restricted (e.g., low-sodium) diet.

[0023] In one embodiment, the stable aqueous solution contains an anti-C5 antibody, such as labulizumab, and seven or fewer other agents. In another embodiment, the stable aqueous solution contains an anti-C5 antibody, such as labulizumab, and six or fewer other agents. In yet another embodiment, the stable aqueous solution contains an anti-C5 antibody, such as labulizumab, and five or fewer other agents. In yet another embodiment, the stable aqueous solution contains an anti-C5 antibody, such as labulizumab, and four or fewer other agents. In yet another embodiment, the stable aqueous solution contains an anti-C5 antibody, such as labulizumab, and three or fewer other agents. In yet another embodiment, the stable aqueous solution contains an anti-C5 antibody, such as labulizumab, and two or fewer other agents. In yet another embodiment, the stable aqueous solution contains an anti-C5 antibody, such as labulizumab, and one or fewer other agents.

[0024] In another embodiment, a stable aqueous solution is labulizumab at a concentration of 100±20 (e.g., 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, or 120) mg / mL, 50±15 (e.g., 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, A solution comprising or consisting of 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65) mM phosphate buffer, 5 ± 3 (e.g., 2, 3, 4, 5, 6, 7, or 8)% sucrose, and 25 ± 10 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) mM arginine, where the solution has a pH of 7.4 ± 0.5 (e.g., 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, or 7.9).

[0025] In one embodiment, a stable aqueous solution comprises: (a) ravulizumab at a concentration of about 100 mg / mL, (b) sodium phosphate at about 50 mM, (c) polysorbate 80 at about 0.05 w / v%, (d) L-arginine at about 25 mM, (e) sucrose at about 50 mg / mL, and (f) water for injection, wherein the solution has a pH of about 7.4 and is contained in a 3 mL single-use vial containing 300 mg of ravulizumab.

[0026] In another embodiment, the stable aqueous solution consists of: (a) ravulizumab at a concentration of about 100 mg / mL, (b) sodium phosphate at about 50 mM, (c) polysorbate 80 at about 0.05 w / v%, (d) L-arginine at about 25 mM, (e) sucrose at about 50 mg / mL, and (f) water for injection, where the solution has a pH of about 7.4 and is contained in a 3 mL single-use vial containing 300 mg of ravulizumab.

[0027] In one embodiment, a stable aqueous solution consists of: (a) labulizumab at a concentration of 100 mg / mL, (b) about 50 mM sodium phosphate, (c) 0.05 w / v% polysorbate 80, (d) 25 mM L-arginine, (e) 50 mg / mL sucrose, and (f) water for injection, where the solution has a pH of about 7.4 and is contained in a 3 mL single-use vial containing 300 mg of labulizumab.

[0028] In one embodiment, a stable aqueous solution comprises: (a) ravulizumab at a concentration of about 100 mg / mL, (b) sodium phosphate at about 50 mM, (c) polysorbate 80 at about 0.05 w / v%, (d) L-arginine at about 25 mM, (e) sucrose at about 5 w / v%, and (f) water for injection, wherein the solution has a pH of about 7.4 and is contained in a 3 mL single-use vial containing 300 mg of ravulizumab.

[0029] In another embodiment, the stable aqueous solution consists of: (a) ravulizumab at a concentration of about 100 mg / mL, (b) sodium phosphate at about 50 mM, (c) polysorbate 80 at about 0.05 w / v%, (d) L-arginine at about 25 mM, (e) sucrose at about 5 w / v%, and (f) water for injection, where the solution has a pH of about 7.4 and is contained in a 3 mL single-use vial containing 300 mg of ravulizumab.

[0030] In one embodiment, a stable aqueous solution consists of: (a) labulizumab at a concentration of 100 mg / mL, (b) about 50 mM sodium phosphate, (c) 0.05 w / v% polysorbate 80, (d) 25 mM L-arginine, (e) 5 w / v% sucrose, and (f) water for injection, wherein the solution has a pH of about 7.4 and is contained in a 3 mL single-use vial containing 300 mg of labulizumab.

[0031] In another embodiment, the stable aqueous solution comprises: (a) ravulizumab at a concentration of about 100 mg / mL, (b) monobasic sodium phosphate at about 33.1 mM, (c) dibasic sodium phosphate at about 16.5 mM, (d) polysorbate 80 at about 0.05 w / v%, (f) L-arginine at about 25 mM, (g) sucrose at about 5 w / v%, and (h) water for injection, wherein the solution has a pH of about 7.4 and is contained in a 3 mL single-use vial containing 300 mg of ravulizumab.

[0032] In another embodiment, the stable aqueous solution consists of: (a) ravulizumab at a concentration of about 100 mg / mL, (b) monobasic sodium phosphate at about 33.1 mM, (c) dibasic sodium phosphate at about 16.5 mM, (d) polysorbate 80 at about 0.05 w / v%, (f) L-arginine at about 25 mM, (g) sucrose at about 5 w / v%, and (h) water for injection, where the solution has a pH of about 7.4 and is contained in a 3 mL single-use vial containing 300 mg of ravulizumab.

[0033] In another embodiment, the stable aqueous solution consists of: (a) labulizumab at a concentration of 100 mg / mL, (b) 33.1 mM monobasic sodium phosphate, (c) 16.5 mM dibasic sodium phosphate, (d) 0.05 w / v% polysorbate 80, (f) 25 mM L-arginine, (g) 5 w / v% sucrose, and (h) water for injection, where the solution has a pH of 7.4 and is contained in a 3 mL single-use vial containing 300 mg of labulizumab.

[0034] In another embodiment, the stable aqueous solution comprises: (a) ravulizumab at a concentration of about 100 mg / mL, (b) monobasic sodium phosphate at about 33.1 mM, (c) dibasic sodium phosphate at about 16.5 mM, (d) polysorbate 80 at about 0.05 w / v%, (f) L-arginine at about 25 mM, (g) sucrose at about 50 mg / mL, and (h) water for injection, where the solution has a pH of about 7.4 and is contained in a 3 mL single-use vial containing 300 mg of ravulizumab.

[0035] In another embodiment, the stable aqueous solution consists of: (a) ravulizumab at a concentration of about 100 mg / mL, (b) monobasic sodium phosphate at about 33.1 mM, (c) dibasic sodium phosphate at about 16.5 mM, (d) polysorbate 80 at about 0.05 w / v%, (f) L-arginine at about 25 mM, (g) sucrose at about 50 mg / mL, and (h) water for injection, where the solution has a pH of about 7.4 and is contained in a 3 mL single-use vial containing 300 mg of ravulizumab.

[0036] In another embodiment, the stable aqueous solution consists of: (a) labulizumab at a concentration of 100 mg / mL, (b) 33.1 mM monobasic sodium phosphate, (c) 16.5 mM dibasic sodium phosphate, (d) 0.05 w / v% polysorbate 80, (f) 25 mM L-arginine, (g) 50 mg / mL sucrose, and (h) water for injection, where the solution has a pH of 7.4 and is contained in a 3 mL single-use vial containing 300 mg of labulizumab.

[0037] In another embodiment, the stable aqueous solution comprises: (a) ravulizumab at a concentration of about 100 mg / mL, (b) sodium phosphate at about 50 mM, (c) polysorbate 80 at about 0.05 w / v%, (d) L-arginine at about 25 mM, (e) sucrose at about 50 mg / mL, and (f) water for injection, where the solution has a pH of about 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of ravulizumab.

[0038] In another embodiment, the stable aqueous solution consists of: (a) ravulizumab at a concentration of about 100 mg / mL, (b) sodium phosphate at about 50 mM, (c) polysorbate 80 at about 0.05 w / v%, (d) L-arginine at about 25 mM, (e) sucrose at about 50 mg / mL, and (f) water for injection, where the solution has a pH of about 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of ravulizumab.

[0039] In another embodiment, the stable aqueous solution consists of: (a) labulizumab at a concentration of 100 mg / mL, (b) about 50 mM sodium phosphate, (c) 0.05 w / v% polysorbate 80, (d) 25 mM L-arginine, (e) 50 mg / mL sucrose, and (f) water for injection, where the solution has a pH of about 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of labulizumab.

[0040] In another embodiment, the stable aqueous solution comprises: (a) ravulizumab at a concentration of about 100 mg / mL, (b) sodium phosphate at about 50 mM, (c) polysorbate 80 at about 0.05 w / v%, (d) L-arginine at about 25 mM, (e) sucrose at about 5 w / v%, and (f) water for injection, where the solution has a pH of about 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of ravulizumab.

[0041] In another embodiment, the stable aqueous solution consists of: (a) ravulizumab at a concentration of about 100 mg / mL, (b) sodium phosphate at about 50 mM, (c) polysorbate 80 at about 0.05 w / v%, (d) L-arginine at about 25 mM, (e) sucrose at about 5 w / v%, and (f) water for injection, where the solution has a pH of about 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of ravulizumab.

[0042] In another embodiment, the stable aqueous solution consists of: (a) labulizumab at a concentration of 100 mg / mL, (b) about 50 mM sodium phosphate, (c) 0.05 w / v% polysorbate 80, (d) 25 mM L-arginine, (e) 5 w / v% sucrose, and (f) water for injection, where the solution has a pH of about 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of labulizumab.

[0043] In another embodiment, the stable aqueous solution comprises: (a) ravulizumab at a concentration of about 100 mg / mL, (b) monobasic sodium phosphate at about 33.1 mM, (c) dibasic sodium phosphate at about 16.5 mM, (d) polysorbate 80 at about 0.05 w / v%, (f) L-arginine at about 25 mM, (g) sucrose at about 5 w / v%, and (h) water for injection, where the solution has a pH of about 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of ravulizumab.

[0044] In another embodiment, the stable aqueous solution consists of: (a) ravulizumab at a concentration of about 100 mg / mL, (b) monobasic sodium phosphate at about 33.1 mM, (c) dibasic sodium phosphate at about 16.5 mM, (d) polysorbate 80 at about 0.05 w / v%, (f) L-arginine at about 25 mM, (g) sucrose at about 5 w / v%, and (h) water for injection, where the solution has a pH of about 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of ravulizumab.

[0045] In another embodiment, the stable aqueous solution consists of: (a) labulizumab at a concentration of 100 mg / mL, (b) 33.1 mM monobasic sodium phosphate, (c) 16.5 mM dibasic sodium phosphate, (d) 0.05 w / v% polysorbate 80, (f) 25 mM L-arginine, (g) 5 w / v% sucrose, and (h) water for injection, where the solution has a pH of 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of labulizumab.

[0046] In another embodiment, the stable aqueous solution comprises: (a) ravulizumab at a concentration of about 100 mg / mL, (b) monobasic sodium phosphate at about 33.1 mM, (c) dibasic sodium phosphate at about 16.5 mM, (d) polysorbate 80 at about 0.05 w / v%, (f) L-arginine at about 25 mM, (g) sucrose at about 50 mg / mL, and (h) water for injection, where the solution has a pH of about 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of ravulizumab.

[0047] In another embodiment, the stable aqueous solution consists of: (a) ravulizumab at a concentration of about 100 mg / mL, (b) monobasic sodium phosphate at about 33.1 mM, (c) dibasic sodium phosphate at about 16.5 mM, (d) polysorbate 80 at about 0.05 w / v%, (f) L-arginine at about 25 mM, (g) sucrose at about 50 mg / mL, and (h) water for injection, where the solution has a pH of about 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of ravulizumab.

[0048] In another embodiment, the stable aqueous solution consists of: (a) labulizumab at a concentration of 100 mg / mL, (b) 33.1 mM monobasic sodium phosphate, (c) 16.5 mM dibasic sodium phosphate, (d) 0.05 w / v% polysorbate 80, (f) 25 mM L-arginine, (g) 50 mg / mL sucrose, and (h) water for injection, where the solution has a pH of 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of labulizumab.

[0049] In another embodiment, the stable aqueous solution is sterile. In another embodiment, the solution is a sterile, translucent, clear to yellowish preservative-free solution. In another embodiment, the solution has a shelf life of 18 months.

[0050] The solutions described herein may be formulated for any preferred method of administration. In one embodiment, the solution is formulated for parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection). In a particular embodiment, the solution is formulated for subcutaneous administration. For example, in one embodiment, a stable aqueous solution contains 100 mg / mL of anti-C5 antibody and is formulated for subcutaneous administration. In another particular embodiment, the solution is formulated for intravenous administration (e.g., via intravenous infusion). For example, in one embodiment, a stable aqueous solution contains 100 mg / mL of ravulizumab and is formulated for intravenous infusion.

[0051] In any one embodiment of the solutions described herein, the anti-C5 antibody (e.g., ravulizumab) maintains at least 95% (e.g., at least 96, 97, 98, or 99%) monomericity, as determined by SEC-HPLC (e.g., gel permeation HPLC), for at least 6 months while stored at 2°C to 8°C. In another embodiment, the anti-C5 antibody maintains at least 95% (e.g., at least 96, 97, 98, or 99%) monomericity, as determined by SEC-HPLC, for at least 9 months while stored at 2°C to 8°C. In yet another embodiment, the anti-C5 antibody maintains at least 95% (e.g., at least 96, 97, 98, or 99%) monomericity, as determined by SEC-HPLC, for at least 1 year while stored at 2°C to 8°C. In yet another embodiment, the anti-C5 antibody maintains at least 95% (e.g., at least 96, 97, 98, or 99%) monomericity, as determined by SEC-HPLC, for at least 18 months while stored at 2°C to 8°C. In another embodiment, the anti-C5 antibody maintains at least 95% (e.g., at least 96, 97, 98, or 99%) monomericity, as determined by SEC-HPLC, for at least two years while stored at 2°C to 8°C.

[0052] In any other embodiment of the solutions described herein, less than 5% of the anti-C5 antibody (e.g., ravulizumab) in the solution agglutinates, as determined by SEC-HPLC (e.g., gel permeation HPLC). In another embodiment, less than 4% of the anti-C5 antibody in the solution agglutinates, as determined by SEC-HPLC. In another embodiment, less than 3% of the anti-C5 antibody in the solution agglutinates, as determined by SEC-HPLC. In another embodiment, less than 2% of the anti-C5 antibody in the solution agglutinates, as determined by SEC-HPLC. In another embodiment, less than 1% of the anti-C5 antibody in the solution agglutinates, as determined by SEC-HPLC.

[0053] In any other embodiment of the solutions described herein, an anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99)% of its C5-binding activity for at least 6 months during storage at 2°C to 8°C, compared to a reference anti-C5 antibody corresponding to the anti-C5 antibody before storage. In another embodiment, an anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99)% of its C5-binding activity for at least 9 months during storage at 2°C to 8°C, compared to a reference anti-C5 antibody corresponding to the anti-C5 antibody before storage. In another embodiment, an anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99)% of its C5-binding activity for at least 1 year while stored at 2°C to 8°C, compared to a reference anti-C5 antibody corresponding to the anti-C5 antibody before storage. In another embodiment, an anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99)% of its C5-binding activity for at least 18 months while stored at 2°C to 8°C, compared to a reference anti-C5 antibody corresponding to the anti-C5 antibody before storage. In another embodiment, an anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) of its C5-binding activity for at least two years during storage at 2°C to 8°C, compared to a reference anti-C5 antibody corresponding to the anti-C5 antibody before storage.In another embodiment, compared to a reference anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) of its C5-binding activity for at least 3 years during storage at 2°C to 8°C.

[0054] In any other embodiment of the solutions described herein, an anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) of its hemolytic inhibitory ability for at least 9 months during storage at 2°C to 8°C, compared to a reference anti-C5 antibody corresponding to the anti-C5 antibody before storage. In any other embodiment of the solutions described herein, an anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) of its hemolytic inhibitory ability for at least 6 months during storage at 2°C to 8°C, compared to a reference anti-C5 antibody corresponding to the anti-C5 antibody before storage. In any other embodiment of the solutions described herein, an anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) of its ability to inhibit hemolysis for at least one year during storage at 2°C to 8°C, compared to a reference anti-C5 antibody corresponding to the anti-C5 antibody before storage. In any other embodiment of the solutions described herein, an anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) of its hemolytic inhibitory ability for at least 18 months during storage at 2°C to 8°C, compared to a reference anti-C5 antibody corresponding to the anti-C5 antibody before storage. In any other embodiment of the solutions described herein, an anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) of its hemolytic inhibitory ability for at least two years during storage at 2°C to 8°C, compared to a reference anti-C5 antibody corresponding to the anti-C5 antibody before storage.In any other embodiment of the solutions described herein, an anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) of its ability to inhibit hemolysis for at least 3 years during storage at 2°C to 8°C, compared to a reference anti-C5 antibody corresponding to the anti-C5 antibody before storage.

[0055] Also provided is a method for treating a human patient suffering from a complement-related disorder, comprising administering to the patient (for example, via intravenous infusion) an amount of a stable aqueous solution described herein that is effective in treating the complement-related disorder. Examples of complement-related disorders include rheumatoid arthritis, antiphospholipid syndrome, lupus nephritis, ischemia-reperfusion injury, thrombotic microangiopathy (TMA), atypical hemolytic uremic syndrome (aHUS), typical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria (PNH), dense deposit disease, neuromyelitis optica, multifocal motor neuropathy, multiple sclerosis, macular degeneration, HELLP syndrome, spontaneous miscarriage, thrombotic thrombocytopenic purpura, microimmune vasculitis, epidermolysis bullosa, recurrent miscarriage, traumatic brain injury, myocarditis, cerebrovascular disease, peripheral vascular disease, renal vascular disease, mesenteric / intestinal vascular disease, vasculitis, Henoch-Schönlein purpura nephritis, and systemic lupus-associated vasculitis. Examples of complement-related disorders include, but are not limited to, rheumatoid arthritis-associated vasculitis, immune complex vasculitis, Takayasu's arteritis, dilated cardiomyopathy, diabetic vasculopathy, Kawasaki disease, venous gas embolism, restenosis after stent placement, rotational atherectomy, percutaneous transcatheter coronary angioplasty, myasthenia gravis, cold agglutinin disease, dermatomyositis, paroxysmal cold hemoglobinuria, antiphospholipid syndrome, Graves' disease, atherosclerosis, Alzheimer's disease, systemic inflammatory response sepsis, septic shock, spinal cord injury, glomerulonephritis, graft rejection, Hashimoto's thyroiditis, type 1 diabetes mellitus, psoriasis, pemphigus, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Goodpasture syndrome, Dego's disease, and fulminant antiphospholipid syndrome. In certain embodiments, the complement-related disorder is aHUS. In other specific embodiments, the complement-related disorder is TMA. In other specific embodiments, the complement-related disorder is PNH.

[0056] In one embodiment, a method for treating a human patient is provided, the method comprising administering a stable aqueous solution to the patient based on the patient's body weight. For example, in one embodiment, a method for treating a human patient suffering from PNH is provided, the method comprising administering a stable aqueous solution to the patient (e.g., via intravenous infusion), wherein the stable aqueous solution has a pH of about 7.4 and comprises or consists of ravulizumab at a concentration of about 100 mg / mL, monobasic sodium phosphate at about 33.1 mM, dibasic sodium phosphate at about 16.5 mM, polysorbate 80 at about 0.05 w / v%, L-arginine at about 25 mM, sucrose at about 50 mg / mL, and water for injection, wherein the stable aqueous solution is (a) On the first day, For patients weighing ≥40kg to <60kg, 2,400mg. For patients weighing ≥60kg to <100kg, 2,700mg, or For patients weighing ≥100 kg, a dose of 3,000 mg; and (b) On day 15, and every 8 weeks thereafter, For patients weighing ≥40kg to <60kg, 3,000mg. For patients weighing ≥60kg to <100kg, 3,300mg, or It is administered to human patients at a dose of 3,600 mg for patients weighing ≥100 kg.

[0057] In one embodiment, a stable aqueous solution is administered to human patients weighing ≥40kg to <60kg at a dose of 2,400mg on day 1, and then at a dose of 3,000mg on day 15 and every 8 weeks thereafter. In another embodiment, the aqueous solution is administered to human patients weighing ≥60kg to <100kg at a dose of 2,700mg on day 1, and then at a dose of 3,300mg on day 15 and every 8 weeks thereafter. In yet another embodiment, the stable aqueous solution is administered to human patients weighing ≥100kg at a dose of 3,000mg on day 1, and then at a dose of 3,600mg on day 15 and every 8 weeks thereafter.

[0058] In another embodiment, a method is provided for treating a human patient suffering from aHUS, the method comprising administering a stable aqueous solution to the patient (e.g., via intravenous infusion), wherein the stable aqueous solution has a pH of about 7.4 and comprises or consists of ravulizumab at a concentration of about 100 mg / mL, monobasic sodium phosphate at about 33.1 mM, dibasic sodium phosphate at about 16.5 mM, polysorbate 80 at about 0.05 w / v%, L-arginine at about 25 mM, sucrose at about 50 mg / mL, and water for injection, wherein the stable aqueous solution is (b) On the first day, For patients weighing ≥5kg to <10kg, 600mg. For patients weighing ≥10kg to <20kg, 600mg. For patients weighing ≥20kg to <30kg, 900mg. For patients weighing ≥30kg to <40kg, 1,200mg. For patients weighing ≥40kg to <60kg, 2,400mg. For patients weighing ≥60kg to <100kg, 2,700mg, or For patients weighing ≥100 kg, a dose of 3,000 mg; and (b) On the 15th day, and every 4 or 8 weeks thereafter, For patients weighing ≥5kg to <10kg, 300mg. For patients weighing ≥10kg to <20kg, 600mg. For patients weighing ≥20kg to <30kg, 2,100mg. For patients weighing ≥30kg to <40kg, 2,700mg. For patients weighing ≥40kg to <60kg, 3,000mg. For patients weighing ≥60kg to <100kg, 3,300mg, or It is administered to human patients at a dose of 3,600 mg for patients weighing ≥100 kg.

[0059] In one embodiment, a stable aqueous solution is administered to human patients weighing ≥5kg to <10kg at a dose of 600mg on day 1, and then at a dose of 300mg on day 15 and every four weeks thereafter. In another embodiment, a stable aqueous solution is administered to human patients weighing ≥10kg to <20kg at a dose of 600mg on day 1, and then at a dose of 600mg on day 15 and every four weeks thereafter. In yet another embodiment, a stable aqueous solution is administered to human patients weighing ≥20kg to <30kg at a dose of 900mg on day 1, and then at a dose of 2,100mg on day 15 and every eight weeks thereafter. In yet another embodiment, a stable aqueous solution is administered to human patients weighing ≥30kg to <40kg at a dose of 1,200mg on day 1, and then at a dose of 2,700mg on day 15 and every eight weeks thereafter. In another embodiment, the stable aqueous solution is administered to human patients weighing ≥40 kg to <60 kg at a dose of 2,400 mg on day 1, and at a dose of 3,000 mg on day 15 and every 8 weeks thereafter. In another embodiment, the stable aqueous solution is administered to human patients weighing ≥60 kg to <100 kg at a dose of 2,700 mg on day 1, and at a dose of 3,300 mg on day 15 and every 8 weeks thereafter. In another embodiment, the stable aqueous solution is administered to human patients weighing ≥100 kg at a dose of 3,000 mg on day 1, and at a dose of 3,600 mg on day 15 and every 8 weeks thereafter. In another embodiment, the stable aqueous solution is supplied in a 3 mL single-use vial containing 300 mg of ravulizumab. In another embodiment, the stable aqueous solution is supplied in an 11 mL single-use vial containing 1,100 mg of ravulizumab.

[0060] In other embodiments, a stable aqueous solution is administered in a fixed, uniform dose regardless of the patient's body weight. For example, the stable aqueous solution may be administered in fixed doses of 1000, 1400, 1600, 1800, 2000, 2400, 3000, or 5400 mg, regardless of the patient's body weight. In specific embodiments, the administration regimen is adjusted to produce the optimal desired response (e.g., an effective response).

[0061] In another embodiment, the stable aqueous solution is administered to a human patient at a dose of 3000 mg during the induction phase. In another embodiment, the stable aqueous solution is administered to a human patient once at a dose of 3000 mg during the induction phase. In another embodiment, the stable aqueous solution is administered to a human patient at a dose of 5400 mg during the maintenance phase. In another embodiment, the stable aqueous solution is administered to a human patient three times at a dose of 5400 mg during the maintenance phase. For example, an anti-C5 antibody, or its antigen-binding fragment, is administered at a dose of 5400 mg on day 29 of the administration cycle, and then every 84 days (or 12 weeks) thereafter during the maintenance phase, i.e., on days 113 and 197 of the administration cycle. In another embodiment, the stable aqueous solution is administered to a human patient at a dose of (a) 3,000 mg on day 1, (b) 5,400 mg four weeks later, and then (c) 5,400 mg every 84 days (or 12 weeks) thereafter. In another embodiment, the stable aqueous solution is administered to human patients in doses of (a) 3,000 mg on day 1 of the induction cycle, and (b) 5,400 mg on day 29 of the maintenance cycle, and subsequently every 84 days (or 12 weeks) thereafter. In another embodiment, the stable aqueous solution is administered to human patients in doses of (a) 3,000 mg on day 1 of the induction cycle, and (b) 5,400 mg on days 29, 113, and 197 of the maintenance cycle. In another embodiment, the stable aqueous solution contains ravulizumab at a concentration of 10 mg / mL. In another embodiment, the stable aqueous solution contains ravulizumab at a concentration of 100 mg / mL.

[0062] The infusion time and rate for administering 100 mg / mL of the stable aqueous solution described herein are significantly (e.g., at least 50%) lower compared to the infusion time and rate for equivalent lower doses (e.g., 10 mg / mL) of the solution. The infusion time and rate are adjustable by the clinician as needed. In one embodiment, the stable aqueous solution is administered to a human patient weighing ≥5 kg to <10 kg at a dose of 600 mg on day 1, with a minimum infusion time of 1.4 hours and a maximum infusion rate of 8 mL / hour. In another embodiment, the stable aqueous solution is administered to a human patient weighing ≥5 kg to <10 kg at a dose of 300 mg on day 15 and every 4 weeks thereafter, with a minimum infusion time of 0.8 hours and a maximum infusion rate of 8 mL / hour. In yet another embodiment, the stable aqueous solution is administered to a human patient weighing ≥10 kg to <20 kg at a dose of 600 mg on day 1, with a minimum infusion time of 0.8 hours and a maximum infusion rate of 16 mL / hour. In another embodiment, the stable aqueous solution is administered to human patients weighing ≥10kg to <20kg at a dose of 600mg on day 15 and every 4 weeks thereafter, with a minimum infusion time of 0.8 hours and a maximum infusion rate of 16mL / hour. In another embodiment, the stable aqueous solution is administered to human patients weighing ≥20kg to <30kg at a dose of 900mg on day 1 at a minimum infusion time of 0.6 hours and a maximum infusion rate of 30mL / hour. In another embodiment, the stable aqueous solution is administered to human patients weighing ≥20kg to <30kg at a dose of 2,100mg on day 15 and every 8 weeks thereafter, with a minimum infusion time of 1.3 hours and a maximum infusion rate of 33mL / hour. In another embodiment, the stable aqueous solution is administered to human patients weighing ≥30kg to <40kg at a dose of 1,200mg on day 1 at a minimum infusion time of 0.5 hours and a maximum infusion rate of 46mL / hour. In another embodiment, a stable aqueous solution is administered to human patients weighing ≥30kg to <40kg at a dose of 2,700mg on day 15 and every 8 weeks thereafter, with a minimum infusion time of 1.1 hours and a maximum infusion rate of 49mL / hour. In yet another embodiment, a stable aqueous solution is administered to human patients weighing ≥40kg to <60kg at a dose of 2,400mg on day 1 at a minimum infusion time of 0.8 hours and a maximum infusion rate of 64mL / hour.In another embodiment, the stable aqueous solution is administered to human patients weighing ≥40kg to <60kg at a dose of 3,000mg on day 15 and every 8 weeks thereafter, with a minimum infusion time of 0.9 hours and a maximum infusion rate of 65mL / hour. In another embodiment, the stable aqueous solution is administered to human patients weighing ≥60kg to <100kg at a dose of 2,700mg on day 1 at a minimum infusion time of 0.6 hours and a maximum infusion rate of 92mL / hour. In another embodiment, the stable aqueous solution is administered to human patients weighing ≥60kg to <100kg at a dose of 3,300mg on day 15 and every 8 weeks thereafter, with a minimum infusion time of 0.7 hours and a maximum infusion rate of 99mL / hour. In another embodiment, the stable aqueous solution is administered to human patients weighing ≥100kg at a dose of 3,000mg on day 1 at a minimum infusion time of 0.4 hours and a maximum infusion rate of 144mL / hour. In another embodiment, a stable aqueous solution is administered to human patients weighing ≥100 kg at a dose of 3,600 mg on day 15 and every 8 weeks thereafter, with a minimum infusion time of 0.5 hours and a maximum infusion rate of 144 mL / hour.

[0063] Further provided are kits containing a therapeutically effective amount of a stable aqueous solution as described herein, suitable for use in the methods described herein. In one embodiment, the kit comprises (i) any of the solutions described herein and (ii) instructions for use. In another embodiment, the kit comprises (i) any of the solutions described herein, (ii) physiological saline (0.9% sodium chloride), and (iii) instructions for use. In yet another embodiment, the kit comprises (i) a formulation containing or comprising ravulizumab at a concentration of about 100 mg / mL, about 33.1 mM monobasic sodium phosphate, about 16.5 mM dibasic sodium phosphate, about 0.05 w / v% polysorbate 80, about 25 mM L-arginine, and about 50 mg / mL sucrose, (ii) physiological saline (0.9% sodium chloride), and (iii) instructions for use. In yet another embodiment, the formulation is lyophilized. In another embodiment, the kit includes a 3 mL single-use vial containing 300 mg of ravulizumab. In yet another embodiment, the kit includes an 11 mL single-use vial containing 1,100 mg of ravulizumab.

[0064] In another embodiment, a method for producing a stable concentrated antibody solution is provided. In one embodiment, a method is provided for producing a stable aqueous solution comprising ravulizumab at a concentration of about 10 mg / mL or less, about 33.1 mM monobasic sodium phosphate, about 16.5 mM dibasic sodium phosphate, about 0.05 w / v% polysorbate 80, about 25 mM L-arginine, about 50 mg / mL sucrose, and water for injection, the method being: i) To provide a first aqueous solution containing approximately 10 mg / mL of ravulizumab, ii) Diafiltration of the first aqueous solution into a mixture of approximately 33.1 mM monobasic sodium phosphate, approximately 16.5 mM dibasic sodium phosphate, approximately 0.05 w / v% polysorbate 80, approximately 25 mM L-arginine, approximately 50 mg / mL sucrose, and water for injection at pH 7.4, thereby producing a second aqueous solution. iii) Concentrating the second aqueous solution to produce a stable aqueous solution containing ravulizumab at a concentration of approximately 100 mg / mL, monobasic sodium phosphate at approximately 33.1 mM, dibasic sodium phosphate at approximately 16.5 mM, polysorbate 80 at approximately 0.05 w / v%, L-arginine at approximately 25 mM, sucrose at approximately 50 mg / mL, and water for injection. The present invention provides, for example, the following items: (Item 1) (a) Rabulizumab at a concentration of approximately 100 mg / mL, (b) Approximately 50 mM sodium phosphate, (c) Approximately 0.05 w / v% polysorbate 80, (d) Approximately 25 mM L-arginine, (e) Sucrose in approximately 50 mg / mL, and (f) A stable aqueous solution containing water for injection, The solution is a stable aqueous solution having a pH of approximately 7.4 and contained in a 3 mL single-use vial containing 300 mg of ravulizumab. (Item 2) (a) Rabulizumab at a concentration of approximately 100 mg / mL, (b) Approximately 50 mM sodium phosphate, (c) Approximately 0.05 w / v% polysorbate 80, (d) Approximately 25 mM L-arginine, (e) Sucrose in approximately 50 mg / mL, and (f) A stable aqueous solution consisting of water for injection, The solution is a stable aqueous solution having a pH of approximately 7.4 and contained in a 3 mL single-use vial containing 300 mg of ravulizumab. (Item 3) (a) Rabulizumab at a concentration of approximately 100 mg / mL, (b) Approximately 33.1 mM monobasic sodium phosphate, (c) Approximately 16.5 mM dibasic sodium phosphate, (d) Approximately 0.05 w / v% polysorbate 80, (f) Approximately 25 mM L-arginine, (g) Approximately 50 mg / mL of sucrose, and (h) A stable aqueous solution containing water for injection, The solution is a stable aqueous solution having a pH of approximately 7.4 and contained in a 3 mL single-use vial containing 300 mg of ravulizumab. (Item 4) (a) Rabulizumab at a concentration of approximately 100 mg / mL, (b) Approximately 33.1 mM monobasic sodium phosphate, (c) Approximately 16.5 mM dibasic sodium phosphate, (d) Approximately 0.05 w / v% polysorbate 80, (f) Approximately 25 mM L-arginine, (g) Approximately 50 mg / mL of sucrose, and (h) A stable aqueous solution consisting of water for injection, The solution is a stable aqueous solution having a pH of approximately 7.4 and contained in a 3 mL single-use vial containing 300 mg of ravulizumab. (Item 5) (a) Rabulizumab at a concentration of 100 mg / mL, (b) 33.1 mM monobasic sodium phosphate, (c) 16.5 mM dibasic sodium phosphate, (d) 0.05 w / v% polysorbate 80, (f) 25 mM L-arginine, (g) 50 mg / mL of sucrose, and (h) A stable aqueous solution consisting of water for injection, The solution is a stable aqueous solution having a pH of 7.4 and contained in a 3 mL single-use vial containing 300 mg of ravulizumab. (Item 6) (a) Rabulizumab at a concentration of approximately 100 mg / mL, (b) Approximately 50 mM sodium phosphate, (c) Approximately 0.05 w / v% polysorbate 80, (d) Approximately 25 mM L-arginine, (e) Sucrose in approximately 50 mg / mL, and (f) A stable aqueous solution containing water for injection, The solution is a stable aqueous solution having a pH of approximately 7.4 and contained in an 11 mL single-use vial containing 1100 mg of ravulizumab. (Item 7) (a) Rabulizumab at a concentration of approximately 100 mg / mL, (b) Approximately 50 mM sodium phosphate, (c) Approximately 0.05 w / v% polysorbate 80, (d) Approximately 25 mM L-arginine, (e) Sucrose in approximately 50 mg / mL, and (f) A stable aqueous solution consisting of water for injection, The solution is a stable aqueous solution having a pH of approximately 7.4 and contained in an 11 mL single-use vial containing 1100 mg of ravulizumab. (Item 8) (a) Rabulizumab at a concentration of approximately 100 mg / mL, (b) Approximately 33.1 mM monobasic sodium phosphate, (c) Approximately 16.5 mM dibasic sodium phosphate, (d) Approximately 0.05 w / v% polysorbate 80, (f) Approximately 25 mM L-arginine, (g) Approximately 50 mg / mL of sucrose, and (h) A stable aqueous solution containing water for injection, The solution is a stable aqueous solution having a pH of approximately 7.4 and contained in an 11 mL single-use vial containing 1100 mg of ravulizumab. (Item 9) (a) Rabulizumab at a concentration of approximately 100 mg / mL, (b) Approximately 33.1 mM monobasic sodium phosphate, (c) Approximately 16.5 mM dibasic sodium phosphate, (d) Approximately 0.05 w / v% polysorbate 80, (f) Approximately 25 mM L-arginine, (g) Approximately 50 mg / mL of sucrose, and (h) A stable aqueous solution consisting of water for injection, The solution is a stable aqueous solution having a pH of approximately 7.4 and contained in an 11 mL single-use vial containing 1100 mg of ravulizumab. (Item 10) (a) Rabulizumab at a concentration of 100 mg / mL, (b) 33.1 mM monobasic sodium phosphate, (c) 16.5 mM dibasic sodium phosphate, (d) 0.05 w / v% polysorbate 80, (f) 25 mM L-arginine, (g) 50 mg / mL of sucrose, and (h) A stable aqueous solution consisting of water for injection, The solution is a stable aqueous solution having a pH of 7.4 and contained in an 11 mL single-use vial containing 1100 mg of ravulizumab. (Item 11) The aforementioned solution is a sterile, stable aqueous solution as described in any one of items 1 to 10. (Item 12) The aforementioned solution is a sterile, translucent, clear to yellowish, preservative-free solution, a stable aqueous solution as described in any one of items 1 to 11. (Item 13) The solution is a stable aqueous solution according to any one of items 1 to 12, having a shelf life of 18 months. (Item 14) Lablizumab is a stable aqueous solution according to any one of items 1 to 13, which maintains at least 97% monomericity as determined by SEC-HPLC for at least 6 months during storage at 2°C to 8°C. (Item 15) A stable aqueous solution according to any one of items 1 to 14, wherein less than 3% of the ravulizumab in the solution aggregates, as determined by SEC-HPLC. (Item 16) The aforementioned solution is a stable aqueous solution as described in any one of items 1 to 15, which is diluted to a concentration of 50 mg / mL of ravulizumab before administration. (Item 17) The aforementioned solution is a stable aqueous solution as described in item 16, which is diluted with physiological saline (0.9% sodium chloride) before administration. (Item 18) The aforementioned solution is a stable aqueous solution as described in item 16 or 17, which is stable for up to 24 hours at 2°C to 8°C (36°F to 46°F) after dilution. (Item 19) The aforementioned solution is a stable aqueous solution according to any one of items 1 to 18, which is suitable for administration by intravenous infusion. (Item 20) A method for treating a human patient suffering from a complement-related disorder, comprising administering to the patient a stable aqueous solution described in any one of items 1 to 19 in an amount effective for treating the complement-related disorder. (Item 21) The aforementioned complement-related diseases include rheumatoid arthritis, antiphospholipid syndrome, lupus nephritis, ischemia-reperfusion injury, thrombotic microangiopathy (TMA), atypical hemolytic uremic syndrome (aHUS), typical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria (PNH), dense deposit disease, neuromyelitis optica, multifocal motor neuropathy, multiple sclerosis, macular degeneration, and HELLP syndrome. Spontaneous miscarriage, thrombotic thrombocytopenic purpura, microimmune vasculitis, epidermolysis bullosa, recurrent miscarriage, traumatic brain injury, myocarditis, cerebrovascular disease, peripheral vascular disease, renal vascular disease, mesenteric / intestinal vascular disease, vasculitis, Henoch-Schönlein purpura nephritis, systemic lupus-associated vasculitis, rheumatoid arthritis-associated vasculitis, immune complex vasculitis, Takayasu's arteriovenous arthritis, dilated cardiomyopathy, diabetic vasculopathy, Kawasaki disease, venous gas embolism, restenosis after stent placement, rotational atherectomy, percutaneous transcatheter coronary angioplasty, The method according to item 20, selected from the group consisting of myasthenia gravis, cold agglutinin disease, dermatomyositis, paroxysmal cold hemoglobinuria, antiphospholipid syndrome, Graves' disease, atherosclerosis, Alzheimer's disease, systemic inflammatory response sepsis, septic shock, spinal cord injury, glomerulonephritis, graft rejection, Hashimoto's thyroiditis, type 1 diabetes mellitus, psoriasis, pemphigus, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Goodpasture syndrome, Dogo's disease, and fulminant antiphospholipid syndrome. (Item 22) The complement-related disorder is TMA, as described in item 21. (Item 23) The complement-related disorder is aHUS, as described in item 21. (Item 24) The complement-related disorder is PNH, as described in item 21. (Item 25) A method for treating a human patient suffering from PNH, comprising administering a stable aqueous solution to the patient, wherein the stable aqueous solution has a pH of approximately 7.4 and contains, or comprises, approximately 100 mg / mL of ravulizumab, approximately 33.1 mM monobasic sodium phosphate, approximately 16.5 mM dibasic sodium phosphate, approximately 0.05 w / v% polysorbate 80, approximately 25 mM L-arginine, approximately 50 mg / mL sucrose, and water for injection. The aforementioned stable aqueous solution is (e) On the first day, For patients weighing ≥40kg to <60kg, 2,400mg. For patients weighing ≥60kg to <100kg, 2,700mg, or For patients weighing ≥100 kg, a dose of 3,000 mg; and (b) On day 15, and every 8 weeks thereafter, For patients weighing ≥40kg to <60kg, 3,000mg. For patients weighing ≥60kg to <100kg, 3,300mg, or A method comprising administering a dose of 3,600 mg to a human patient whose body weight is ≥100 kg. (Item 26) The method according to item 25, wherein the stable aqueous solution is administered to human patients weighing ≥40kg to <60kg at a dose of 2,400mg on day 1, and at a dose of 3,000mg on day 15 and every 8 weeks thereafter. (Item 27) The method according to item 25, wherein the stable aqueous solution is administered to human patients with a body weight of ≥60kg to <100kg at a dose of 2,700mg on day 1, and at a dose of 3,300mg on day 15 and every 8 weeks thereafter. (Item 28) The method according to item 25, wherein the stable aqueous solution is administered to human patients with a body weight of ≥100 kg at a dose of 3,000 mg on day 1, and at a dose of 3,600 mg on day 15 and every 8 weeks thereafter. (Item 29) A method for treating a human patient suffering from aHUS, comprising administering a stable aqueous solution to the patient, wherein the stable aqueous solution has a pH of approximately 7.4 and contains approximately 100 mg / mL of ravulizumab, approximately 33.1 mM of monobasic sodium phosphate, and approximately 16.5 mM of dibasic sodium phosphate. A stable aqueous solution comprising or consisting of sodium phosphate, approximately 0.05 w / v% polysorbate 80, approximately 25 mM L-arginine, approximately 50 mg / mL sucrose, and water for injection, is provided. (f) On the first day, For patients weighing ≥5kg to <10kg, 600mg. For patients weighing ≥10kg to <20kg, 600mg. For patients weighing ≥20kg to <30kg, 900mg. For patients weighing ≥30kg to <40kg, 1,200mg. For patients weighing ≥40kg to <60kg, 2,400mg. For patients weighing ≥60kg to <100kg, 2,700mg, or For patients weighing ≥100 kg, a dose of 3,000 mg; and (b) On the 15th day, and every 4 or 8 weeks thereafter, For patients weighing ≥5kg to <10kg, 300mg. For patients weighing ≥10kg to <20kg, 600mg. For patients weighing ≥20kg to <30kg, 2,100mg. For patients weighing ≥30kg to <40kg, 2,700mg. For patients weighing ≥40kg to <60kg, 3,000mg. For patients weighing ≥60kg to <100kg, 3,300mg, or A method comprising administering a dose of 3,600 mg to a human patient whose body weight is ≥100 kg. (Item 30) The method according to item 29, wherein the stable aqueous solution is administered to human patients with a body weight of ≥5kg to <10kg at a dose of 600mg on day 1, and at a dose of 300mg on day 15 and every four weeks thereafter. (Item 31) The method according to item 29, wherein the stable aqueous solution is administered to human patients weighing ≥10kg to <20kg at a dose of 600mg on day 1, and at a dose of 600mg on day 15 and every 4 weeks thereafter. (Item 32) The method according to item 29, wherein the stable aqueous solution is administered to human patients weighing ≥20kg to <30kg at a dose of 900mg on day 1, and at a dose of 2,100mg on day 15 and every 8 weeks thereafter. (Item 33) The method according to item 29, wherein the stable aqueous solution is administered to human patients weighing ≥30kg to <40kg at a dose of 1,200mg on day 1, and at a dose of 2,700mg on day 15 and every 8 weeks thereafter. (Item 34) The method according to item 29, wherein the stable aqueous solution is administered to human patients weighing ≥40kg to <60kg at a dose of 2,400mg on day 1, and at a dose of 3,000mg on day 15 and every 8 weeks thereafter. (Item 35) The method according to item 29, wherein the stable aqueous solution is administered to human patients weighing ≥60kg to <100kg at a dose of 2,700mg on day 1, and at a dose of 3,300mg on day 15 and every 8 weeks thereafter. (Item 36) The method according to item 29, wherein the stable aqueous solution is administered to human patients with a body weight of ≥100 kg at a dose of 3,000 mg on day 1, and at a dose of 3,600 mg on day 15 and every 8 weeks thereafter. (Item 37) The stable aqueous solution is supplied in a 3 mL single-use vial containing 300 mg of ravulizumab. The method described in any one of items 20 to 36. (Item 38) A stable aqueous solution is supplied in an 11 mL single-use vial containing 1,100 mg of ravulizumab, according to the method described in any one of items 20 to 36. (Item 39) The method according to any one of items 20 to 36, wherein the stable aqueous solution is administered by intravenous infusion. (Item 40) (i) A stable aqueous solution as described in any one of items 1 to 19, and (ii) A treatment kit equipped with instructions for use. (Item 41) (i) A stable aqueous solution as described in any one of items 1 to 19, (ii) Physiological saline (0.9% sodium chloride), and (iii) A treatment kit that includes instructions for use. (Item 42) (i) A formulation containing or comprising approximately 100 mg / mL of ravulizumab, approximately 33.1 mM monobasic sodium phosphate, approximately 16.5 mM dibasic sodium phosphate, approximately 0.05 w / v% polysorbate 80, approximately 25 mM L-arginine, and approximately 50 mg / mL of sucrose. (ii) Physiological saline (0.9% sodium chloride), and (iii) A treatment kit that includes instructions for use. (Item 43) The aforementioned formulation is freeze-dried, as described in item 42 of the therapeutic kit. (Item 44) A method for producing a stable aqueous solution containing ravulizumab at a concentration of approximately 10 mg / mL or less, approximately 33.1 mM monobasic sodium phosphate, approximately 16.5 mM dibasic sodium phosphate, approximately 0.05 w / v% polysorbate 80, approximately 25 mM L-arginine, approximately 50 mg / mL sucrose, and water for injection, i) To provide a first aqueous solution containing approximately 10 mg / mL of ravulizumab, ii) Diafiltration of the first aqueous solution into a mixture of approximately 33.1 mM monobasic sodium phosphate, approximately 16.5 mM dibasic sodium phosphate, approximately 0.05 w / v% polysorbate 80, approximately 25 mM L-arginine, approximately 50 mg / mL sucrose, and water for injection at pH 7.4, thereby producing a second aqueous solution. iii) A method comprising concentrating the second aqueous solution to produce a stable aqueous solution containing ravulizumab at a concentration of about 100 mg / mL, monobasic sodium phosphate at about 33.1 mM, dibasic sodium phosphate at about 16.5 mM, polysorbate 80 at about 0.05 w / v%, L-arginine at about 25 mM, sucrose at about 50 mg / mL, and water for injection. [Brief explanation of the drawing]

[0065] [Figure 1] This is a schematic diagram showing the design of a Phase II clinical trial ("Study 201") in patients with PNH. [Modes for carrying out the invention]

[0066] This disclosure features a specific stable aqueous solution containing a high concentration of an anti-C5 antibody (e.g., ravulizumab). The solution can be used in a variety of therapeutic applications, such as methods for treating or preventing complement-related disorders. Exemplary solutions, formulations, therapeutic kits, and methods for producing and using any of the above are described in detail below and illustrated in the examples, without any limitation.

[0067] I. Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. Any methods and compositions similar to or equivalent to those described herein may be used to carry out or test the present invention, but preferred methods and compositions are described herein.

[0068] The singular forms "a," "an," and "the" refer to multiple objects unless the context explicitly indicates otherwise.

[0069] In particular, the term "about" in relation to a given quantity or number means that a deviation of plus or minus 10 percent (±10%) (e.g., ±5%) is included.

[0070] The term "pharmaceutical formulation" refers to a preparation in which the biological activity of the active ingredient is clearly effective, and which does not contain any additional ingredients that are significantly toxic to the target of administration.

[0071] As used herein, an "aqueous" pharmaceutical composition is a composition suitable for pharmaceutical use in which the aqueous carrier is water. A composition suitable for pharmaceutical use may be sterile, homogeneous, and / or isotonic. Aqueous pharmaceutical compositions may be prepared directly in aqueous form and / or reconstituted from lyophilized products.

[0072] An "isotonic" formulation is one that has essentially the same osmotic pressure as human blood. Isotonic formulations generally have an osmotic pressure of approximately 275-350 mOsm / kg. The term "hypotonic" refers to a formulation with an osmotic pressure lower than that of human blood. Similarly, the term "hypertonic" refers to a formulation with an osmotic pressure higher than that of human blood. Isotonicity can be measured, for example, using vapor pressure or an ice-cooled osmometer. An "isotonic agent" is a compound that makes a formulation isotonic.

[0073] As used herein, the “osmolarity” of a solution refers to the number of osmoles of solute per kilogram of solvent. Osmolarity is an indicator of the number of particles present in a solution and does not depend on the size or weight of the particles. It can only be measured by using properties of the solution that depend solely on the particle concentration. These properties are vapor pressure depression, freezing point depression, boiling point elevation, and osmotic pressure, which are collectively referred to as colligative properties.

[0074] A "sterilized" formulation is sterile, meaning that it is free from or essentially free from all living microorganisms and their spores.

[0075] A “stable” formulation is one in which, when used herein, the antibodies contained herein essentially retain their physical and / or chemical stability and / or biological activity during storage. Various analytical techniques for measuring protein stability are available in the art and are discussed in Peptide and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, NY, Pubs. (1991) and Jones, A. Adv. Drug Delivery Rev. 10:29-90 (1993). The stability of anti-C5 antibody formulations can be measured at a selected temperature after a selected period. For example, increased aggregate formation after storage is an indicator of instability of aqueous anti-C5 antibody formulations. In addition to aggregate formation, retention of the original clarity, color, and odor throughout the shelf life are indicators used to observe the stability of aqueous anti-C5 antibody solutions described herein.

[0076] If an antibody does not substantially show signs of aggregation, precipitation, and / or denaturation when visually inspected for color and / or clarity, or measured by ultraviolet scattering or size exclusion chromatography, then the antibody "maintains its physical stability" in the pharmaceutical formulation.

[0077] The term "aggregation" refers to the process by which naturally folded proteins assemble to form aggregates containing non-natural structures. Aggregation can occur even under physiologically non-denatured conditions, is irreversible, and often results in inactive, and in some cases, immunogenic and toxic, non-natural aggregates.

[0078] As used herein, the term “low to undetectable levels of aggregation” refers to a sample containing aggregations of approximately 5% or less, approximately 4% or less, approximately 3% or less, approximately 2% or less, approximately 1% or less, and approximately 0.5% or less relative to the weight of the protein, as measured by gel permeation high-performance liquid chromatography (GP-HPLC), high-speed size exclusion chromatography (HPSEC), or static light scattering (SLS) techniques.

[0079] An antibody “retains its chemical stability” in a pharmaceutical formulation if its chemical stability over a given time is such that the antibody is still considered to retain its biological activity as defined below. Chemical stability can be assessed by detecting and quantifying chemically altered forms of the antibody. Chemical alterations may involve resizing (e.g., clipping), amidation, racemization, hydrolysis, oxidation, β-elimination, and disulfide exchange, which can be assessed using known techniques, such as size exclusion chromatography, SDS-PAGE, matrix-assisted laser desorption / ionization / time-of-flight mass spectrometry (MALDI / TOF MS), and / or ion-exchange chromatography.

[0080] If an antibody in a pharmaceutical formulation is biologically active for its intended use, the antibody “retains its biological activity” in the pharmaceutical formulation. For example, if the biological activity of an antibody in a pharmaceutical formulation is within approximately 30%, 20%, or 10% (within assay error) of the biological activity shown at the time of preparation of the pharmaceutical formulation (as determined, for example, by an antigen-binding assay), then the biological activity is retained. In this specification, “biological activity” of a monoclonal antibody refers to the antibody’s ability to bind to an antigen. This may further include an antibody that binds to an antigen and produces a measurable biological response that can be measured in vitro or in vivo.

[0081] The "shelf life" of a pharmaceutical product, such as an aqueous solution containing an anti-C5 antibody, is the length of time the product can be stored before degradation occurs. For example, shelf life can be defined as the time it takes for 0.1%, 0.5%, 1%, 5%, or 10% of the product to decompose.

[0082] As used herein, the term "antibody" refers to a polypeptide comprising at least one antigen-binding site derived from an antibody (e.g., a VH / VL region or Fv, or CDR). Antibodies include known forms of antibodies. For example, an antibody can be a human antibody, a humanized antibody, a bispecific antibody, or a chimeric antibody. An antibody can also be a Fab, Fab’2, ScFv, SMIP, Affibody®, nanobody, or domain antibody. An antibody can be of any of the following isotypes: IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD, and IgE. An antibody can be a natural antibody or an antibody modified by protein modification techniques (e.g., by mutation, deletion, substitution, conjugation to a non-antibody moiety). For example, an antibody can contain one or more variant amino acids (compared to a natural antibody) that alter the properties of the antibody (e.g., functional properties). For example, many such changes that affect, for example, half-life, effector function, and / or the immune response to the antibody in a patient are known in the art. The term antibody further includes artificial or modified polypeptide constructs that contain at least one antigen-binding site derived from an antibody.

[0083] As used herein, the terms "specific binding", "selective binding", "selectively binds", and "specifically binds" refer to an antibody binding to an epitope of a given antigen but not to other antigens. Typically, an antibody has an equilibrium dissociation constant (K -8 M, 10 -9 M, or 10 -10 M, or even less, such as less than about 10 -7 M, determined, for example, by surface plasmon resonance (SPR) technology in a BIACORE® 2000 surface plasmon resonance instrument using, for example, a given antigen, such as C5, as an analyte and the antibody as a ligand, or by Scatchard analysis of the binding of the antibody to antigen-positive cells. D(ii) binds to the given antigen with an affinity at least twice as high as the affinity for binding to nonspecific antigens other than the given antigen or closely related antigens (e.g., BSA, casein). Therefore, unless otherwise noted, an antibody that "specifically binds to human C5" is approximately 10 -8 M, 10 -9 M, or 10 -10 M, or even less than 10 -7 K below M D This refers to antibodies that bind to soluble or cell-binding human C5.

[0084] As used herein, the term "surface plasmon resonance" refers to, for example, the BIAcore system (Pharmacia Biosensor AB, Uppsala, Sweden). This refers to an optical phenomenon that enables the analysis of real-time biospecific interactions by detecting changes in protein concentration within a biosensor matrix using and Piscataway (NJ). For further explanation, see Jonsson, U., et al. (1993) Ann. Biol. Clin. 51:19-26; Jonsson, U., et al. See al. (1991) Biotechniques 11:620-627; Johnson, B., et al. (1995) J.Mol.Recognit.8:125-131; and Johnson, B., et al. (1991) Anal.Biochem.198:268-277.

[0085] When used in this specification, the term "K off This term is intended to refer to the off-rate constant of the dissociation of antibodies from an antibody / antigen complex.

[0086] When used in this specification, the term "K d This term is intended to refer to the dissociation constant of a specific antibody-antigen interaction.

[0087] As used herein, the terms “subject” or “patient” are used interchangeably and refer to mammals such as humans, mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, monkeys, cows, horses, and pigs. In one embodiment, the patient is a human patient (e.g., a human patient with a complement-related disorder).

[0088] As used herein, the terms “to treat,” “to treat,” and “treatment” refer to the therapeutic actions described herein. A “treatment” method involves administering to a subject any combination disclosed herein in order to cure, delay, reduce the severity of, or restore one or more symptoms of a disease or disorder or a recurrent disease or disorder, or to prolong the subject’s survival beyond what would be expected in the absence of such treatment.

[0089] As used herein, “effective treatment” means treatment that results in a beneficial effect, such as the recovery of at least one symptom of a disease or disorder. A beneficial effect may take the form of improvement above baseline, i.e., improvement above the measurement or observation made before the initiation of therapy with this method. Effective treatment may mean the alleviation of at least one symptom of a disease or condition.

[0090] The term “effective dose” refers to the amount of an agent that provides a desired biological, therapeutic, and / or prophylactic outcome. This outcome may be the reduction, improvement, mitigation, decrease, delay, and / or relief of one or more signs, symptoms, or causes of a disease or condition, or any other desired change in the biological system. In one embodiment, the “effective dose” is the amount of a stable aqueous solution sufficient to alleviate at least one symptom of a disease or condition. The effective dose may be administered in one or more doses.

[0091] As used herein, the terms “induction” and “induction phase” are used interchangeably and refer to the first stage of treatment.

[0092] As used herein, the terms “maintenance” and “maintenance phase” are used interchangeably and refer to the second stage of treatment. In certain embodiments, treatment is continued as long as clinical benefit is observed or until uncontrollable toxicity or disease progression occurs.

[0093] II. Anti-C5 antibody An anti-C5 antibody (or a VH / VL domain derived therefrom) suitable for use in the present invention can be produced using methods well known in the art. Alternatively, an anti-C5 antibody recognized in the art may be used. An antibody that competes with any of these art-recognized antibodies in terms of binding to C5 may also be used.

[0094] Exemplary anti-C5 antibodies are ULTOMIRIS® (labulizumab), or its antigen-binding fragments and variants, which include heavy and light chains having the sequences shown in SEQ ID NOs. 14 and 11, respectively. Labulizumab (also known as BNJ441 and ALXN1210) is described in International Publication US2015 / 019225 and U.S. Patent No. 9,079,949, whose teachings are incorporated herein by reference. The terms ULTOMIRIS®, labulizumab, BNJ441, and ALXN1210 may be used interchangeably throughout this document. Labulizumab selectively binds to human complement protein C5 and inhibits its cleavage into C5a and C5b during complement activation. This inhibition prevents the release of the pro-inflammatory mediator C5a and the formation of the cytolytic pore-forming membrane attack complex (MAC) C5b-9, while preserving the proximal or initial components (e.g., C3 and C3b) of complement activation essential for microbial opsonization and immune complex removal.

[0095] In other embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of ravulizumab. Thus, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of ravulizumab having the sequence described in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of the VL region of ravulizumab having the sequence described in SEQ ID NO: 8. In another embodiment, the antibody comprises the heavy chain CDR1, CDR2, and CDR3 domains having the sequences described in SEQ ID NOs: 19, 18, and 3, respectively, and the light chain CDR1, CDR2, and CDR3 domains having the sequences described in SEQ ID NOs: 4, 5, and 6, respectively. In yet another embodiment, the antibody comprises the VH and VL regions having the amino acid sequences described in SEQ ID NO: 12 and SEQ ID NO: 8, respectively.

[0096] Another exemplary anti-C5 antibody is antibody BNJ421, which comprises a heavy chain and a light chain having the sequences shown in SEQ ID NOs. 20 and 11, respectively, or its antigen-binding fragment and variants. BNJ421 (also known as ALXN1211) is described in International Publication US2015 / 019225 and U.S. Patent No. 9,079,949, whose teachings are incorporated herein by reference.

[0097] In other embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of BNJ421. Thus, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of BNJ421 having the sequence described in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of the VL region of BNJ421 having the sequence described in SEQ ID NO: 8. In another embodiment, the antibody comprises the heavy chain CDR1, CDR2, and CDR3 domains having the sequences described in SEQ ID NOs: 19, 18, and 3, respectively, and the light chain CDR1, CDR2, and CDR3 domains having the sequences described in SEQ ID NOs: 4, 5, and 6, respectively. In yet another embodiment, the antibody comprises the VH and VL regions having the amino acid sequences described in SEQ ID NO: 12 and SEQ ID NO: 8, respectively.

[0098] The exact boundaries of the CDR can be defined in various ways depending on the method. In some embodiments, the location of the CDR or framework region within the light chain or heavy chain variable domain may be as defined by Kabat et al. [(1991) “Sequences of Proteins of Immunological Interest.” NIH Publication No. 91-3242, USD Department of Health and Human Services, Bethesda, MD]. In such cases, the CDR may be referred to as “Kabat CDR” (e.g., “Kabat LCDR2” or “Kabat HCDR1”). In some embodiments, the location of the CDR in the light chain or heavy chain variable region may be as defined by Chothia et al. (1989) Nature 342:877-883. Thus, these regions may be referred to as “Chothia CDR” (e.g., “Chothia LCDR2” or “Chothia HCDR3”). In some embodiments, the location of the CDR in the light chain and heavy chain variable region may be as defined by the Kabat-Chothia combination definition. In these embodiments, these regions may be referred to as “combined Kabat-Chothia CDRs.” Thomas et al. [(1996) Mol Immunol 33(17 / 18):1389-1401] illustrate the identification of CDR boundaries according to the definitions of Kabat and Chothia.

[0099] In some embodiments, the anti-C5 antibodies described herein include the following amino acid sequence, or include a heavy chain CDR1 consisting of the following: [ka] In some embodiments, the anti-C5 antibodies described herein include the following amino acid sequence, or include a heavy chain CDR2 consisting of the following: [ka] In some embodiments, the anti-C5 antibodies described herein include a heavy chain variable region comprising the following amino acid sequence: [ka]

[0100] In some embodiments, the anti-C5 antibodies described herein include a light chain variable region comprising the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQNVLNTPLTFGQGTKVEIK (Sequence ID 8).

[0101] The anti-C5 antibodies described herein may, in some embodiments, include a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn) with a higher affinity than the native human Fc constant region from which the variant human Fc constant region is induced. For example, this Fc constant region may include one or more (e.g., 2, 3, 4, 5, 6, 7, or 8 or more) amino acid substitutions relative to the native human Fc constant region from which the variant human Fc constant region is induced. These substitutions may increase the binding affinity of an IgG antibody containing the variant Fc constant region to FcRn at pH 6.0 while maintaining the pH-dependent interaction. Methods for testing whether one or more substitutions in the Fc constant region of an antibody increase the affinity of the Fc constant region to FcRn at pH 6.0 (while maintaining the pH-dependent interaction) are known in the art and illustrated in the examples. See, for example, International Publication US2015 / 019225 and U.S. Patent No. 9,079,949, whose entire disclosures are incorporated herein by reference.

[0102] Substitutions that enhance the binding affinity of the antibody Fc constant region to FcRn are known in the art and include, for example, (1) the M252Y / S254T / T256E triple substitution described by Dall'Acqua et al. (2006) J Biol Chem 281:23514-23524; (2) the M428L or T250Q / M428L substitution described by Hinton et al. (2004) J Biol Chem 279:6213-6216 and Hinton et al. (2006) J Immunol 176:346-356; and (3) the N434A or T307 / E380A / N434A substitution described by Petkova et al. (2006) Int Immunol 18(12):1759-69. Additional substitution pairs, such as P257I / Q311I, P257I / N434H, and D376V / N434H, are described, for example, in Datta-Mannan et al. (2007) J Biol Chem 282(3):1709-1717, the entire disclosure of which is incorporated herein by reference.

[0103] In some embodiments, the variant constant region has a substitution to valine at EU amino acid residue 255. In some embodiments, the variant constant region has a substitution to asparagine at EU amino acid residue 309. In some embodiments, the variant constant region has a substitution to isoleucine at EU amino acid residue 312. In some embodiments, the variant constant region has a substitution at EU amino acid residue 386.

[0104] In some embodiments, the variant Fc constant region contains 30 or fewer amino acid substitutions, insertions, or deletions (e.g., 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 or fewer) compared to the derived native constant region. In some embodiments, the variant Fc constant region contains one or more amino acid substitutions selected from the group consisting of M252Y, S254T, T256E, N434S, M428L, V259I, T250I, and V308F. In some embodiments, the variant human Fc constant region contains methionine at position 428 and asparagine at position 434, respectively, in EU numbering. In some embodiments, the variant Fc steady-state region includes, for example, the 428L / 434S double substitution described in U.S. Patent No. 8,088,376.

[0105] In some embodiments, the precise locations of these mutations may be shifted from the natural human Fc constant region for antibody modification. For example, the 428L / 434S double substitution used in IgG2 / 4 chimeric Fc may correspond to 429L and 435S, found in the M429L and N435S variants in ravulizumab (BNJ441), the entire disclosure of which is incorporated herein by reference in U.S. Patent No. 9,079,949.

[0106] In some embodiments, the variant constant region includes substitutions at amino acid positions (EU numbering) 237, 238, 239, 248, 250, 252, 254, 255, 256, 257, 258, 265, 270, 286, 289, 297, 298, 303, 305, 307, 308, 309, 311, 312, 314, 315, 317, 325, 332, 334, 360, 376, 380, 382, ​​384, 385, 386, 387, 389, 424, 428, 433, 434, or 436 relative to the native human Fc constant region. In some embodiments, substitutions are made from methionine to glycine at position 237; from alanine to proline at position 238; from lysine to serine at position 239; from isoleucine to lysine at position 248; from alanine, phenylalanine, isoleucine, methionine, glutamine, serine, valine, tryptophan, or tyrosine to threonine at position 250; from phenylalanine, tryptophan, or tyrosine to methionine at position 252; from threonine to serine at position 254; from glutamic acid to arginine at position 255; from aspartic acid, glutamic acid, or glutamine to threonine at position 256; from alanine, glycine, isoleucine, leucine, methionine, asparagine, serine, threonine, or valine to proline at position 257; from histidine to glutamic acid at position 258; from alanine to aspartic acid at position 265; or from phenylalanine at position 270. Aspartic acid; asparagine from alanine or glutamic acid at position 286; threonine from histidine at position 289; asparagine from alanine at position 297; serine from glycine at position 298; valine from alanine at position 303; valine from alanine at position 305; alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, p Threonine from lorine, glutamine, arginine, serine, valine, tryptophan, or tyrosine; valine from alanine, phenylalanine, isoleucine, leucine, methionine, proline, glutamine, or threonine at position 308; leucine or valine from alanine, aspartic acid, glutamic acid, proline, or arginine at position 309; glutamine from alanine, histidine, or isoleucine at position 311;Aspartic acid from alanine or histidine at position 312; leucine from lysine or arginine at position 314; asparagine from alanine or histidine at position 315; lysine from alanine at position 317; asparagine from glycine at position 325; isoleucine from valine at position 332; lysine from leucine at position 334; lysine from histidine at position 360; aspartic acid from alanine at position 376; glutamic acid from alanine at position 380; glutamic acid from alanine at position 382; asparagine or serine from alanine at position 384; glycine from aspartic acid or histidine at position 385; glutamine from proline at position 386; 3 Selected from the group consisting of: proline from glutamic acid at position 87; asparagine from alanine or serine at position 389; serine from alanine at position 424; methionine from alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, asparagine, proline, glutamine, serine, threonine, valine, tryptophan, or tyrosine at position 428; histidine from lysine at position 433; asparagine from alanine, phenylalanine, histidine, serine, tryptophan, or tyrosine at position 434; and tyrosine or phenylalanine from histidine at position 436 (all EU numbering).

[0107] Suitable anti-C5 antibodies for use in the methods described herein include, in some embodiments, a heavy chain polypeptide comprising the amino acid sequence shown in SEQ ID NO: 14 and / or a light chain polypeptide comprising the amino acid sequence shown in SEQ ID NO: 11. Alternatively, suitable anti-C5 antibodies for use in the methods described herein include, in some embodiments, a heavy chain polypeptide comprising the amino acid sequence shown in SEQ ID NO: 20 and / or a light chain polypeptide comprising the amino acid sequence shown in SEQ ID NO: 11.

[0108] In one embodiment, the antibody has an affinity dissociation constant (K) of at least 0.1 (e.g., at least 0.15, 0.175, 0.2, 0.25, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775, 0.8, 0.825, 0.85, 0.875, 0.9, 0.925, 0.95, or 0.975) nM at pH 7.4 and 25°C (and otherwise under physiological conditions). D ) binds to C5. In some embodiments, an anti-C5 antibody, or the K of its antigen-binding fragment, is used. D The saturation is 1 nM or less (for example, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, or 0.2 nM or less).

[0109] In other embodiments, [(K of the antibody against C5 at pH 6.0 and C D ) / (K of antibody against C5 at pH 7.4 and 25°C) D )] is greater than 21 (for example, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, These are 250, 260, 270, 280, 290, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, or over 8000.

[0110] Methods for determining whether an antibody binds to a protein antigen and / or the affinity of an antibody to a protein antigen are known in the art. For example, antibody binding to protein antigens can be detected and / or quantified using a variety of techniques, including but not limited to Western blotting, dot blotting, surface plasmon resonance (SPR) (e.g., BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ), or enzyme-linked immunosorbent assay (ELISA). For example, see Benny KCLo (2004) “Antibody Engineering: Methods and Protocols,”Humana Press(ISBN:1588290921);Johne et al.(1993)J Immunol Meth 160:191-198;Jonsson et al.(1993)Ann Biol Clin See 51:19-26 and Jonsson et al. (1991) Biotechniques 11:620-627. Furthermore, methods for measuring affinity (e.g., dissociation and binding constants) are described in the examples.

[0111] When used herein, the term "k a "k" refers to the rate constant of antibody binding to an antigen. d " refers to the rate constant of antibody dissociation from antibody / antigen complex. Also, the term "K" D This refers to the equilibrium dissociation constant of antibody-antigen interaction. The equilibrium dissociation constant is estimated from the ratio of the velocity constants (K D =k a / k d Such determinations are preferably made at 25°C or 37°C (see Examples). For example, the dynamics of antibodies binding to human C5 can be determined at pH 8.0, 7.4, 7.0, 6.5, and 6.0 using an anti-Fc capture method that immobilizes the antibody via surface plasmon resonance (SPR) on a BIAcore3000 instrument.

[0112] In one embodiment, an anti-C5 antibody, or its antigen-binding fragment, blocks the generation or activity of C5a and / or C5b active fragments of the C5 protein (e.g., human C5 protein). This blocking effect inhibits, for example, the pro-inflammatory effect of C5a and the generation of the C5b-9 membrane attack complex (MAC) on the cell surface.

[0113] Methods for determining whether the specific antibodies described herein inhibit C5 cleavage are known in the art. Inhibition of human complement component C5 can reduce the cytolytic capacity of complement in the body fluid of interest. Such reduction in the cytolytic capacity of complement present in body fluids is described, for example, in Kabat and Mayer (eds.), "Experimental Immunochemistry, 2 nd Measurement can be performed by conventional hemolysis assays, such as the hemolysis assay described in "Edition," 135-240, Springfield, IL, CC Thomas (1961), pages 135-139, or by conventional modifications of this assay, such as the chicken erythrocyte hemolysis method described in Hillmen et al. (2004) N Engl J Med 350(6):552, or by methods well known in the art. Methods for determining whether a candidate compound inhibits the cleavage of human C5 to morphology C5a and C5b are known in the art, such as Evans et al. (1995) Mol Immunol This is described in 32(16):1183-95. For example, the concentrations and / or physiological activities of C5a and C5b in body fluids can be measured by methods well known in the art. In the case of C5b, hemolysis assays or assays for soluble C5b-9 discussed herein can be used. Other assays known in the art may also be used. These, or other suitable types of assays, can be used to screen for candidate drugs capable of inhibiting human complement component C5.

[0114] Using immunological techniques such as ELISA, but not limited to it, the protein concentrations of C5 and / or its degradation products can be measured to determine the ability of an anti-C5 antibody or its antigen-binding fragment to inhibit the conversion of C5 to a biologically active product. In some embodiments, the production of C5a is measured. In some embodiments, terminal complement formation is detected using a C5b-9 neoepitope-specific antibody.

[0115] A hemolysis assay can be used to determine the inhibitory activity of an anti-C5 antibody or its antigen-binding fragment against complement activation. To determine the effect of an anti-C5 antibody or its antigen-binding fragment against classical complement pathway-mediated hemolysis in a serum test solution in vitro, target cells are used, for example, sheep erythrocytes coated with hemolysin or chicken erythrocytes sensitized with an anti-chicken erythrocyte antibody. The percentage of lysis is normalized by considering 100% lysis as equivalent to lysis occurring in the absence of the inhibitor. In some embodiments, the classical complement pathway is activated by a human IgM antibody, for example, as used in the Wieslab® Classical Pathway Complement Kit (Wieslab® COMPL CP310, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with an anti-C5 antibody or its antigen-binding fragment in the presence of a human IgM antibody. The amount of C5b-9 produced is measured by contacting the mixture with an enzyme-labeled anti-C5b-9 antibody and a fluorescent substrate, and measuring the absorbance at an appropriate wavelength. As a control, the test serum is incubated in the absence of an anti-C5 antibody or its antigen-binding fragment. In some embodiments, the test serum is C5-deficient serum reconstituted with a C5 polypeptide.

[0116] To determine the effect of an anti-C5 antibody or its antigen-binding fragment on alternative pathway-mediated hemolysis, unsensitized rabbit or guinea pig erythrocytes may be used as target cells. In some embodiments, the serum test solution is C5-deficient serum reconstituted with a C5 polypeptide. The percentage of lysis is normalized by considering 100% lysis as equivalent to lysis occurring in the absence of the inhibitor. In some embodiments, the alternative complement pathway is activated by a lipopolysaccharide molecule, for example, as used in the Wieslab® Alternative Pathway Complement Kit (Wieslab® COMPL AP330, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with an anti-C5 antibody or its antigen-binding fragment in the presence of lipopolysaccharide. The amount of C5b-9 produced is measured by contacting the mixture with an enzyme-labeled anti-C5b-9 antibody and a fluorescent substrate and measuring the fluorescence at an appropriate wavelength. As a control, the test serum is incubated in the absence of the anti-C5 antibody or its antigen-binding fragment.

[0117] In some embodiments, C5 activity or its inhibition is quantified using the CH50eq assay. The CH50eq assay is a method for measuring total classical complement activity in serum. This assay is a lysis assay that uses antibody-sensitized erythrocytes as activators of the classical complement pathway, and various dilutions of the test serum, to determine the amount (CH50) required to obtain 50% lysis. The percentage of hemolysis can be determined, for example, using a spectrophotometer. The CH50eq assay provides an indirect measure of terminal complement complex (TCC) formation, because the TCC itself directly governs the hemolysis being measured.

[0118] The assay is well known and commonly performed by those skilled in the art. Briefly, to activate the classical complement pathway, an undiluted serum sample (e.g., a reconstituted human serum sample) is added to a microassay well containing antibody-sensitized red blood cells, thereby generating TCCs. The activated serum is then diluted in a microassay well coated with a capture reagent (e.g., an antibody that binds to one or more components of TCCs). The TCCs present in the activated sample bind to a monoclonal antibody coating the surface of the microassay well. The wells are washed, and a detection reagent, which is detectably labeled to recognize the bound TCCs, is added to each well. The detectable label may be, for example, fluorescent or enzymatic. The assay results are expressed in units of CH50 equivalents per milliliter (CH50 U Eq / mL).

[0119] Inhibition, for example with respect to terminal complement activity, includes a reduction of at least 5% (e.g., at least 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60)% in terminal complement activity, for example, in a hemolysis assay or CH50eq assay, compared to the effect of a control antibody (or its antigen-binding fragment) under similar conditions and at equimolar concentrations. Substantial inhibition, as used herein, means inhibition of a given activity (e.g., terminal complement activity) by at least 40% (e.g., at least 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% or more). In some embodiments, the anti-C5 antibodies described herein contain one or more amino acid substitutions to the CDR of eculizumab (i.e., SEQ ID NOs: 1-6), but still retain at least 30% (e.g., at least 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95%) of the complement inhibitory activity of eculizumab in a hemolysis assay or CH50eq assay.

[0120] The anti-C5 antibodies described herein have a human serum half-life of at least 20 days (for example, at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55) days. In another embodiment, the anti-C5 antibodies described herein have a human serum half-life of at least 40 days. In another embodiment, the anti-C5 antibodies described herein have a human serum half-life of about 43 days. In another embodiment, the anti-C5 antibodies described herein have a human serum half-life of 39 to 48 days. Methods for measuring the serum half-life of an antibody are known in the art. In some embodiments, the anti-C5 antibody or its antigen-binding fragment described herein has a serum half-life that is at least 20% (e.g., at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250, 300, 400, 500)% longer than the serum half-life of eculizumab, as measured in one of the mouse model systems described in the Examples (e.g., C5-deficient / NOD / scid mouse or hFcRn transgenic mouse model system).

[0121] In one embodiment, an antibody competes with the antibody described herein for binding to the same epitope on C5 and / or binds to the same epitope on C5. The term “binding to the same epitope” with respect to two or more antibodies means that the antibodies bind to the same segment of amino acid residues, as determined by a given method. Techniques for determining whether an antibody binds to the “same epitope on C5” as the antibody described herein include, for example, epitope mapping methods, e.g., X-ray analysis of the antigen:antibody complex crystals providing atomic resolution of the epitope, and hydrogen / deuterium exchange mass spectrometry (HDX-MS). Other methods monitor the binding of antibodies to peptide antigen fragments or mutated variant forms of antigens, where loss of binding due to alteration of amino acid residues in the antigen sequence is often considered an indicator of the epitope component. Furthermore, combinatorial calculation methods for epitope mapping may also be used. These methods depend on the ability of the antibody of interest to affinity isolate specific short peptides from combinatorial phage display peptide libraries. Antibodies having the same VH and VL sequences, or the same CDR1, 2, and 3 sequences, are predicted to bind to the same epitope.

[0122] An antibody that "competes with another antibody for binding to a target" refers to an antibody that (partially or completely) inhibits the binding of another antibody to the target. Whether two antibodies compete with each other for binding to a target, i.e., whether one antibody inhibits the binding of the other antibody to the target, and to what extent, can be determined using known competition experiments. In certain embodiments, an antibody competes with another antibody for binding to the target and inhibits the binding of the other antibody to the target by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. The level of inhibition or competition may differ depending on which antibody is a "blocking antibody" (i.e., a cold antibody that is initially incubated with the target). Competing antibodies bind to the same epitope, overlapping epitope, or adjacent epitope (as is evident, for example, by steric hindrance).

[0123] The anti-C5 antibodies or their antigen-binding fragments used in the methods described herein may be produced using various techniques recognized in the art. Monoclonal antibodies can be obtained by various techniques known to those skilled in the art. Briefly, spleen cells derived from animals immunized with the desired antigen are generally immortalized by fusion with myeloma cells (see Kohler & Milstein, Eur. J. Immunol. 6:511-519 (1976)). Alternative immortalization methods include transformation with Epstein-Barr virus, oncogenes, or retroviruses, or other methods well known in the art. Colonies resulting from a single immortalized cell are screened for the production of antibodies having the desired specificity and affinity for the antigen, and the yield of monoclonal antibodies produced by such cells can be enhanced by various techniques, including intraperitoneal injection of vertebrate hosts. Alternatively, DNA sequences encoding monoclonal antibodies or their binding fragments can be isolated by screening a human B cell-derived DNA library according to the general protocol outlined by Huse, et al., Science 246:1275-1281 (1989).

[0124] III. Highly concentrated anti-C5 antibody solution Stable aqueous solutions containing an anti-C5 antibody (e.g., ravulizumab) are provided herein. The aqueous solutions described herein may be sterile, pharmaceutical-grade compositions for administration to subjects to treat or prevent complement-related disorders such as PNH, TMA, or aHUS. The solutions described herein may be formulated according to standard methods. Pharmaceutical formulations are in a well-established art, for example, Gennaro (2000) “Remington: The Science and Practice of Pharmacy,” 2000. thEdition, Lippincott, Williams & Wilkins (ISBN: 0683306472); Ansel et al. (1999) “Pharmaceutical Dosage Forms and Drug Delivery Systems,” 7 th Edition, Lippincott Williams & Wilkins Publishers (ISBN:0683305727); and Kibbe (2000) “Handbook of Pharmaceutical Excipients American Pharmaceutical Association,” 3 rd Further details are provided in Edition (ISBN: 091733096X). Suitable formulations for the high-concentration antibody solutions described herein are illustrated in the examples.

[0125] The aqueous solutions described herein contain high concentrations of antibodies that bind to human complement component C5, such as ravulizumab. Such solutions may also be referred to herein as “high-concentration antibody solutions.” As used herein, “high concentration” of anti-C5 antibody (e.g., ravulizumab) in an aqueous solution means at least 40 mg / mL, equal to or greater than this (e.g., at least 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 1 This is the antibody concentration (50, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or 300 mg / mL, or equal to or greater than this). In one embodiment, the anti-C5 antibody is present in the solution at a concentration greater than 100 mg / mL (e.g., greater than 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 195 mg / mL). In another embodiment, the anti-C5 antibody is present in the solution at a concentration greater than 200 mg / mL (e.g., greater than 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, or 295 mg / mL). In yet another embodiment, the anti-C5 antibody is present in the solution at a concentration greater than 300 mg / mL.In another embodiment, the antibody is in solution in concentrations of, for example, 40 mg / mL to 200 mg / mL, 50 mg / mL to 200 mg / mL, 60 mg / mL to 200 mg / mL, 70 mg / mL to 200 mg / mL, 80 mg / mL to 200 mg / mL, 90 mg / mL to 200 mg / mL, 100 mg / mL to 200 mg / mL, 110 mg / mL to 200 mg / mL, 120 mg / mL to 200 mg / mL, 130 mg / mL to 200 mg / mL, 140 mg / mL to 200 mg / mL, 150 mg / mL and above. 200mg / mL, 40mg / mL~100mg / mL, 50mg / mL~100mg / mL, 60mg / mL~100mg / mL, 70mg / mL~100mg / mL, 80mg / mL~100mg / mL, 90mg / mL~100mg / mL, 40mg / mL~150mg / mL, 50mg / mL~150mg / mL, 60mg / mL~150mg / mL, 70mg / mL~150mg / mL, 80mg / mL~150mg / mL, 90mg / mL~150mg / mL, 100mg / mL~ 150mg / mL, 110mg / mL~150mg / mL, 120mg / mL~150mg / mL, 40mg / mL~50mg / mL, 40mg / mL~250mg / mL, 50mg / mL~250mg / mL, 60mg / mL~250mg / mL , 70mg / mL~250mg / mL, 80mg / mL~250mg / mL, 90mg / mL~250mg / mL, 100mg / mL~250mg / mL, 110mg / mL~250mg / mL, 120mg / mL~250mg / mL, 130mg It exists at concentrations of 1 / mL to 250 mg / mL, 140 mg / mL to 250 mg / mL, 150 mg / mL to 250 mg / mL, 160 mg / mL to 250 mg / mL, 170 mg / mL to 250 mg / mL, 180 mg / mL to 250 mg / mL, 190 mg / mL to 250 mg / mL, 200 mg / mL to 250 mg / mL, greater than 200 mg / mL (e.g., at least 201 mg / mL) to 250 mg / mL, or greater than 200 mg / mL (e.g., 201 mg / mL or more) to 300 mg / mL.

[0126] The characteristic aqueous solutions provide anti-C5 antibodies (e.g., ravulizumab) formulated therein, exhibiting remarkable physical and chemical stability, as well as functional stability. For example, the formulations described herein can maintain the structural integrity of anti-C5 antibodies (e.g., ravulizumab) present in high concentrations in the solution. In one embodiment, the solution is suitable for storage at 2–8°C (e.g., 4°C). In another embodiment, the solution is formulated for storage at temperatures below 0°C (e.g., -20°C or -80°C). In yet another embodiment, the solution is formulated for storage at 2–8°C (e.g., 4°C) for up to 3 years (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 1.5 years, 2 years, 2.5 years, or 3 years). In yet another embodiment, the solution is suitable for storage at 2–8°C (e.g., 4°C) for at least 1, 2, or 3 years.

[0127] As illustrated in the examples described herein, the solutions described herein are suitable for maintaining anti-C5 antibodies mainly in monomer form at a concentration of approximately 100 mg / mL for up to two years at approximately 2°C to 8°C. When used herein, the anti-C5 antibodies formulated at high concentrations in the characteristic aqueous solutions are determined, for example, by size exclusion chromatography or high-performance liquid chromatography (SEC-HPLC such as gel permeable HPLC), to ensure that at least 95% of the antibodies are present in the solution (e.g., at least 95.1, 95.2, 95.3, 95.4, 95.5, 95.6, 95.7, 95.8, 95.9, 96, 96.1, 96.2, 96.3, 96.4, 96.5, 96.6, 96.7). If monomeric (96.8, 96.9, 97, 97.1, 97.2, 97.3, 97.4, 97.5, 97.6, 97.7, 97.8, 97.9, 98, 98.1, 98.2, 98.3, 98.4, 98.5, 98.6, 98.7, 98.8, 98.9, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9%, or more), then it is either "primarily monomeric" or "primarily in monomeric form." In one embodiment, the anti-C5 antibody in the solution described herein can remain primarily monomeric for at least one month (for example, at least two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twelve, twenty-one, twenty-two, twenty-three, twenty-four months, or longer) after being stored at approximately 2°C to eighteen (for example, at 1, two, three, four, five, six, seven, eighteen, nineteen, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty-one, twenty-one, twenty-two, twenty-three, twenty-four months, or longer) after being stored at approximately 2°C to eighteen (for example, at 1, two, three, fourteen, fiveteen, sixteen, seventeen, eighteen, nineteen, twenty-one, twenty-one, twenty-two, twenty-three, twenty-four months, or longer).

[0128] In any one embodiment of the solutions described herein, the anti-C5 antibody (e.g., ravulizumab) maintains at least 95% (e.g., at least 96, 97, 98, or 99%) monomericity, as determined by SEC-HPLC (e.g., gel permeation HPLC), for at least 6 months while stored at 2°C to 8°C. In another embodiment, the anti-C5 antibody maintains at least 95% (e.g., at least 96, 97, 98, or 99%) monomericity, as determined by SEC-HPLC, for at least 9 months while stored at 2°C to 8°C. In yet another embodiment, the anti-C5 antibody maintains at least 95% (e.g., at least 96, 97, 98, or 99%) monomericity, as determined by SEC-HPLC, for at least 1 year while stored at 2°C to 8°C. In yet another embodiment, the anti-C5 antibody maintains at least 95% (e.g., at least 96, 97, 98, or 99%) monomericity, as determined by SEC-HPLC, for at least 18 months while stored at 2°C to 8°C. In another embodiment, the anti-C5 antibody maintains at least 95% (e.g., at least 96, 97, 98, or 99%) monomericity, as determined by SEC-HPLC, for at least two years while stored at 2°C to 8°C.

[0129] In another embodiment, less than 5% of the antibody in solution (e.g., less than 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or less than 0.1%) is oligomeric, aggregated, and / or fragmented. As used herein, antibody fragmentation refers to improperly assembled components or degradation products of the whole antibody having a molecular weight lower than the whole antibody. Such fragmentation forms include, but are not limited to, free monomer heavy chain polypeptides, dimer heavy chain polypeptides (e.g., disulfide-linked heavy chain polypeptides), dimer heavy chain polypeptides bound to one light chain polypeptide, monomer heavy chain polypeptides bound to one light chain polypeptide, or further degradation products or fragments of light chain or heavy chain polypeptides. In some embodiments, less than 2% of the antibody (e.g., less than 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or less than 0.1%) aggregates for at least one month after storage at 2°C to 8°C (e.g., at least two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nine, twenty, twelve, eleven, twenty-two, twenty-three, twenty-four months, or longer).In some embodiments, less than 1% of the antibody (e.g., less than 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1%) fragments after storage at 2°C to 8°C for at least one month (e.g., at least two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nine, twenty, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty, twenty) or longer. Methods for determining the amount of monomeric antibody present in solution and the amount of oligomer, aggregated, or fragmented forms of anti-C5 antibody are described herein and illustrated in the examples. For example, a person skilled in the art can determine the percentage of all fragmented, unfolded intermediates and / or agglutinated antibody species present in a given solution using, for example, size exclusion chromatography (SEC-HPLC such as gel permeation HPLC), static light scattering (SLS), Fourier transform infrared spectroscopy (FTIR), circular dichroism (CD), urea-induced protein unfolding techniques, endogenous tryptophan fluorescence, non-reduced sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and differential scanning calorimetry (DSC).

[0130] In any one embodiment of the solutions described herein, less than 5% of the anti-C5 antibody (e.g., ravulizumab) in the solution agglutinates, as determined by SEC-HPLC (e.g., gel permeation HPLC). In another embodiment, less than 4% of the anti-C5 antibody in the solution agglutinates, as determined by SEC-HPLC. In yet another embodiment, less than 3% of the anti-C5 antibody in the solution agglutinates, as determined by SEC-HPLC. In yet another embodiment, less than 2% of the anti-C5 antibody in the solution agglutinates, as determined by SEC-HPLC. In yet another embodiment, less than 1% of the anti-C5 antibody in the solution agglutinates, as determined by SEC-HPLC.

[0131] As described herein, anti-C5 antibodies containing the characteristic solutions herein should be stored at 2°C to 8°C for at least one month (for example, at least two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, thirteen months, fourteen months, fifteen months, sixteen months, seventeen months, eighteen months, nineteen months, twenty months, twenty months, twenty months, twenty months, twenty months, twenty months). It can maintain at least 90% (e.g., 91, 92, 93, 94, 95, 96, 97, 98, 99, or even 100%) of its biological / functional activity (e.g., its ability to bind to human C5) for a period of months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, 36 months, or longer.

[0132] In another embodiment, the anti-C5 antibody (e.g., ravulizumab) present in the solution described herein is stored at 2°C to 8°C for at least one month (e.g., at least two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, thirteen months, fourteen months, fifteen months, sixteen months, seventeen months, eighteen months, nine months, ten months, eleven months, twelve months, thirteen months, fourteen months, fifteen months, sixteen months, seventeen months, eighteen months, nineteen months, twenty months). The antibody can retain at least 90% (e.g., 91, 92, 93, 94, 95, 96, 97, 98, 99, or even 100%) of its hemolytic activity for a period of months, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 months, or longer. A suitable hemolysis assay for determining whether an antibody in a characteristic solution retains its activity is described herein and known in the art (e.g., an in vitro hemolysis assay using bird or pig erythrocytes). A suitable method for evaluating the ability of an antibody preparation to bind to human complement component C5 is known in the art and described herein.

[0133] In any other embodiment of the solutions described herein, an anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99)% of its C5-binding activity for at least 6 months during storage at 2°C to 8°C, compared to a reference anti-C5 antibody corresponding to the anti-C5 antibody before storage. In another embodiment, an anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99)% of its C5-binding activity for at least 9 months during storage at 2°C to 8°C, compared to a reference anti-C5 antibody corresponding to the anti-C5 antibody before storage. In another embodiment, an anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99)% of its C5-binding activity for at least 1 year while stored at 2°C to 8°C, compared to a reference anti-C5 antibody corresponding to the anti-C5 antibody before storage. In another embodiment, an anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99)% of its C5-binding activity for at least 18 months while stored at 2°C to 8°C, compared to a reference anti-C5 antibody corresponding to the anti-C5 antibody before storage. In another embodiment, an anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) of its C5-binding activity for at least two years during storage at 2°C to 8°C, compared to a reference anti-C5 antibody corresponding to the anti-C5 antibody before storage.In another embodiment, compared to a reference anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) of its C5-binding activity for at least 3 years during storage at 2°C to 8°C.

[0134] In any other embodiment of the solutions described herein, an anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) of its hemolytic inhibitory ability for at least 9 months during storage at 2°C to 8°C, compared to a reference anti-C5 antibody corresponding to the anti-C5 antibody before storage. In any other embodiment of the solutions described herein, an anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) of its hemolytic inhibitory ability for at least 6 months during storage at 2°C to 8°C, compared to a reference anti-C5 antibody corresponding to the anti-C5 antibody before storage. In any other embodiment of the solutions described herein, an anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) of its ability to inhibit hemolysis for at least one year during storage at 2°C to 8°C, compared to a reference anti-C5 antibody corresponding to the anti-C5 antibody before storage. In any other embodiment of the solutions described herein, an anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) of its hemolytic inhibitory ability for at least 18 months during storage at 2°C to 8°C, compared to a reference anti-C5 antibody corresponding to the anti-C5 antibody before storage. In any other embodiment of the solutions described herein, an anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) of its hemolytic inhibitory ability for at least two years during storage at 2°C to 8°C, compared to a reference anti-C5 antibody corresponding to the anti-C5 antibody before storage.In any other embodiment of the solutions described herein, an anti-C5 antibody (e.g., ravulizumab) retains at least 80% (e.g., at least 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) of its ability to inhibit hemolysis for at least 3 years during storage at 2°C to 8°C, compared to a reference anti-C5 antibody corresponding to the anti-C5 antibody before storage.

[0135] The aqueous solutions described herein may contain one or more common agents (e.g., one or more excipients and / or additives, such as buffers, sugars or saccharides, salts, surfactants, solubilizers, diluents, binders, stabilizers, salts, lipophilic solvents, amino acids, chelating agents, and / or preservatives).

[0136] In one embodiment, the aqueous solution contains one or more buffers. As used herein, the term “buffer” means one or more components that, when added to an aqueous solution, can protect the solution from pH changes when an acid or alkali is added or when diluted with a solvent. In one embodiment, the solution contains at least one buffer. Non-limiting examples of typical buffers that may be included in a washing solution include Tris(tris(hydroxymethyl)methylamine), bis-tris, bis-trispropane, histidine, triethanolamine, diethanolamine, formate, acetate, MES(2-(N-morpholino)ethanesulfonic acid), phosphate, HEPES(4-2-hydroxyethyl-1-piperazineethanesulfonic acid), citrate, MOPS(3-(N-morpholino)propanesulfonic acid), TAPS(3{ Examples include [tris(hydroxymethyl)methyl]amino}propanesulfonic acid), bicine (N,N-bis(2-hydroxyethyl)glycine), tricine (N-tris(hydroxymethyl)methylglycine), TES (2-{[tris(hydroxymethyl)methyl]amino}ethanesulfonic acid), PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid), cacodylate (dimethylarsinic acid), SSC (sodium citrate saline solution), and sodium phosphate.

[0137] In another embodiment, the buffer is an amino acid. The amino acid may be one selected from the group consisting of, for example, histidine (e.g., L-histidine), serine (e.g., L-serine), and glycine (e.g., L-glycine). In another embodiment, the solution contains two or more buffers.

[0138] In one embodiment, the characteristic solution does not contain free amino acids as a buffer. In another embodiment, the characteristic solution contains only one free amino acid (e.g., histidine) as a buffer. In yet another embodiment, the characteristic solution may contain two or more (e.g., two, three, four, five, six, or seven or more) different amino acids, such as serine and histidine, as buffers.

[0139] The concentration of the buffer solution is sufficient to maintain the desired pH and may also be varied, for example, to maintain the isotonicity of the formulation. Typical concentrations of conventional buffers used in parenteral formulations can be found below: Pharmaceutical Dosage Form: Parenteral Medications, Volume 1, 2nd Edition, Chapter 5, p.194, De Luca and Boylan, “Formulation of Small Volume Parenterals”, Table 5: Commonly used additives in Parenteral Product. In one embodiment, the concentration of one or more buffers in the formulation is between approximately 10 mM and 300 mM. In another embodiment, the solution contains at least one buffer at a concentration between 10 mM and 200 mM. In another embodiment, the aqueous solution described herein contains a buffer at a concentration of at least 10 mM (for example, at least 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 mM or more).In another embodiment, the aqueous solution is approximately 10mM-50mM, 15mM-50mM, 20mM-50mM, 25mM-50mM, 30mM-50mM, 40mM-50mM, 10mM-100mM, 15mM-100mM, 20mM-100mM, 25mM-100mM, 30mM-100mM, 40mM-100mM, 10mM-150mM, 15mM-1 50mM, 20mM~150mM, 25mM~150mM, 30mM~150mM, 40mM~150mM, 50mM~100mM, 60mM~100mM, 70mM~100 mM, 80mM~100mM, 50mM~150mM, 60mM~150mM, 70mM~150mM, 80mM~150mM, 90mM~150mM, 100mM~150m M, 10mM~200mM, 15mM~200mM, 20mM~200mM, 25mM~200mM, 30mM~200mM, 40mM~200mM, 50mM~200mM, 60mM~200mM, 70mM~200mM, 80mM~200mM, 90mM~200mM, 100mM~200mM, 150mM~200mM, 10mM~250mM, The product contains a buffer at concentrations of 15mM-250mM, 20mM-250mM, 25mM-250mM, 30mM-250mM, 40mM-250mM, 50mM-250mM, 60mM-250mM, 70mM-250mM, 80mM-250mM, 90mM-250mM, 100mM-250mM, 150mM-250mM, or 200mM-250mM. In another embodiment, the concentration of the buffer in the formulation is about 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 90 mM, 95 mM, or about 100 mM. In another embodiment, the buffer is present in the solution at a concentration of at least 20 mM or equal to 20 mM. In another embodiment, the buffer is present in the solution at a concentration of at least 25 mM or equal to 25 mM. In another embodiment, the buffer is present in the solution at a concentration of at least 50 mM or equal to 50 mM. In embodiments in which the characteristic solution contains two or more different buffers (e.g., at least two, three, four, five, six, seven, eight, nine, or ten or more), each of the two or more buffers may be present independently at, for example, one of the concentrations described above.

[0140] In certain embodiments, the buffer is monobasic sodium phosphate. In other specific embodiments, the buffer is dibasic sodium phosphate. In yet another specific embodiment, the buffer is monobasic sodium phosphate at a concentration of about 33.1 mM. In yet another specific embodiment, the buffer is dibasic sodium phosphate at a concentration of about 16.5 mM.

[0141] In one embodiment, the solution contains one or more surfactants, such as anionic, cationic, or nonionic surfactants. As used herein, the term “surfactant” refers to a surface-active molecule that contains both a hydrophobic moiety (e.g., an alkyl chain) and a hydrophilic moiety (e.g., a carboxyl group and a carboxylate group). In one embodiment, the surfactant in the formulation is a nonionic surfactant. In a particular embodiment, the surfactant in the formulation is a polyoxyethylene sorbitan fatty acid ester, such as polysorbate 20, 40, 60, 80, or one or more of these. In one embodiment, the surfactant in the formulation is polysorbate 80 (Tween 80). The amount of surfactant added to the formulation is sufficient to reduce aggregation of the formulated antibody and / or minimize the formation of particles in the formulation. For example, the surfactant may be present in the formulation in an amount of about 0.001% to about 1%, or about 0.001% to about 0.5%, or about 0.01% to about 0.2%. In one embodiment, the aqueous solution contains a surfactant in an amount of at least, or about 0.001% (for example, at least, or about 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0. It contains at concentrations of 17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, or 0.5% or more. In another embodiment, the aqueous solution contains 0.2% or less of a pharmaceutically acceptable surfactant (e.g., 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13, 0.12, 0.11, 0.10, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, or 0.001% or less).

[0142] In another embodiment, the formulation contains polysorbate at a concentration of about 0.001% to about 0.5%, about 0.005% to about 0.2%, about 0.01% to about 0.1%, or about 0.02% to about 0.06%, or about 0.03% to about 0.05% (w / v). In a particular embodiment, the formulation contains polysorbate at a concentration of 0.01%, or 0.02%, or 0.03%, or 0.04%, or 0.05%, or 0.06%, or 0.07%, or 0.08%, or 0.09%, or 0.1%, or 0.15%, or 0.2% (w / v). In a particular embodiment, the surfactant is present in the formulation at an amount of 0.02% or about 0.04% (w / v). In one embodiment, the surfactant is present in the formulation at an amount of 0.05% (w / v).

[0143] In one embodiment, the formulation contains at least about 0.01%, at least about 0.02%, at least about 0.05%, at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, or at least about 0.5% of polysorbate 80. In certain embodiments, the formulation contains approximately 0.01% to approximately 0.5%, approximately 0.01% to approximately 0.3%, approximately 0.001% to approximately 0.2%, approximately 0.02% to approximately 0.5%, approximately 0.02% to approximately 0.3%, approximately 0.02% to approximately 0.2%, approximately 0.05% to approximately 0.5%, approximately 0.05% to approximately 0.3%, approximately 0.05% to approximately 0.2%, approximately 0.075% to approximately 0.5%, approximately 0.075% to approximately 0.3%, or approximately 0.075% to approximately 0.2% of polysorbate 80. In further embodiments, the formulation contains approximately 0.01%, approximately 0.02%, approximately 0.05%, approximately 0.1%, approximately 0.2%, approximately 0.3%, approximately 0.4%, or approximately 0.5% of polysorbate 80. In one embodiment, the formulation contains about 0.05% polysorbate 80. In one embodiment, the formulation contains about 0.04% polysorbate 80. In one embodiment, the formulation contains about 0.03% polysorbate 80. In one embodiment, the formulation contains about 0.02% polysorbate 80. In one embodiment, the formulation contains about 0.01% polysorbate 80.

[0144] In one embodiment, the aqueous solution contains one or more salts, such as sodium chloride, potassium chloride, or magnesium chloride. In some embodiments, the aqueous solutions described herein contain salts at a concentration of at least 10 mM (for example, at least 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 mM or more). In some embodiments, the aqueous solutions described herein may contain salts at concentrations of less than 200 mM or about 200 mM (e.g., less than 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, 60, 50, 40, 30, 25, 20, 15, or 10 mM, or about 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, 60, 50, 40, 30, 25, 20, 15, or 10 mM).In some embodiments, the aqueous solutions described herein are approximately 10mM-50mM, 15mM-50mM, 20mM-50mM, 25mM-50mM, 30mM-50mM, 40mM-50mM, 10mM-100mM, 15mM-100mM, 20mM-100mM, 25mM-100mM, 30mM-100mM, 40mM-100mM, 10mM-15 0mM, 15mM~150mM, 20mM~150mM, 25mM~150mM, 30mM~150mM, 40mM~150mM, 50mM~100mM, 60mM~100mM , 70mM~100mM, 80mM~100mM, 50mM~150mM, 60mM~150mM, 70mM~150mM, 80mM~150mM, 90mM~150mM, 100 mM~150mM, 10mM~200mM, 15mM~200mM, 20mM~200mM, 25mM~200mM, 30mM~200mM, 40mM~200mM, 50mM~ 200mM, 60mM~200mM, 70mM~200mM, 80mM~200mM, 90mM~200mM, 100mM~200mM, 150mM~200mM, 10mM~25 The solution may contain salts at concentrations of 0 mM, 15 mM to 250 mM, 20 mM to 250 mM, 25 mM to 250 mM, 30 mM to 250 mM, 40 mM to 250 mM, 50 mM to 250 mM, 60 mM to 250 mM, 70 mM to 250 mM, 80 mM to 250 mM, 90 mM to 250 mM, 100 mM to 250 mM, 150 mM to 250 mM, or 200 mM to 250 mM. In embodiments in which the characteristic solution contains two or more different salts (e.g., at least two, three, four, five, six, seven, eight, nine, or ten or more), each of the two or more salts may exist independently at, for example, one of the concentrations mentioned above. In certain embodiments, the aqueous solution contains sodium chloride.

[0145] In one embodiment, the aqueous solution contains one or more carbohydrate excipients. Suitable carbohydrate excipients are, for example, Katakam and Banga (1995) J Pharm Pharmacol 47(2):103-107; Andya et al. (2003) AAPS PharmSci 5(2):Article 10; and Shire (2009) “Current Trends in Monoclonal Antibody This is described in "Development and Manufacturing," Volume 11, Springer, 354 pages. Suitable carbohydrate excipients for use in the solutions described herein include, but are not limited to, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, and sorbose; disaccharides such as lactose, sucrose, trehalose, and cellobiose; polysaccharides such as maltodextrin, dextran, and starch; and sugar alcohols such as mannitol, xylitol, maltitol, lactitol, and sorbitol. In one embodiment, the carbohydrate excipient is present in the solution characteristic of the present invention in an amount of at least, or about 0.5% (for example, at least, or about The excipients are present at concentrations of 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10%, or more. In embodiments in which the characteristic solution contains two or more different carbohydrate excipients (e.g., at least two, three, four, five, six, seven, eight, nine, or ten or more), each excipient can independently exist at any of the above concentrations.

[0146] In another embodiment, the stable aqueous solution contains one or more stabilizers.

[0147] Examples of stabilizers include, but are not limited to, polyols, sugars (e.g., sucrose or trehalose), amino acids (e.g., arginine), amines, and salting-out salts. In one embodiment, the solution contains at least one stabilizer at a concentration of 2% to 10%. In another embodiment, the solution contains at least one stabilizer at a concentration of 10 mM to 50 mM. In yet another embodiment, the stabilizer is present in the solution at a concentration of at least 20 mM or equal to 20 mM. In yet another embodiment, the stabilizer is present in the solution at a concentration of at least 25 mM or equal to 25 mM. In yet another embodiment, the stabilizer is present in the solution at a concentration of at least 50 mM or equal to 50 mM. In yet another embodiment, the solution contains 5% sucrose. In another embodiment, the solution contains about 30 mg / mL to 60 mg / mL of sucrose (for example, about 30 mg / mL, 31 mg / mL, 32 mg / mL, 33 mg / mL, 34 mg / mL, 35 mg / mL, 36 mg / mL, 37 mg / mL, 38 mg / mL, 39 mg / mL, 40 mg / mL, 41 mg / mL, 42 mg / mL, 43 mg / mL, 44 mg / mL, 45 mg / mL, 46 mg / mL, 47 mg / mL, 48 mg / mL, 49 mg / mL, 50 mg / mL, 51 mg / mL, 52 mg / mL, 53 mg / mL, 54 mg / mL, 55 mg / mL, 56 mg / mL, 57 mg / mL, 58 mg / mL, 59 mg / mL, or 60 mg / mL). In a particular embodiment, the solution contains 50 mg / mL of sucrose. In another embodiment, the solution contains 20-30 mM arginine (e.g., L-arginine). For example, in one embodiment, the solution contains 20 mM arginine, 21 mM arginine, 22 mM arginine, 23 mM arginine, 24 mM arginine, 25 mM arginine, 26 mM arginine, 27 mM arginine, 28 mM arginine, 29 mM arginine, or 30 mM arginine. In a particular embodiment, the solution contains 25 mM L-arginine.

[0148] In another embodiment, the solution includes water for injection.

[0149] In another embodiment, the pH is 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, or 7.9. In another embodiment, the pH of the solution is 7.0 to 7.4. In another embodiment, the pH of the solution is 7.2 to 7.8. In another embodiment, the pH of the solution is 7.2 to 7.6. In a particular embodiment, the pH of the solution is 7.4.

[0150] In another embodiment, the solution is in any container suitable for storing drugs and other therapeutic compositions. For example, the solution may be contained in a sealed and sterile vial, ampoule, syringe, cartridge, or plastic or glass container of a predetermined volume. Various types of vials, including, for example, glass or plastic vials, can be used to contain the solution of the present invention. In one embodiment, the vial is a 3 mL single-use vial. In another embodiment, the vial is a 3 mL single-use vial containing 300 mg of ravulizumab. In another embodiment, the vial is an 11 mL single-use vial. In another embodiment, the vial is an 11 mL single-use vial containing 1,100 mg of ravulizumab.

[0151] In another embodiment, the solution is diluted before administration. For example, in one embodiment, the solution is diluted with physiological saline (0.9% sodium chloride) before administration. In another embodiment, the solution is diluted to a concentration of 50 ± 15 mg / mL of ravulizumab (e.g., 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65 mg / mL of ravulizumab) before administration. In a specific embodiment, the solution is diluted to a concentration of approximately 50 mg / mL of ravulizumab before administration. In another embodiment, the solution is stable for up to 24 hours at 2°C to 8°C (36°F to 46°F) after dilution. In another embodiment, the amount of saline solution (e.g., sodium chloride) may be arbitrarily reduced, for example, when administering the solution to a patient on a sodium-restricted (e.g., low-sodium) diet.

[0152] In one embodiment, the stable aqueous solution contains an anti-C5 antibody, such as labulizumab, and seven or fewer other agents. In another embodiment, the stable aqueous solution contains an anti-C5 antibody, such as labulizumab, and six or fewer other agents. In yet another embodiment, the stable aqueous solution contains an anti-C5 antibody, such as labulizumab, and five or fewer other agents. In yet another embodiment, the stable aqueous solution contains an anti-C5 antibody, such as labulizumab, and four or fewer other agents. In yet another embodiment, the stable aqueous solution contains an anti-C5 antibody, such as labulizumab, and three or fewer other agents. In yet another embodiment, the stable aqueous solution contains an anti-C5 antibody, such as labulizumab, and two or fewer other agents. In yet another embodiment, the stable aqueous solution contains an anti-C5 antibody, such as labulizumab, and one or fewer other agents.

[0153] In another embodiment, a stable aqueous solution is labulizumab at a concentration of 100±20 (e.g., 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, or 120) mg / mL, 50±15 (e.g., 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, A solution comprising or consisting of 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65) mM phosphate buffer, 5 ± 3 (e.g., 2, 3, 4, 5, 6, 7, or 8)% sucrose, and 25 ± 10 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) mM arginine, where the solution has a pH of 7.4 ± 0.5 (e.g., 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, or 7.9).

[0154] In one embodiment, a stable aqueous solution comprises: (a) ravulizumab at a concentration of about 100 mg / mL, (b) sodium phosphate at about 50 mM, (c) polysorbate 80 at about 0.05 w / v%, (d) L-arginine at about 25 mM, (e) sucrose at about 50 mg / mL, and (f) water for injection, wherein the solution has a pH of about 7.4 and is contained in a 3 mL single-use vial containing 300 mg of ravulizumab.

[0155] In another embodiment, the stable aqueous solution consists of: (a) ravulizumab at a concentration of about 100 mg / mL, (b) sodium phosphate at about 50 mM, (c) polysorbate 80 at about 0.05 w / v%, (d) L-arginine at about 25 mM, (e) sucrose at about 50 mg / mL, and (f) water for injection, where the solution has a pH of about 7.4 and is contained in a 3 mL single-use vial containing 300 mg of ravulizumab.

[0156] In one embodiment, a stable aqueous solution consists of: (a) labulizumab at a concentration of 100 mg / mL, (b) about 50 mM sodium phosphate, (c) 0.05 w / v% polysorbate 80, (d) 25 mM L-arginine, (e) 50 mg / mL sucrose, and (f) water for injection, where the solution has a pH of about 7.4 and is contained in a 3 mL single-use vial containing 300 mg of labulizumab.

[0157] In one embodiment, a stable aqueous solution comprises: (a) ravulizumab at a concentration of about 100 mg / mL, (b) sodium phosphate at about 50 mM, (c) polysorbate 80 at about 0.05 w / v%, (d) L-arginine at about 25 mM, (e) sucrose at about 5 w / v%, and (f) water for injection, wherein the solution has a pH of about 7.4 and is contained in a 3 mL single-use vial containing 300 mg of ravulizumab.

[0158] In another embodiment, the stable aqueous solution consists of: (a) ravulizumab at a concentration of about 100 mg / mL, (b) sodium phosphate at about 50 mM, (c) polysorbate 80 at about 0.05 w / v%, (d) L-arginine at about 25 mM, (e) sucrose at about 5 w / v%, and (f) water for injection, where the solution has a pH of about 7.4 and is contained in a 3 mL single-use vial containing 300 mg of ravulizumab.

[0159] In one embodiment, a stable aqueous solution consists of: (a) labulizumab at a concentration of 100 mg / mL, (b) about 50 mM sodium phosphate, (c) 0.05 w / v% polysorbate 80, (d) 25 mM L-arginine, (e) 5 w / v% sucrose, and (f) water for injection, wherein the solution has a pH of about 7.4 and is contained in a 3 mL single-use vial containing 300 mg of labulizumab.

[0160] In another embodiment, the stable aqueous solution comprises: (a) ravulizumab at a concentration of about 100 mg / mL, (b) monobasic sodium phosphate at about 33.1 mM, (c) dibasic sodium phosphate at about 16.5 mM, (d) polysorbate 80 at about 0.05 w / v%, (f) L-arginine at about 25 mM, (g) sucrose at about 5 w / v%, and (h) water for injection, wherein the solution has a pH of about 7.4 and is contained in a 3 mL single-use vial containing 300 mg of ravulizumab.

[0161] In another embodiment, the stable aqueous solution consists of: (a) ravulizumab at a concentration of about 100 mg / mL, (b) monobasic sodium phosphate at about 33.1 mM, (c) dibasic sodium phosphate at about 16.5 mM, (d) polysorbate 80 at about 0.05 w / v%, (f) L-arginine at about 25 mM, (g) sucrose at about 5 w / v%, and (h) water for injection, where the solution has a pH of about 7.4 and is contained in a 3 mL single-use vial containing 300 mg of ravulizumab.

[0162] In another embodiment, the stable aqueous solution consists of: (a) labulizumab at a concentration of 100 mg / mL, (b) 33.1 mM monobasic sodium phosphate, (c) 16.5 mM dibasic sodium phosphate, (d) 0.05 w / v% polysorbate 80, (f) 25 mM L-arginine, (g) 5 w / v% sucrose, and (h) water for injection, where the solution has a pH of 7.4 and is contained in a 3 mL single-use vial containing 300 mg of labulizumab. In another embodiment, the stable aqueous solution comprises: (a) ravulizumab at a concentration of about 100 mg / mL, (b) monobasic sodium phosphate at about 33.1 mM, (c) dibasic sodium phosphate at about 16.5 mM, (d) polysorbate 80 at about 0.05 w / v%, (f) L-arginine at about 25 mM, (g) sucrose at about 50 mg / mL, and (h) water for injection, where the solution has a pH of about 7.4 and is contained in a 3 mL single-use vial containing 300 mg of ravulizumab.

[0163] In another embodiment, the stable aqueous solution consists of: (a) ravulizumab at a concentration of about 100 mg / mL, (b) monobasic sodium phosphate at about 33.1 mM, (c) dibasic sodium phosphate at about 16.5 mM, (d) polysorbate 80 at about 0.05 w / v%, (f) L-arginine at about 25 mM, (g) sucrose at about 50 mg / mL, and (h) water for injection, where the solution has a pH of about 7.4 and is contained in a 3 mL single-use vial containing 300 mg of ravulizumab.

[0164] In another embodiment, the stable aqueous solution consists of: (a) labulizumab at a concentration of 100 mg / mL, (b) 33.1 mM monobasic sodium phosphate, (c) 16.5 mM dibasic sodium phosphate, (d) 0.05 w / v% polysorbate 80, (f) 25 mM L-arginine, (g) 50 mg / mL sucrose, and (h) water for injection, where the solution has a pH of 7.4 and is contained in a 3 mL single-use vial containing 300 mg of labulizumab.

[0165] In another embodiment, the stable aqueous solution comprises: (a) ravulizumab at a concentration of about 100 mg / mL, (b) sodium phosphate at about 50 mM, (c) polysorbate 80 at about 0.05 w / v%, (d) L-arginine at about 25 mM, (e) sucrose at about 50 mg / mL, and (f) water for injection, where the solution has a pH of about 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of ravulizumab.

[0166] In another embodiment, the stable aqueous solution consists of: (a) ravulizumab at a concentration of about 100 mg / mL, (b) sodium phosphate at about 50 mM, (c) polysorbate 80 at about 0.05 w / v%, (d) L-arginine at about 25 mM, (e) sucrose at about 50 mg / mL, and (f) water for injection, where the solution has a pH of about 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of ravulizumab.

[0167] In another embodiment, the stable aqueous solution consists of: (a) labulizumab at a concentration of 100 mg / mL, (b) about 50 mM sodium phosphate, (c) 0.05 w / v% polysorbate 80, (d) 25 mM L-arginine, (e) 50 mg / mL sucrose, and (f) water for injection, where the solution has a pH of about 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of labulizumab.

[0168] In another embodiment, the stable aqueous solution comprises: (a) ravulizumab at a concentration of about 100 mg / mL, (b) sodium phosphate at about 50 mM, (c) polysorbate 80 at about 0.05 w / v%, (d) L-arginine at about 25 mM, (e) sucrose at about 5 w / v%, and (f) water for injection, where the solution has a pH of about 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of ravulizumab.

[0169] In another embodiment, the stable aqueous solution consists of: (a) ravulizumab at a concentration of about 100 mg / mL, (b) sodium phosphate at about 50 mM, (c) polysorbate 80 at about 0.05 w / v%, (d) L-arginine at about 25 mM, (e) sucrose at about 5 w / v%, and (f) water for injection, where the solution has a pH of about 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of ravulizumab.

[0170] In another embodiment, the stable aqueous solution consists of: (a) labulizumab at a concentration of 100 mg / mL, (b) about 50 mM sodium phosphate, (c) 0.05 w / v% polysorbate 80, (d) 25 mM L-arginine, (e) 5 w / v% sucrose, and (f) water for injection, where the solution has a pH of about 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of labulizumab.

[0171] In another embodiment, the stable aqueous solution comprises: (a) ravulizumab at a concentration of about 100 mg / mL, (b) monobasic sodium phosphate at about 33.1 mM, (c) dibasic sodium phosphate at about 16.5 mM, (d) polysorbate 80 at about 0.05 w / v%, (f) L-arginine at about 25 mM, (g) sucrose at about 5 w / v%, and (h) water for injection, where the solution has a pH of about 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of ravulizumab.

[0172] In another embodiment, the stable aqueous solution consists of: (a) ravulizumab at a concentration of about 100 mg / mL, (b) monobasic sodium phosphate at about 33.1 mM, (c) dibasic sodium phosphate at about 16.5 mM, (d) polysorbate 80 at about 0.05 w / v%, (f) L-arginine at about 25 mM, (g) sucrose at about 5 w / v%, and (h) water for injection, where the solution has a pH of about 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of ravulizumab.

[0173] In another embodiment, the stable aqueous solution consists of: (a) labulizumab at a concentration of 100 mg / mL, (b) 33.1 mM monobasic sodium phosphate, (c) 16.5 mM dibasic sodium phosphate, (d) 0.05 w / v% polysorbate 80, (f) 25 mM L-arginine, (g) 5 w / v% sucrose, and (h) water for injection, where the solution has a pH of 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of labulizumab. In another embodiment, the stable aqueous solution comprises: (a) ravulizumab at a concentration of about 100 mg / mL, (b) monobasic sodium phosphate at about 33.1 mM, (c) dibasic sodium phosphate at about 16.5 mM, (d) polysorbate 80 at about 0.05 w / v%, (f) L-arginine at about 25 mM, (g) sucrose at about 50 mg / mL, and (h) water for injection, where the solution has a pH of about 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of ravulizumab.

[0174] In another embodiment, the stable aqueous solution consists of: (a) ravulizumab at a concentration of about 100 mg / mL, (b) monobasic sodium phosphate at about 33.1 mM, (c) dibasic sodium phosphate at about 16.5 mM, (d) polysorbate 80 at about 0.05 w / v%, (f) L-arginine at about 25 mM, (g) sucrose at about 50 mg / mL, and (h) water for injection, where the solution has a pH of about 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of ravulizumab.

[0175] In another embodiment, the stable aqueous solution consists of: (a) labulizumab at a concentration of 100 mg / mL, (b) 33.1 mM monobasic sodium phosphate, (c) 16.5 mM dibasic sodium phosphate, (d) 0.05 w / v% polysorbate 80, (f) 25 mM L-arginine, (g) 50 mg / mL sucrose, and (h) water for injection, where the solution has a pH of 7.4 and is contained in an 11 mL single-use vial containing 1100 mg of labulizumab.

[0176] In another embodiment, the stable aqueous solution is sterile. In another embodiment, the solution is a sterile, translucent, clear to yellowish preservative-free solution. In another embodiment, the solution has a shelf life of 18 months.

[0177] The solutions described herein may be formulated for any preferred method of administration. In one embodiment, the solution is formulated for parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection). In a particular embodiment, the solution is formulated for subcutaneous administration. For example, in one embodiment, a stable aqueous solution contains 100 mg / mL of anti-C5 antibody and is formulated for subcutaneous administration. In another particular embodiment, the solution is formulated for intravenous administration (e.g., via intravenous infusion). For example, in one embodiment, a stable aqueous solution contains 100 mg / mL of ravulizumab and is formulated for intravenous infusion.

[0178] III. Treatment method The solutions described may be used to treat a variety of diseases and conditions in human patients. In one embodiment, the solution may be used to treat complement-related disorders including, but not limited to, rheumatoid arthritis (RA), antiphospholipid syndrome, lupus nephritis, ischemia-reperfusion injury, thrombotic microangiopathy (TMA), atypical hemolytic uremic syndrome (aHUS), typical or infectious hemolytic uremic syndrome (tHUS), dense deposit disease (DDD), paroxysmal nocturnal hemoglobinuria (PNH), neuromyelitis optica (NMO), multifocal motor neuropathy (MMN), multiple sclerosis (MS), macular degeneration (e.g., age-related macular degeneration (AMD)), hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, thrombotic thrombocytopenic purpura (TTP), spontaneous miscarriage, microimmune vasculitis, epidermolysis bullosa, recurrent miscarriage, and traumatic brain injury (e.g., Holers (2008) Immunological Reviews). See 223:300-316 and Holers and Thurman (2004) Molecular Immunology 41:147-152.

[0179] In another embodiment, complement-related disorders include, but are not limited to, diabetes-related vascular disorders (e.g., ocular), central retinal vein occlusion, cardiovascular disorders, myocarditis, cerebrovascular disorders, peripheral (e.g., musculoskeletal) vascular disorders, renal vascular disorders, mesenteric / intestinal vascular disorders, vascular regeneration to grafts and / or regrafts, vasculitis, Henoch-Schönlein purpura nephritis, lupus erythematosus-associated vasculitis, rheumatoid arthritis-associated vasculitis, immune complex vasculitis, Takayasu's arteritis, dilated cardiomyopathy, diabetic vasculopathy, Kawasaki disease (arteritis), venous gas embolism (VGE), and restenosis after stent placement, rotational atherectomy, and percutaneous transcatheter arterial angioplasty (PTCA) (see, for example, U.S. Patent Application Publication No. 20070172483).

[0180] Additional complement-related disorders include, but are not limited to, myasthenia gravis, cold agglutinin disease, dermatomyositis, Graves' disease, atherosclerosis, Alzheimer's disease, Guillain-Barré syndrome, Degaud's disease, graft rejection (e.g., transplant rejection), sepsis, burns (e.g., severe burns), systemic inflammatory septic nephrosis, septic shock, spinal cord injury, glomerulonephritis, Hashimoto's thyroiditis, type 1 diabetes mellitus, psoriasis, pemphigus, autoimmune hemolytic anemia (AIHA), idiopathic thrombocytopenic purpura (ITP), Goodpasture syndrome, antiphospholipid syndrome (APS), fulminant APS (CAPS), amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and chronic inflammatory demyelinating neuropathy.

[0181] In another embodiment, the solutions described herein can be used to treat thrombotic microangiopathy (TMA), TMA associated with complement-related disorders such as any of the complement-related disorders described herein, including atypical hemolytic uremic syndrome (aHUS).

[0182] Complement-related disorders include, but are not limited to, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), interstitial lung disease, alpha-1 antitrypsin deficiency, emphysema, bronchiectasis, bronchiolitis obstructive, periodontitis, sarcoidosis, pulmonary fibrosis, and collagen vascular disease.

[0183] In another embodiment, the solutions described herein are administered to a subject to treat, prevent, or improve at least one symptom of a complement-related inflammatory response (e.g., a complement-related inflammatory response pattern of complement-related disorder) in the subject. For example, the compositions can be used to treat, prevent, and / or improve one or more symptoms associated with complement-related inflammatory responses such as graft rejection / graft-versus-host disease (GVHD), reperfusion injury (e.g., after cardiopulmonary bypass or tissue transplantation), and tissue injury following burns (e.g., severe burns), blunt trauma, spinal cord injury, or other forms of trauma such as frostbite. For example, see Park et al. (1999) Anesth Analg 99(1):42-48; Tofukuji et al. (1998) J Thorac Cardiovasc Surg 116(6):1060-1068; Schmid et al. (1997) Shock 8(2):119-124; and Bless et al. (1999) Am J Physiol 276(1):L57-L63.

[0184] In another embodiment, complement-mediated disorders include, but are not limited to, cardiovascular disorders, myocarditis, cerebrovascular disorders, peripheral (e.g., musculoskeletal) vascular disorders, renal vascular disorders, mesenteric / intestinal vascular disorders, vascular regeneration to grafts and / or regrafts, vasculitis, Henoch-Schönlein purpura nephritis, lupus erythematosus-associated vasculitis, rheumatoid arthritis-associated vasculitis, immune complex vasculitis, organ or tissue transplantation, Takayasu's arteriovenous arthritis, capillary leak syndrome, dilated cardiomyopathy, diabetic vasculopathy, thoracoabdominal aortic aneurysm, Kawasaki disease (arteritis), venous gas embolism (VGE), and restenosis after stent placement, rotational atherectomy, and percutaneous transcatheter coronary angioplasty (PTCA) (see, for example, U.S. Patent Application Publication No. 20070172483). In one embodiment, a method is provided for treating a human patient, the method comprising administering a stable aqueous solution to the patient based on the patient's body weight. For example, in one embodiment, a method is provided for treating a human patient suffering from PNH, the method comprising administering a stable aqueous solution to the patient (e.g., via intravenous infusion), wherein the stable aqueous solution has a pH of about 7.4 and contains or comprises ravulizumab at a concentration of about 100 mg / mL, monobasic sodium phosphate at about 33.1 mM, dibasic sodium phosphate at about 16.5 mM, polysorbate 80 at about 0.05 w / v%, L-arginine at about 25 mM, sucrose at about 50 mg / mL, and water for injection, wherein the stable aqueous solution is (c) On the first day, For patients weighing ≥40kg to <60kg, 2,400mg. For patients weighing ≥60kg to <100kg, 2,700mg, or For patients weighing ≥100 kg, a dose of 3,000 mg; and (b) On day 15, and every 8 weeks thereafter, For patients weighing ≥40kg to <60kg, 3,000mg. For patients weighing ≥60kg to <100kg, 3,300mg, or It is administered to human patients at a dose of 3,600 mg for patients weighing ≥100 kg.

[0185] In one embodiment, a stable aqueous solution is administered to human patients weighing ≥40kg to <60kg at a dose of 2,400mg on day 1, and then at a dose of 3,000mg on day 15 and every 8 weeks thereafter. In another embodiment, the aqueous solution is administered to human patients weighing ≥60kg to <100kg at a dose of 2,700mg on day 1, and then at a dose of 3,300mg on day 15 and every 8 weeks thereafter. In yet another embodiment, the stable aqueous solution is administered to human patients weighing ≥100kg at a dose of 3,000mg on day 1, and then at a dose of 3,600mg on day 15 and every 8 weeks thereafter.

[0186] In another embodiment, a method is provided for treating a human patient suffering from aHUS, the method comprising administering a stable aqueous solution to the patient (e.g., via intravenous infusion), wherein the stable aqueous solution has a pH of about 7.4 and comprises or consists of ravulizumab at a concentration of about 100 mg / mL, monobasic sodium phosphate at about 33.1 mM, dibasic sodium phosphate at about 16.5 mM, polysorbate 80 at about 0.05 w / v%, L-arginine at about 25 mM, sucrose at about 50 mg / mL, and water for injection, wherein the stable aqueous solution is (d) On the first day, For patients weighing ≥5kg to <10kg, 600mg. For patients weighing ≥10kg to <20kg, 600mg. For patients weighing ≥20kg to <30kg, 900mg. For patients weighing ≥30kg to <40kg, 1,200mg. For patients weighing ≥40kg to <60kg, 2,400mg. For patients weighing ≥60kg to <100kg, 2,700mg, or For patients weighing ≥100 kg, a dose of 3,000 mg; and (b) On the 15th day, and every 4 or 8 weeks thereafter, For patients weighing ≥5kg to <10kg, 300mg. For patients weighing ≥10kg to <20kg, 600mg. For patients weighing ≥20kg to <30kg, 2,100mg. For patients weighing ≥30kg to <40kg, 2,700mg. For patients weighing ≥40kg to <60kg, 3,000mg. For patients weighing ≥60kg to <100kg, 3,300mg, or It is administered to human patients at a dose of 3,600 mg for patients weighing ≥100 kg.

[0187] In one embodiment, a stable aqueous solution is administered to human patients weighing ≥5kg to <10kg at a dose of 600mg on day 1, and then at a dose of 300mg on day 15 and every four weeks thereafter. In another embodiment, a stable aqueous solution is administered to human patients weighing ≥10kg to <20kg at a dose of 600mg on day 1, and then at a dose of 600mg on day 15 and every four weeks thereafter. In yet another embodiment, a stable aqueous solution is administered to human patients weighing ≥20kg to <30kg at a dose of 900mg on day 1, and then at a dose of 2,100mg on day 15 and every eight weeks thereafter. In yet another embodiment, a stable aqueous solution is administered to human patients weighing ≥30kg to <40kg at a dose of 1,200mg on day 1, and then at a dose of 2,700mg on day 15 and every eight weeks thereafter. In another embodiment, the stable aqueous solution is administered to human patients weighing ≥40 kg to <60 kg at a dose of 2,400 mg on day 1, and at a dose of 3,000 mg on day 15 and every 8 weeks thereafter. In another embodiment, the stable aqueous solution is administered to human patients weighing ≥60 kg to <100 kg at a dose of 2,700 mg on day 1, and at a dose of 3,300 mg on day 15 and every 8 weeks thereafter. In another embodiment, the stable aqueous solution is administered to human patients weighing ≥100 kg at a dose of 3,000 mg on day 1, and at a dose of 3,600 mg on day 15 and every 8 weeks thereafter. In another embodiment, the stable aqueous solution is supplied in a 3 mL single-use vial containing 300 mg of ravulizumab. In another embodiment, the stable aqueous solution is supplied in an 11 mL single-use vial containing 1,100 mg of ravulizumab.

[0188] In other embodiments, a method is provided for treating a human patient, the method comprising administering a stable aqueous solution to the patient in a fixed, uniform dose regardless of the patient's body weight. For example, the stable aqueous solution may be administered in fixed doses of 1000, 1400, 1600, 1800, 2000, 2400, 3000, or 5400 mg, regardless of the patient's body weight. In certain embodiments, the administration regimen is adjusted to produce the optimal desired response (e.g., an effective response).

[0189] In another embodiment, the stable aqueous solution is administered to a human patient at a dose of 3000 mg during the induction phase. In another embodiment, the stable aqueous solution is administered to a human patient once at a dose of 3000 mg during the induction phase. In another embodiment, the stable aqueous solution is administered to a human patient at a dose of 5400 mg during the maintenance phase. In another embodiment, the stable aqueous solution is administered to a human patient three times at a dose of 5400 mg during the maintenance phase. For example, an anti-C5 antibody, or its antigen-binding fragment, is administered at a dose of 5400 mg on day 29 of the administration cycle, and then every 84 days (or 12 weeks) thereafter during the maintenance phase, i.e., on days 113 and 197 of the administration cycle. In another embodiment, the stable aqueous solution is administered to a human patient at a dose of (a) 3,000 mg on day 1, (b) 5,400 mg four weeks later, and then (c) 5,400 mg every 84 days (or 12 weeks) thereafter. In another embodiment, the stable aqueous solution is administered to human patients in doses of (a) 3,000 mg on day 1 of the induction cycle, and (b) 5,400 mg on day 29 of the maintenance cycle, and subsequently every 84 days (or 12 weeks) thereafter. In another embodiment, the stable aqueous solution is administered to human patients in doses of (a) 3,000 mg on day 1 of the induction cycle, and 5,400 mg on days 29, 113, and 197 of the maintenance cycle. In another embodiment, the stable aqueous solution contains ravulizumab at a concentration of 10 mg / mL. In another embodiment, the stable aqueous solution contains ravulizumab at a concentration of 100 mg / mL.

[0190] The infusion time and rate for administering 100 mg / mL of the stable aqueous solution described herein are significantly (e.g., at least 50%) lower compared to the infusion time and rate for equivalent lower doses (e.g., 10 mg / mL) of the solution. The infusion time and rate are adjustable by the clinician as needed. In one embodiment, the stable aqueous solution is administered to a human patient weighing ≥5 kg to <10 kg at a dose of 600 mg on day 1, with a minimum infusion time of 1.4 hours and a maximum infusion rate of 8 mL / hour. In another embodiment, the stable aqueous solution is administered to a human patient weighing ≥5 kg to <10 kg at a dose of 300 mg on day 15 and every 4 weeks thereafter, with a minimum infusion time of 0.8 hours and a maximum infusion rate of 8 mL / hour. In yet another embodiment, the stable aqueous solution is administered to a human patient weighing ≥10 kg to <20 kg at a dose of 600 mg on day 1, with a minimum infusion time of 0.8 hours and a maximum infusion rate of 16 mL / hour. In another embodiment, the stable aqueous solution is administered to human patients weighing ≥10kg to <20kg at a dose of 600mg on day 15 and every 4 weeks thereafter, with a minimum infusion time of 0.8 hours and a maximum infusion rate of 16mL / hour. In another embodiment, the stable aqueous solution is administered to human patients weighing ≥20kg to <30kg at a dose of 900mg on day 1 at a minimum infusion time of 0.6 hours and a maximum infusion rate of 30mL / hour. In another embodiment, the stable aqueous solution is administered to human patients weighing ≥20kg to <30kg at a dose of 2,100mg on day 15 and every 8 weeks thereafter, with a minimum infusion time of 1.3 hours and a maximum infusion rate of 33mL / hour. In another embodiment, the stable aqueous solution is administered to human patients weighing ≥30kg to <40kg at a dose of 1,200mg on day 1 at a minimum infusion time of 0.5 hours and a maximum infusion rate of 46mL / hour. In another embodiment, a stable aqueous solution is administered to human patients weighing ≥30kg to <40kg at a dose of 2,700mg on day 15 and every 8 weeks thereafter, with a minimum infusion time of 1.1 hours and a maximum infusion rate of 49mL / hour. In yet another embodiment, a stable aqueous solution is administered to human patients weighing ≥40kg to <60kg at a dose of 2,400mg on day 1 at a minimum infusion time of 0.8 hours and a maximum infusion rate of 64mL / hour.In another embodiment, the stable aqueous solution is administered to human patients weighing ≥40kg to <60kg at a dose of 3,000mg on day 15 and every 8 weeks thereafter, with a minimum infusion time of 0.9 hours and a maximum infusion rate of 65mL / hour. In another embodiment, the stable aqueous solution is administered to human patients weighing ≥60kg to <100kg at a dose of 2,700mg on day 1 at a minimum infusion time of 0.6 hours and a maximum infusion rate of 92mL / hour. In another embodiment, the stable aqueous solution is administered to human patients weighing ≥60kg to <100kg at a dose of 3,300mg on day 15 and every 8 weeks thereafter, with a minimum infusion time of 0.7 hours and a maximum infusion rate of 99mL / hour. In another embodiment, the stable aqueous solution is administered to human patients weighing ≥100kg at a dose of 3,000mg on day 1 at a minimum infusion time of 0.4 hours and a maximum infusion rate of 144mL / hour. In another embodiment, a stable aqueous solution is administered to human patients weighing ≥100 kg at a dose of 3,600 mg on day 15 and every 8 weeks thereafter, with a minimum infusion time of 0.5 hours and a maximum infusion rate of 144 mL / hour.

[0191] IV. Combination Therapy In one embodiment, the solutions described herein are administered to a patient as monotherapy. In another embodiment, they are administered in combination with one or more additional agents and / or other therapies (e.g., suitable for the treatment of complement-related disorders). For example, combination therapy may involve administering to a human patient one or more additional agents (e.g., anticoagulants, antihypertensives, or anti-inflammatory agents (e.g., steroids)) that provide therapeutic benefits to the patient. In one embodiment, the solutions described herein are administered in combination with anti-inflammatory agents (e.g., NSAIDs, corticosteroids, anti-TNF agents such as methotrexate, hydroxychloroquine, etanercept, and infliximab, B-cell depleting agents such as rituximab, interleukin-1 antagonists, or T-cell costimulators such as abatacept).

[0192] Additional medications to treat complement-related disorders in the patient vary depending on the specific disease being treated, but are not limited to: one or more antihypertensive drugs (e.g., angiotensin-converting enzyme inhibitors, labetalol, hydralazine, nifedipine, calcium channel antagonists, nitroglycerin, or sodium nitroferricyanide), anticoagulants, corticosteroids (e.g., prednisone), immunosuppressants (e.g., vincristine or cyclosporine A), anticoagulants (e.g., warfarin (Coumadin), aspirin, heparin, phenindione, fondaparinux, hydraparinux), thrombin inhibitors (e.g., argatroban, repiridine, bivalirudine, or dabigatran), and alpha-fibrinolytic agents (e.g., anclod, alpha- Examples include aminocaproic acid, anti-plasmin-α1, prostacyclin, and defibrotide, antihypertensive agents (e.g., labetalol, hydralazine, nifedipine, calcium channel antagonists, nitroglycerin, or sodium nitroferricyanide), lipid-lowering agents (e.g., inhibitors of hydroxymethylglutaryl-CoA reductase), antiepileptic agents (e.g., magnesium sulfate), antithrombotic agents (e.g., heparin, antithrombin, prostacyclin, or low-dose aspirin), sympathomimetic agents (e.g., albuterol), antibiotics, deoxyribonucleases (e.g., Pulmozyme®), anticholinergic agents, anti-IgE inhibitors (e.g., anti-IgE antibodies), corticosteroids, or nonsteroidal anti-inflammatory drugs (NSAIDs).A variety of NSAIDs are available, some of which are over-the-counter drugs including ibuprofen (Advil®, Motrin®, Nuprin®) and naproxen (Alleve®), and many others including meloxicam (Mobic®), etodolac (Lodine®), nabumetone (Relafen®), sulindac (Clinoril®), tolmetin (Tolectin®), magnesium choline salicylate (Trilasate®), diclofenac (Cataflam®, Voltaren®, Arthrotec®), diflunisal (Dolobid®), indomethacin (Indocin®), ketoprofen (Orudis®, Oruvail®), oxaprozin (Daypro®), and piroxicam (Feldene®) are available by prescription (see, for example, Mihu et al. (2007) J Gastrointestin Liver Dis 16(4):419-424). In another embodiment, the solution described herein can be formulated for administration to a patient in combination with intravenous gamma globulin therapy (IVIG), plasmapheresis, plasma exchange, or hemodialysis.

[0193] In one embodiment, the solution and one or more additional agents and / or therapies are administered simultaneously. In another embodiment, the solution is administered before one or more additional agents and / or therapies are administered. In another embodiment, the solution is administered after one or more additional agents and / or therapies are administered. When the antibody solution described herein is used in combination with a second active agent, the agents (e.g., anti-C5 antibody and the second agent) may be formulated separately or together. For example, the solution and the agent may be mixed together, for example, immediately prior to administration and administered together, or may be administered separately, for example, simultaneously or at different times.

[0194] V. Kits and Unit Dosage Forms Also provided herein are kits comprising a stable aqueous solution containing an anti-C5 antibody, such as ravulizumab, or an antigen-binding fragment thereof, in a therapeutically effective amount suitable for administration to a human patient (e.g., a patient having a complement-related disorder). The kit may optionally also include instructions, for example, a dosing schedule, to enable a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to administer the solution to a patient.

[0195] The kit may also contain suitable means for delivering one or more solutions to a patient who needs it, e.g., a patient suffering from, suspected of having, or at risk of developing a complement-related disorder. In one embodiment, the means is suitable for intravenous delivery of the solution to the patient.

[0196] Optionally, the kit includes a plurality of packages of single-dose solutions each containing an effective amount of the solution for a single administration. The kit may also include the equipment or device necessary to administer the solution. For example, the kit can provide one or more pre-filled syringes containing the solution.

[0197] In one embodiment, the kit comprises (i) any of the solutions described herein, and (ii) instructions for use. In another embodiment, the kit comprises (i) any of the solutions described herein, (ii) physiological saline (0.9% sodium chloride), and (iii) instructions for use. In another embodiment, the kit comprises (i) a formulation comprising or consisting of ravulizumab at a concentration of about 100 mg / mL, about 33.1 mM monobasic sodium phosphate, about 16.5 mM dibasic sodium phosphate, about 0.05 w / v% polysorbate 80, about 25 mM L-arginine, and about 50 mg / mL sucrose, (ii) physiological saline (0.9% sodium chloride), and (iii) instructions for use. In another embodiment, the formulation is lyophilized. In another embodiment, the kit includes a 3 mL single-use vial containing 300 mg of ravulizumab. In another embodiment, the kit includes an 11 mL single-use vial containing 1,100 mg of ravulizumab.

[0198] VI. Method for preparing high-concentration antibody solutions Methods for preparing high-concentration anti-C5 antibody solutions are also provided herein. In one embodiment, a method is provided for producing a stable aqueous solution containing ravulizumab at a concentration of about 10 mg / mL or less, about 33.1 mM monobasic sodium phosphate, about 16.5 mM dibasic sodium phosphate, about 0.05 w / v% polysorbate 80, about 25 mM L-arginine, about 50 mg / mL sucrose, and water for injection, and the method is as follows: i) To provide a first aqueous solution containing approximately 10 mg / mL of ravulizumab, ii) Diafiltration of the first aqueous solution into a mixture of approximately 33.1 mM monobasic sodium phosphate, approximately 16.5 mM dibasic sodium phosphate, approximately 0.05 w / v% polysorbate 80, approximately 25 mM L-arginine, approximately 50 mg / mL sucrose, and water for injection at pH 7.4, thereby producing a second aqueous solution. iii) Concentrating the second aqueous solution to produce a stable aqueous solution containing ravulizumab at a concentration of approximately 100 mg / mL, monobasic sodium phosphate at approximately 33.1 mM, dibasic sodium phosphate at approximately 16.5 mM, polysorbate 80 at approximately 0.05 w / v%, L-arginine at approximately 25 mM, sucrose at approximately 50 mg / mL, and water for injection.

[0199] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which this disclosure pertains. Methods and materials for use in this disclosure are described herein. Other suitable methods and materials known in the art may also be used. Materials, methods, and examples are illustrative and not intended to limit. All publications, patent applications, patents, sequences, database entries (e.g., PUBMED, NCBI, or UNIPROT accession numbers), and other references mentioned herein are incorporated in their entirety by reference. [Examples]

[0200] Example 1: Formulation A sterile aqueous solution containing 100 mg / mL of ULTOMIRIS® (ravulizumab) in 50 mM sodium phosphate, 25 mM L-arginine, 5% (w / v) sucrose, and 0.05% (w / v) polysorbate 80 at pH 7.4 was prepared in 3 ml and 11 mL glass vials with stoppers. The solution is designed for infusion by dilution in commercially available physiological saline (0.9% sodium chloride).

[0201] A. Formulations The quantitative and qualitative composition of the formulation is shown in Table 1. Excipients are tested against the United States Pharmacopeia (USP), the European Pharmacopoeia (Ph.Eur.), and / or the Japanese Pharmacopoeia (JP). The vial content of ravulizumab is based on the extractable amount.

[0202] [Table 1]

[0203] The container closure system consists of a USP / Ph.Eur. Type 1 glass vial, a butyl rubber stopper laminated with Flurotec®, and an aluminum seal with a polypropylene flip-off cap.

[0204] ULTOMIRIS® (ravulizumab) injection 100 mg / mL is a sterile, translucent, clear to yellowish, preservative-free solution for intravenous use. Each single-dose vial contains 300 mg or 1,100 mg of ULTOMIRIS® (ravulizumab) at a concentration of 100 mg / mL at pH 7.4. Each mL also contains polysorbate 80 (0.5 mg) (plant-derived), sodium chloride (8.77 mg), dibasic sodium phosphate (4.42 mg), monobasic sodium phosphate (4.57 mg), L-arginine (4.33 mg), sucrose (50 mg), and water for injection (USP).

[0205] The product is available as a preservative-free solution supplied in single-use vials with the following potencies per carton.

[0206] [Table 2]

[0207] ULTOMIRIS® (ravulizumab) vials should be stored refrigerated in their original carton at 2°C to 8°C (36°F to 46°F) to protect them from light. They should not be frozen or shaken.

[0208] B. Adaptation ULTOMIRIS® (ravulizumab) is indicated for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH), and for the treatment of complement-mediated thrombotic microangiopathy (TMA) in adult and pediatric patients aged 1 month or older with atypical hemolytic uremic syndrome (aHUS). ULTOMIRIS® (ravulizumab) is indicated for Shiga toxin E. coli-associated hemolytic uremic syndrome. This treatment is not suitable for patients with hemolytic uremic syndrome (STEC-HUS).

[0209] C. Medication and Administration Patients will receive meningococcal disease vaccination in accordance with current ACIP guidelines to reduce the risk of serious infection. If ULTOMIRIS® (ravulizumab) therapy is started immediately and the vaccine is administered less than two weeks prior to the start of ULTOMIRIS® (ravulizumab) therapy, the patient will receive two weeks of antimicrobial prophylaxis.

[0210] The recommended dosing regimen for adult patients with PNH weighing 40 kg or more consists of a loading dose administered by intravenous infusion and subsequent maintenance dosing. As shown in Table 3, the dose is administered based on the patient's weight. Starting 2 weeks after administration of the loading dose, the maintenance dose is initiated at intervals of once every 8 weeks. The dosing schedule may sometimes be changed within 7 days from the scheduled infusion date (except for the first maintenance dose of ULTOMIRIS® (ravulizumab)), but subsequent doses should be administered according to the original schedule.

[0211]

Table 3

[0212] The recommended dosing regimen for adult patients with aHUS weighing 5 kg or more and pediatric patients 1 month of age or older consists of a loading dose administered by intravenous infusion and subsequent maintenance dosing. As shown in Table 4, the dose is administered based on the patient's weight. Starting 2 weeks after administration of the loading dose, the maintenance dose is initiated once every 8 weeks or once every 4 weeks (depending on weight).

[0213] The dosing schedule may sometimes be changed within​​​​​​​​​​​​​Administration of PE / PI (plasmapheresis, plasma exchange, or fresh frozen plasma infusion) may reduce serum concentrations of ULTOMIRIS® (ravulizumab).

[0216] D. Preparation Each vial of ULTOMIRIS® (ravulizumab) is intended for single-dose use only. ULTOMIRIS® (ravulizumab) is supplied in single-dose vials containing 300 mg / 3 mL (100 mg / mL) and 1,100 mg / 11 mL (100 mg / mL). ULTOMIRIS® (ravulizumab) 100 mg / mL (3 mL and 11 mL vials) and 10 mg / mL (30 mL vial) should not be mixed.

[0217] ULTOMIRIS® (labulizumab) requires dilution to a final concentration of 50 mg / mL in 3 mL and 11 mL vials, or to a final concentration of 5 mg / mL in a 30 mL vial. The following sterile techniques are used for the preparation of ULTOMIRIS. 1. The number of vials to be diluted is determined based on the individual patient's weight and prescribed dosage. 2. Visually inspect the solution in the vial before dilution. The solution should not contain any particulate matter or precipitate. If evidence of particulate matter or precipitate is present, the solution should not be used. 3. Dispense the calculated amount of ULTOMIRIS® (ravulizumab) from an appropriate number of vials and dilute it in an infusion bag using 0.9% sodium chloride injection (USP) to a final concentration of 50 mg / mL in 3 mL and 11 mL vials, or to a final concentration of 5 mg / mL in a 30 mL vial. Gently mix the product. It should not be frozen or shaken, and should be protected from light. 4. Administer the prepared solution immediately after preparation. The injectable solution should be administered through a 0.2 or 0.22 micrometer filter. 5. If the diluted ULTOMIRIS® (ravulizumab) infusion solution is not to be used immediately, store it refrigerated at 2°C to 8°C (36°F to 46°F) for more than 24 hours, including the expected infusion time. Once removed from refrigeration, the diluted ULTOMIRIS® (ravulizumab) infusion solution should be administered within 6 hours if prepared in 3 mL or 11 mL vials of ULTOMIRIS® (ravulizumab).

[0218] E. Administration ULTOMIRIS® (ravulizumab) is administered intravenously. ULTOMIRIS® (ravulizumab) is diluted to a final concentration of 50 mg / mL in the 100 mg / mL formulation (3 mL and 11 mL vials). ULTOMIRIS® (ravulizumab) is administered via a 0.2 or 0.22 micrometer filter. The loading and maintenance doses for ULTOMIRIS® (ravulizumab) 100 mg / mL (3 mL and 11 mL vials) are listed in Tables 5 and 6 below.

[0219] [Table 5]

[0220] [Table 6]

[0221] Before administration, allow the mixture to reach room temperature (18°C to 25°C, 64°F to 77°F). Do not heat the mixture with any heat source other than the ambient air temperature.

[0222] If an adverse reaction occurs during administration of ULTOMIRIS® (ravulizumab), the infusion may be slowed or discontinued at the physician's discretion. The patient should be observed for signs or symptoms of an infusion reaction for at least one hour after the completion of the infusion.

[0223] Example 2: Interim analysis of a Phase 2 study evaluating the efficacy, safety, and pharmacokinetics of intravenous ravulizumab 100 mg / ml in patients with PNH. ULTOMIRIS® (ravulizumab) has demonstrated proven efficacy (e.g., control of intravascular hemolysis, transfusion independence, and minimal breakthrough hemolysis) and safety in two large Phase 3 clinical trials and in real-world PNH populations. Therefore, an interim analysis of the Phase 2 open-label multiple dose escalation study extension (NCT02605993) was conducted to characterize the efficacy, safety, pharmacokinetics (PK), and immunogenicity of ULTOMIRIS® (ravulizumab) after a change in formulation (from 10 mg / mL intravenous (IV) to 100 mg / mL IV).

[0224] In summary, four different ULTOMIRIS® (ravulizumab) dosing regimens were administered to complement-inhibitor-naive adults with PNH, following the protocol described in International Publication No. 2017 / 123636, whose contents are expressly incorporated herein by reference (Cohorts 1-4; see figures). In the extension phase, Cohorts 1-3 switched to weight-based dosing, and subsequently, in the later stages of the extension period, all cohorts changed from ULTOMIRIS® (ravulizumab) 10 mg / mL IV to 100 mg / mL IV. Data before and after the formulation change were then compared. Efficacy (lactate dehydrogenase levels), safety, PK (serum ULTOMIRIS® (ravulizumab) trough concentration), and immunogenicity were evaluated. Analysis of Cohorts 1-3 (who received weight-based dosing every 8 weeks (q8w)) was grouped. The results for Cohort 4 (administered every 12 weeks) are presented separately. Adverse events (AEs) were coded using the Medical Dictionary for Regulatory Activities version 21.0. Patients were given informed consent, and approval was granted by the relevant healthcare institution's ethics committee.

[0225] A total of 25 patients who received ULTOMIRIS® (ravulizumab) 10 mg / mL IV switched to 100 mg / mL IV. The majority of patients were male (76.0%, n=19). Ethnicity was reported as non-Hispanic or Latino (84.0%, n=21), Hispanic or Latino (4.0%, n=1), or not provided (12.0%, n=3). Patients reported their race as Caucasian (60.0%, n=15), Asian (24.0%, n=6), "other" (4.0%, n=1), or did not disclose this information (12.0%, n=3). The mean (standard deviation [SD]) age at the first infusion was 44.6 (16.5) years. At baseline, mean (SD) weight, height, and body mass index were 78.1 (14.8) kg, 174.8 (10.6) cm, and 25.4 (3.2) kg / m², respectively. 2 No significant differences in mean lactate dehydrogenase levels or serum trough concentrations were observed after the formulation change. The overall exposure-adjusted rates for therapeutic adverse reactions (TEAEs) and serious adverse events (AEs) were comparable for both formulations, and all reported TEAEs were considered unrelated to ULTOMIRIS® (ravulizumab). No deaths, discontinuations, or positive anti-drug antibody responses occurred before or after the formulation change. In adult patients weighing 40-60 kg, using the 100 mg / mL formulation reduced infusion time by 87 minutes compared to the 10 mg / mL formulation (57 minutes [100 mg / mL] vs. 144 minutes [10 mg / mL]). Infusion time was reduced by 78 minutes for patients weighing 60-100 kg (42 minutes [100 mg / mL] vs. 120 minutes [10 mg / mL]) and by 102 minutes for patients weighing >100 kg (30 minutes [100 mg / mL] vs. 132 minutes [10 mg / mL]).

[0226] In this interim analysis, the efficacy, safety, pharmacokinetics, and immunogenicity of ULTOMIRIS® (ravulizumab) IV 100 mg / mL were equivalent to those of the IV 10 mg / mL formulation, and the higher concentration formulation was well-tolerated in patients with PNH. ULTOMIRIS® (ravulizumab) IV 100 mg / mL formulation enabled a significant reduction in infusion time compared to the lower concentration formulation (reducing maintenance dose infusion time in adults by 78-102 minutes compared to the 10 mg / mL formulation), improving patient convenience.

[0227] [Table 7]

[0228] [Table 8]

[0229] [Table 9]

[0230] [Table 10]

Claims

[Claim 1] The invention described in the specification.

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