Pharmaceutical composition for treating or preventing c5 related disease and method for treating or preventing c5 related disease

Abstract

To provide a pharmaceutical composition for treating or preventing C5 related disease and an effective dosage regimen thereof, and a method for treating or preventing C5 related disease which uses the pharmaceutical composition and the dosage regimen.SOLUTION: This invention relates to a pharmaceutical composition for treating or preventing C5 related disease and a method for treating or preventing C 5 related disease. This invention also relates to a dosage regimen of an anti-C5 antibody or a pharmaceutical composition containing the anti-C5 antibody.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to the dosage regimen of anti-C5 antibodies. [Background technology]

[0002] The complement system plays a central role in the clearance of immune complexes and in the immune response to infectious agents, foreign antigens, virus-infected cells, and tumor cells. There are approximately 25-30 complement proteins, which are found as a complex collection of plasma proteins and membrane cofactors. Complement components achieve their immune defense function by interacting in a series of complex enzymatic cleavage and membrane binding events. The resulting complement cascade leads to the production of products with opsonic, immunoregulatory, and cytolytic functions.

[0003] It is now widely accepted that the complement system is activated through three distinct pathways: the classical, lectin, and alternative pathways. These pathways share many elements and, although initially distinct, converge and share the same terminal complement components (C5 to C9) that are involved in the activation and destruction of target cells.

[0004] The classical pathway is usually activated by the formation of antigen-antibody complexes. Independently, the first step in activation of the lectin pathway is the binding of specific lectins, such as mannan-binding lectin (MBL), H-ficolin, M-ficolin, L-ficolin, and the C-type lectin CL-11. In contrast, the alternative pathway spontaneously undergoes low-level turnover activation, which can be easily amplified on foreign or other abnormal surfaces (bacteria, yeast, virus-infected cells, or damaged tissues). These pathways converge at the point where complement component C3 is cleaved by active proteases to yield C3a and C3b.

[0005] C3a is an anaphylatoxin. C3b binds to bacteria and other cells, as well as certain viruses and immune complexes, tagging them for removal from the circulation (a role known as opsonization). C3b also complexes with other components to form C5 convertase, which cleaves C5 into C5a and C5b.

[0006] C5 is a 190 kDa protein found in normal serum at approximately 80 μg / ml (0.4 μM). C5 is glycosylated, with approximately 1.5-3% of its mass attributable to carbohydrate. Mature C5 is a heterodimer of a 115 kDa α-chain disulfide-linked to a 75 kDa β-chain. C5 is synthesized as a 1676 amino acid single-chain precursor protein (pro-C5 precursor) (see, for example, US Pat. No. 5,993,331 and US Pat. No. 5,993,331). The pro-C5 precursor is cleaved to yield the β-chain as an amino-terminal fragment and the α-chain as a carboxyl-terminal fragment. The α-chain and β-chain polypeptide fragments are linked to each other via disulfide bonds to constitute the mature C5 protein.

[0007] Mature C5 is cleaved into C5a and C5b fragments during activation of the complement pathway. C5a is cleaved from the α-chain of C5 by C5 convertase as an amino-terminal fragment containing the first 74 amino acids of the α-chain. The remaining part of mature C5 is the fragment C5b, which contains the remainder of the α-chain disulfide-linked to the β-chain. Approximately 20% of the 11 kDa mass of C5a is attributable to carbohydrate.

[0008] C5a is another anaphylatoxin. C5b combines with C6, C7, C8, and C9 to form the membrane attack complex (MAC, C5b-9, terminal complement complex (TCC)) on the surface of target cells. When sufficient numbers of MACs are inserted into the target cell membrane, MAC pores are formed, mediating rapid osmotic lysis of the target cell.

[0009] As mentioned above, C3a and C5a are anaphylatoxins. They can induce degranulation of mast cells, which releases histamine and other inflammatory mediators, which leads to smooth muscle contraction, increased vascular permeability, leukocyte activation, and other inflammatory phenomena, such as cell proliferation leading to cell hyperplasia. C5a also functions as a chemotactic peptide that helps attract granulocytes, such as neutrophils, eosinophils, basophils, and monocytes, to the site of complement activation.

[0010] The activity of C5a is regulated by the plasma enzyme carboxypeptidase N, which removes the carboxy-terminal arginine from C5a to form the C5a-des-Arg derivative, which exhibits only 1% of the anaphylactic and polymorphonuclear chemotactic activity of unmodified C5a.

[0011] A properly functioning complement system provides a robust defense against infectious microorganisms, but inappropriate regulation or activation of complement has been implicated in the pathogenesis of a variety of disorders, including, for example, rheumatoid arthritis (RA); lupus nephritis; ischemia-reperfusion injury; paroxysmal nocturnal hemoglobinuria (PNH); atypical hemolytic uremic syndrome (aHUS); dense deposit disease (DDD); macular degeneration (e.g., age-related macular degeneration (AMD)); hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; thrombotic thrombocytopenic purpura (TTP); spontaneous fetal loss; oligoimmune vasculitis; epidermolysis bullosa; recurrent abortion; multiple sclerosis (MS); traumatic brain injury; and injury resulting from myocardial infarction, cardiopulmonary bypass, and hemodialysis (see, for example, Non-Patent Document 1). Thus, inhibition of excessive or uncontrolled activation of the complement cascade can provide clinical benefit to patients with such diseases.

[0012] Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder in which red blood cells are damaged and therefore destroyed more rapidly than normal red blood cells. PNH results from the clonal expansion of hematopoietic stem cells that carry somatic mutations in the PIG-A (phosphatidylinositol glycan class A) gene, located on the X chromosome. Mutations in PIG-A lead to an early inhibition of synthesis of glycosylphosphatidylinositol (GPI), a molecule required to anchor many proteins to the cell surface. As a result, blood cells in PNH lack GPI-anchored proteins, including the complement regulatory proteins CD55 and CD59. Under normal circumstances, these complement regulatory proteins block the formation of MAC on the cell surface, thereby preventing lysis of red blood cells. The absence of GPI-anchored proteins causes complement-mediated hemolysis in PNH.

[0013] PNH is characterized by hemolytic anemia (a reduction in red blood cell count), hemoglobinuria (the presence of hemoglobin in the urine, especially noticeable after sleep), and hemoglobinemia (the presence of hemoglobin in the bloodstream). Individuals affected by PNH have been known to have attacks, defined herein as the appearance of dark urine. Hemolytic anemia is due to the intravascular destruction of red blood cells by complement components. Other known symptoms include speech impairment, fatigue, erectile dysfunction, thrombosis, and recurrent abdominal pain.

[0014] Eculizumab is a humanized monoclonal antibody against the complement protein C5, and is the first therapeutic agent approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) (see, for example, Non-Patent Document 2). Eculizumab inhibits the cleavage of C5 by C5 convertase into C5a and C5b, thereby preventing the generation of the terminal complement complex C5b-9. Both C5a and C5b-9 cause the terminal complement-mediated events characteristic of PNH and aHUS (see also Patent Documents 3, 4, 5, and 6).

[0015] Several reports have described anti-C5 antibodies. For example, Patent Document 7 described an anti-C5 antibody that binds to the α-chain of C5 but not to C5a and blocks the activation of C5, while Patent Document 8 described an anti-C5 monoclonal antibody that inhibits the formation of C5a. On the other hand, Patent Document 9 described an anti-C5 antibody that recognizes a proteolytic site for C5 convertase on the α-chain of C5 and inhibits the conversion of C5 to C5a and C5b. Patent Document 10 described an anti-C5 antibody that inhibits the conversion of C5 to C5a and C5b by recognizing a proteolytic site for C5 convertase on the α-chain of C5 at least 1×10 7 M -1 described an anti-C5 antibody with an affinity constant of

[0016] Antibodies (IgG) bind to neonatal Fc receptors (FcRn) and have a long plasma residence time. Binding of IgG to FcRn is typically observed under acidic conditions (e.g., pH 6.0) and rarely observed under neutral conditions (e.g., pH 7.4). Typically, IgG is nonspecifically taken up into cells via endocytosis and returns to the cell surface by binding to endosomal FcRn under acidic conditions in endosomes. IgG then dissociates from FcRn under neutral conditions in plasma. IgG that fails to bind to FcRn is degraded in lysosomes. If the FcRn-binding ability of IgG under acidic conditions is lost by introducing a mutation into its Fc region, IgG is not recycled from endosomes to plasma, which leads to a significant decrease in the plasma retention of IgG. In order to improve the plasma retention of IgG, a method for enhancing its FcRn binding under acidic conditions has been reported. When the FcRn binding of IgG under acidic conditions is improved by introducing amino acid substitutions into its Fc region, the IgG is recycled from endosomes to plasma more efficiently, and thereby shows improved plasma retention. On the other hand, it has also been reported that IgG with enhanced FcRn binding under neutral conditions does not dissociate from FcRn under neutral conditions in plasma, even when it returns to the cell surface via its binding to FcRn under acidic conditions in endosomes, and as a result, its plasma retention remains unchanged or even deteriorates (see, for example, Non-Patent Document 3; Non-Patent Document 4; Non-Patent Document 5).

[0017] Recently, antibodies that bind to antigens in a pH-dependent manner have been reported (see, for example, Patent Document 11 and Patent Document 12). These antibodies bind strongly to antigens under neutral conditions in plasma and dissociate from antigens under acidic conditions in endosomes. After dissociation from antigens, the antibodies can bind to antigens again when recycled to plasma via FcRn. Thus, a single antibody molecule can bind to multiple antigen molecules repeatedly. In general, the plasma retention of antigens is much shorter than that of antibodies with the above-mentioned FcRn-mediated recycling mechanism. Thus, when an antigen binds to an antibody, the antigen usually exhibits extended plasma retention, which leads to an increase in the plasma concentration of the antigen. Meanwhile, it has been reported that the above-mentioned antibodies that bind to antigens in a pH-dependent manner dissociate from antigens in endosomes during the FcRn-mediated recycling process, and therefore clear antigens from plasma more quickly than typical antibodies. Patent Document 13 also describes a computer modeling analysis showing that antibodies that bind to C5 in a pH-dependent manner can prolong antigen knockdown. [Prior art documents] [Patent documents]

[0018] [Patent Document 1] U.S. Patent No. 6,355,245 [Patent Document 2] U.S. Patent No. 7,432,356 [Patent Document 3] WO2005 / 074607 [Patent Document 4] WO2007 / 106585 [Patent Document 5] WO2008 / 069889 [Patent Document 6] WO2010 / 054403 [Patent Document 7] WO95 / 29697 [Patent Document 8] WO2002 / 30985 [Patent Document 9] WO2004 / 007553 [Patent Document 10] WO2010 / 015608 [Patent Document 11] WO2009 / 125825 [Patent Document 12] WO2011 / 122011 [Patent Document 13] WO2011 / 111007 [Non-patent literature]

[0019] [Non-Patent Document 1] Holers et al., Immunol. Rev. 223:300-316 (2008) [Non-Patent Document 2] Dmytrijuk et al., The Oncologist 13(9):993-1000 (2008) [Non-Patent Document 3] Yeung et al., J Immunol. 182(12): 7663-7671 (2009) [Non-Patent Document 4] Datta-Mannan et al., J Biol. Chem. 282(3):1709-1717 (2007) [Non-Patent Document 5] Dall'Acqua et al., J. Immunol. 169(9):5171-5180 (2002) Summary of the Invention

[0020] The present invention provides pharmaceutical compositions for treating or preventing C5-related diseases and methods for treating or preventing C5-related diseases. The present invention also provides dosage regimens for anti-C5 antibodies or pharmaceutical compositions comprising anti-C5 antibodies.

[0021] The present inventors have investigated the dosage regimen of an anti-C5 antibody that is effective for treating and / or preventing C5-related diseases, and have found that intravenous administration of the anti-C5 antibody rapidly increases the plasma concentration of the antibody to a level above the therapeutically effective level, and that subcutaneous administration of the antibody after intravenous administration maintains the concentration at that level.

[0022] The inventors have also discovered suitable conditions for dosing, including the dose of antibody, the frequency and interval of intravenous or subcutaneous administration, the interval between intravenous and subcutaneous administration, and switching from other drugs.

[0023] The present invention particularly relates to: [1] A pharmaceutical composition for treating or preventing a C5-related disease, comprising: The composition is formulated for subcutaneous injection, comprises an anti-C5 antibody, and is administered subcutaneously; a first dose of the composition is administered after a dose of another pharmaceutical composition is administered intravenously; The other pharmaceutical composition is formulated for intravenous administration and comprises the anti-C5 antibody. [2] A pharmaceutical composition for treating or preventing a C5-related disease, comprising: The composition is formulated for intravenous injection, comprises an anti-C5 antibody, and is administered intravenously; a dose of said composition is administered before a first dose of another pharmaceutical composition is administered subcutaneously; The other pharmaceutical composition is formulated for subcutaneous injection and comprises the anti-C5 antibody. [3] The pharmaceutical composition of [1] or [2], wherein the first dose of the composition for subcutaneous injection is administered on the same day as the dose of the composition for intravenous injection, or 1 day to 28 days thereafter. [4] Any of the pharmaceutical compositions according to [1] to [3], wherein the composition for subcutaneous injection is administered once every 3 to 42 days. [5] Any of the pharmaceutical compositions according to [1] to [4], wherein the composition for intravenous injection is administered two or more times, once every hour to once every 14 days. [6] Any of the pharmaceutical compositions according to [1] to [5], wherein the composition for subcutaneous injection is administered in a single dose of 17 to 6,000 mg of the antibody. [7] Any of the pharmaceutical compositions according to [1] to [6], wherein the composition for intravenous injection is administered in a single dose of 50 to 5,000 mg of the antibody. [8] Any of the pharmaceutical compositions of [1] to [7], wherein the composition is for treating or preventing a C5-related disease in a subject who has been treated with at least one pharmaceutical agent for treating or preventing the disease, and a first dose of the composition for intravenous injection is administered after the final dose of the pharmaceutical agent. [9] The pharmaceutical composition of [8], wherein the first dose of the composition for intravenous injection is administered 3 days or more after the last dose of the pharmaceutical agent.

[10] The pharmaceutical composition of [8] or [9], wherein the pharmaceutical comprises an siRNA targeting C5 mRNA or an anti-C5 antibody different from the anti-C5 antibody contained in the composition.

[11] The pharmaceutical composition according to any one of [8] to

[10] , wherein the pharmaceutical contains eculizumab or a derivative thereof.

[12] A pharmaceutical composition for treating or preventing a C5-related disease, comprising: The pharmaceutical composition is formulated for subcutaneous injection and comprises an anti-C5 antibody, the pharmaceutical composition being administered subcutaneously in a single dose of 17 to 6,000 mg of the antibody.

[13] A pharmaceutical composition for treating or preventing a C5-related disease, comprising: The pharmaceutical composition is formulated for intravenous injection, comprises an anti-C5 antibody, and is administered intravenously in a single dose of 50-5,000 mg of the antibody.

[14] Any of the pharmaceutical compositions of [1] to

[13] , wherein the C5-related disease is any one selected from the group consisting of rheumatoid arthritis (RA); lupus nephritis; ischemia-reperfusion injury; paroxysmal nocturnal hemoglobinuria (PNH); atypical hemolytic uremic syndrome (aHUS); dense deposit disease (DDD); macular degeneration; HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome; thrombotic thrombocytopenic purpura (TTP); spontaneous fetal loss; oligoimmune vasculitis; epidermolysis bullosa; habitual abortion; multiple sclerosis (MS); traumatic brain injury; and damage resulting from myocardial infarction, cardiopulmonary bypass, or hemodialysis.

[15] A method for treating or preventing a C5-related disease, comprising: administering intravenously to a subject a first pharmaceutical composition formulated for intravenous injection and comprising an anti-C5 antibody; and After said administration of said first composition, administering subcutaneously to said subject a second pharmaceutical composition formulated for subcutaneous injection and comprising said anti-C5 antibody.

[16] The method of

[15] , wherein the first dose of the second composition is administered on the same day as the final dose of the first composition, or 1 to 28 days thereafter.

[17] The method of

[15] or

[16] , wherein the second composition is administered once every 3 to 42 days.

[18] Any of the methods

[15] to

[17] , wherein the first composition is administered two or more times, from once every hour to once every 14 days.

[19] Any of the methods

[15] to

[18] , wherein the second composition is administered in a single dose of 17 to 6,000 mg of the antibody.

[20] Any of the methods

[15] to

[19] , wherein the first composition is administered in a single dose of 50 to 5,000 mg of the antibody.

[21] Any of the methods

[15] to

[20] , which is a method for treating or preventing a C5-related disease in a subject who has been treated with at least one pharmaceutical agent for treating or preventing the disease, wherein a first dose of the first composition is administered after a final dose of the pharmaceutical agent has been administered.

[22] The method of

[21] , wherein the initial dose of the first composition is administered 3 days or more after the final dose of the pharmaceutical agent is administered.

[23] The method of

[21] or

[22] , wherein the pharmaceutical agent comprises an siRNA targeting C5 mRNA or an anti-C5 antibody different from the anti-C5 antibody contained in the first composition.

[24] Any of the methods

[21] to

[23] , wherein the pharmaceutical agent comprises eculizumab or a derivative thereof.

[25] A method for treating or preventing a C5-related disease, comprising the step of administering to a subject a pharmaceutical composition comprising an anti-C5 antibody via subcutaneous injection at a dose of 17 to 6,000 mg of the antibody.

[26] A method for treating or preventing a C5-related disease, comprising the step of administering to a subject a pharmaceutical composition containing an anti-C5 antibody via intravenous injection at a dose of 50 to 5,000 mg of the antibody.

[27] Any of the methods of

[15] to

[26] , wherein the C5-related disease is any one selected from the group consisting of rheumatoid arthritis (RA); lupus nephritis; ischemia-reperfusion injury; paroxysmal nocturnal hemoglobinuria (PNH); atypical hemolytic uremic syndrome (aHUS); dense deposit disease (DDD); macular degeneration; hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; thrombotic thrombocytopenic purpura (TTP); spontaneous fetal loss; oligoimmune vasculitis; epidermolysis bullosa; habitual abortion; multiple sclerosis (MS); traumatic brain injury; and damage resulting from myocardial infarction, cardiopulmonary bypass, or hemodialysis.

[28] Use of an anti-C5 antibody in the manufacture of a pharmaceutical composition for treating or preventing a C5-related disease, comprising: The composition is formulated for subcutaneous injection, comprises an anti-C5 antibody, and is administered subcutaneously; the first dose of the composition is administered after a dose of another pharmaceutical composition is administered intravenously; The other pharmaceutical composition is formulated for intravenous injection and comprises the anti-C5 antibody.

[29] Use of an anti-C5 antibody in the manufacture of a pharmaceutical composition for treating or preventing a C5-related disease, comprising: The composition is formulated for intravenous injection, comprises an anti-C5 antibody, and is administered intravenously; wherein one dose of the composition is administered before a first dose of another pharmaceutical composition is subcutaneously administered; The other pharmaceutical composition is formulated for subcutaneous injection and comprises the anti-C5 antibody.

[30] The use of

[28] or

[29] , wherein the first dose of the composition for subcutaneous injection is administered on the same day as the dose of the composition for intravenous injection, or 1 to 28 days thereafter.

[31] Use of any of

[28] to

[30] , wherein the composition for subcutaneous injection is given once every 3 to 42 days.

[32] Use of any of

[28] to

[31] , wherein the composition for intravenous injection is administered two or more times, from once every hour to once every 14 days.

[33] Use of any of

[28] to

[32] , wherein the composition for subcutaneous injection is given in a single dose of 17 to 6,000 mg of the antibody.

[34] The use of any of

[28] to

[33] , wherein the composition for intravenous injection is given in a single dose of 50 to 5,000 mg of the antibody.

[35] The composition for intravenous injection and the composition for subcutaneous injection are for treating or preventing a C5-related disease in a subject who has been treated with at least one medicament for treating or preventing the disease; The use of any of

[28] to

[34] , wherein the first dose of the composition for intravenous injection is administered after the final dose of the pharmaceutical agent.

[36] The use of

[35] , wherein the first dose of the composition for intravenous injection is administered 3 days or more after the last dose of the pharmaceutical agent.

[37] The use of

[35] or

[36] , wherein the pharmaceutical agent comprises an siRNA targeting C5 mRNA or an anti-C5 antibody different from the anti-C5 antibody contained in the composition.

[38] Use of any of

[35] to

[37] , wherein the pharmaceutical agent contains eculizumab or a derivative thereof.

[39] Use of an anti-C5 antibody in the manufacture of first and second pharmaceutical compositions for treating or preventing a C5-related disease, comprising: the first pharmaceutical composition is formulated for intravenous injection, contains an anti-C5 antibody, and is administered intravenously; the second pharmaceutical composition is formulated for subcutaneous injection, contains the anti-C5 antibody, and is administered subcutaneously; The administration of the first and second pharmaceutical compositions is performed in the order of one or more intravenous doses of the first pharmaceutical composition and one or more subcutaneous doses of the second pharmaceutical composition.

[40] Use of an anti-C5 antibody in the manufacture of a pharmaceutical composition for treating or preventing a C5-related disease, comprising: The composition is formulated for subcutaneous injection, comprises an anti-C5 antibody, and is administered subcutaneously in a dose of 17 to 6,000 mg of the antibody.

[41] Use of an anti-C5 antibody in the manufacture of a pharmaceutical composition for treating or preventing a C5-related disease, comprising: The composition is formulated for intravenous injection, comprises an anti-C5 antibody, and is administered intravenously in a single dose of 50 to 5,000 mg of the antibody.

[42] Use of any of

[28] to

[41] , wherein the C5-related disease is any one selected from the group consisting of: rheumatoid arthritis (RA); lupus nephritis; ischemia-reperfusion injury; paroxysmal nocturnal hemoglobinuria (PNH); atypical hemolytic uremic syndrome (aHUS); dense deposit disease (DDD); macular degeneration; HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome; thrombotic thrombocytopenic purpura (TTP); spontaneous fetal loss; oligoimmune vasculitis; epidermolysis bullosa; habitual abortion; multiple sclerosis (MS); traumatic brain injury; and damage resulting from myocardial infarction, cardiopulmonary bypass, or hemodialysis.

[43] A product for treating or preventing a C5-related disease, comprising: (i) a container; (ii) a pharmaceutical composition within the container, the pharmaceutical composition being formulated for subcutaneous injection, the pharmaceutical composition comprising an anti-C5 antibody, and the pharmaceutical composition being administered subcutaneously; and (iii) a written instruction that the pharmaceutical composition should be administered following intravenous administration of a dose of another pharmaceutical composition, The other pharmaceutical composition is formulated for intravenous injection and comprises the anti-C5 antibody.

[44] A product for treating or preventing a C5-related disease, comprising: (i) a container; (ii) a pharmaceutical composition in the container, the pharmaceutical composition being formulated for intravenous injection, the pharmaceutical composition comprising an anti-C5 antibody, and the pharmaceutical composition being administered intravenously; and (iii) a written instruction that the pharmaceutical composition should be administered before a first dose of another pharmaceutical composition is administered subcutaneously, The other pharmaceutical composition is formulated for subcutaneous injection and comprises the anti-C5 antibody.

[45] A product for treating or preventing a C5-related disease, comprising: 1. An article of manufacture comprising: (i) a first container; (ii) a first pharmaceutical composition in the first container, the first pharmaceutical composition being formulated for intravenous injection, the first pharmaceutical composition comprising an anti-C5 antibody, and the second pharmaceutical composition being administered intravenously; (iii) a second container; (iv) a second pharmaceutical composition in the second container, the second pharmaceutical composition being formulated for subcutaneous injection, the second pharmaceutical composition comprising the anti-C5 antibody, and the second pharmaceutical composition being administered subcutaneously; and (v) a written instruction explaining that the first pharmaceutical composition and the second pharmaceutical composition should be administered in the following order: one or more intravenous doses of the first pharmaceutical composition for intravenous injection and one or more subcutaneous doses of the second pharmaceutical composition for subcutaneous injection.

[46] A product for treating or preventing a C5-related disease in a subject who has been treated with at least one pharmaceutical agent for treating or preventing the disease, The product of any of

[43] to

[45] , wherein the documentation further explains that any first dose of the pharmaceutical composition must be administered after the final dose of the medication.

[47] A product for treating or preventing a C5-related disease, comprising: 1. An article of manufacture comprising: (i) a container; (ii) a pharmaceutical composition within the container, the pharmaceutical composition comprising an anti-C5 antibody formulated for subcutaneous injection; and (iii) a written instruction that the pharmaceutical composition should be administered subcutaneously in a dose of between 17 and 6,000 mg of the antibody.

[48] ​​A product for treating or preventing a C5-related disease, comprising: 1. An article of manufacture comprising: (i) a container; (ii) a pharmaceutical composition within the container, the pharmaceutical composition comprising an anti-C5 antibody formulated for intravenous injection; and (iii) a written instruction that the pharmaceutical composition should be administered intravenously in a single dose of 50-5,000 mg of the antibody.

[49] Any of the products of

[43] to

[48] , wherein the C5-related disease is any one selected from the group consisting of: rheumatoid arthritis (RA); lupus nephritis; ischemia-reperfusion injury; paroxysmal nocturnal hemoglobinuria (PNH); atypical hemolytic uremic syndrome (aHUS); dense deposit disease (DDD); macular degeneration; hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; thrombotic thrombocytopenic purpura (TTP); spontaneous fetal loss; oligoimmune vasculitis; epidermolysis bullosa; habitual abortion; multiple sclerosis (MS); traumatic brain injury; and damage resulting from myocardial infarction, cardiopulmonary bypass, or hemodialysis. [Brief description of the drawings]

[0024] [Figure 1] Figure 1 shows the time course of plasma 305LO15 concentrations in cynomolgus monkeys following subcutaneous (a) or intravenous (b) injection of the antibody 305LO15. Plasma 305LO15 concentrations were measured by ELISA. Points represent the mean values ​​from three males or three females in (a) and six males or six females in (b). [Diagram 2] Figure 2 shows the time course of plasma 305LO15 concentrations in cynomolgus monkeys following an initial intravenous injection of antibody 305LO15 followed by subcutaneous maintenance injections. Plasma 305LO15 concentrations were measured by ELISA. Each point represents the average value from five males or five females. [Figure 3a] Figure 3a is a graph plotting the plasma concentration of free C5 against the respective plasma concentration of antibody for each indicated dose and route: IV, intravenous injection; SC, subcutaneous injection. [Figure 3b] Figure 3b is a graph plotting the measured complement activity against the respective plasma concentration of antibody for each indicated dose and route: IV, intravenous injection; SC, subcutaneous injection. [Figure 4a] Figure 4a shows the simulated time course of plasma 305LO15 concentrations in the dosing regimen designed for the Part 1 clinical trial. IV, intravenous injection; SC, subcutaneous injection. [Figure 4b] Figure 4b shows the simulated time course of plasma 305LO15 concentrations for the dosing regimen designed for the second part clinical trial: SC, subcutaneous injection; QW, weekly dosing. [Figure 4c] Figure 4c shows the simulated time course of plasma 305LO15 concentrations for the dosing regimens designed for the Part 3 clinical trial: SC, subcutaneous injection; QW, once weekly; Q2W, once every 2 weeks; Q4W, once every 4 weeks. [Diagram 5] FIG. 5 shows profiles of immune complexes formed by eculizumab (ECZ), human C5 (hC5), and / or 305LO15 analyzed by in vitro size-exclusion chromatography at pH 7.4 (top panel) and pH 6.0 (bottom panel). [Figure 6] Figure 6 shows individual real and simulated plasma 305LO15 concentration-time profiles in healthy subjects receiving a 75 mg intravenous infusion (60 min). The grey shaded area is the 95% prediction interval of the 305LO15 concentration-time simulated profiles. The solid line indicated by the arrow is the median of the 305LO15 concentration-time simulated profiles. The dashed line represents the 40 μg / mL PD threshold. [Figure 7]Figure 7 shows individual actual and simulated plasma 305LO15 concentration-time profiles in healthy subjects receiving a 125 mg intravenous infusion (60 min). The grey shaded area is the 95% prediction interval of the 305LO15 concentration-time simulated profiles. The solid line indicated by the arrow is the median of the 305LO15 concentration-time simulated profiles. The dashed line represents the 40 μg / mL PD threshold. [Figure 8] Figure 8 shows individual actual and simulated plasma 305LO15 concentration-time profiles in healthy subjects receiving 100 mg SC. The grey shaded area is the 95% prediction interval for the 305LO15 concentration-time simulated profiles. The solid line indicated by the arrow is the median of the 305LO15 concentration-time simulated profiles. For simulations performed on a single 100 mg SC dose, 90% bioavailability was estimated. The dashed line represents the 40 μg / mL PD threshold. [Figure 9] Figure 9 shows the relationship between plasma 305LO15 concentration and hemolytic activity (LIA) after a single intravenous or subcutaneous injection in healthy subjects. Ex vivo LIA dose-response curves were generated using human plasma samples spiked with various concentrations of 305LO15. [Figure 10a] FIG. 10a shows the time profile of serum LDH levels in a PNH patient (Patient X) who received an IV dose of 375 mg 305LO15 on day 1, an IV dose of 500 mg 305LO15 on day 8, an IV dose of 1000 mg 305LO15 on day 22, an SC dose of 170 mg 305LO15 on day 36, and an SC dose of 170 mg 305LO15 on day 43 in the second part study. [Figure 10b] FIG. 10b shows the time profile of hemolytic activity (LIA) in a PNH patient (Patient X) who received a 375 mg 305LO15 IV dose on day 1, a 500 mg 305LO15 IV dose on day 8, a 1000 mg 305LO15 IV dose on day 22, a 170 mg 305LO15 SC dose on day 36, and a 170 mg 305LO15 SC dose on day 43 in the second part study. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] Description of the Aspects The techniques and procedures described or cited herein are generally well understood and may be found in, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual 3d edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY;Current Protocols in Molecular Biology (FM Ausubel, et al. eds., (2003));the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (MJ MacPherson, BD Hames and GR Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Animal Cell Culture (RI Freshney, ed. (1987));Oligonucleotide Synthesis (MJ Gait, ed., 1984);Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (JE Cellis, ed., 1998) Academic Press; Animal Cell Culture (RI Freshney), ed., 1987); Introduction to Cell and Tissue Culture (JP Mather and PE Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, JB Griffiths, and DG Newell, eds., 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (DM Weir and C.C.Blackwell, eds.);Gene Transfer Vectors for Mammalian Cells (JM Miller and MP Calos, eds., 1987);PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994);Current Protocols in Immunology (JE Coligan et al., eds., 1991);Short Protocols in Molecular Biology (Wiley and Sons, 1999);Immunobiology (CA Janeway and P. Travers, 1997);Antibodies (P. Finch, 1997);Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989);Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000);Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and JD Capra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (VT DeVita et al., eds., JB Lippincott Company, 1993), using conventional techniques commonly employed by those of skill in the art.

[0026] I. Definition "Dosage interval" (the interval between individual doses) refers to the interval between the administration of the nth dose (n is an integer equal to or greater than 1) and the administration of the (n+1)th dose.

[0027] II. Pharmaceutical Compositions for Subcutaneous Injection The pharmaceutical composition formulated for subcutaneous injection in the present invention is for treating or preventing C5-related disease, contains anti-C5 antibody, and is administered subcutaneously. Subcutaneous injection can be performed using a general device and method for administering pharmaceutical composition to subcutaneous tissue by injection. Also, a device and method dedicated to subcutaneous injection can be selected.

[0028] Exemplary Anti-C5 Antibodies The anti-C5 antibody is not limited to a particular embodiment and can be appropriately selected from known anti-C5 antibodies. The term "anti-C5 antibody" or "antibody that binds to C5" refers to an antibody that can bind to C5 with sufficient affinity such that the antibody is useful as a therapeutic agent in targeting C5.

[0029] In one aspect, anti-C5 antibodies inhibit the activation of C5. In certain embodiments, anti-C5 antibodies prevent the cleavage of C5 to form C5a and C5b, thereby preventing the generation of anaphylatoxin activity associated with C5a as well as the assembly of C5b-9 membrane attack complex (MAC) associated with C5b. In certain embodiments, anti-C5 antibodies block the conversion of C5 to C5a and C5b by C5 convertase. In certain embodiments, anti-C5 antibodies block the access of C5 convertase to the cleavage site on C5. In certain embodiments, anti-C5 antibodies block the hemolytic activity caused by the activation of C5. In further embodiments, anti-C5 antibodies inhibit the activation of C5 via the classical pathway and / or the alternative pathway.

[0030] In one aspect, the pharmaceutical compositions of the invention are useful for treating or preventing C5-related diseases based at least in part on the above-described activity of anti-C5 antibodies in inhibiting the activation of C5.

[0031] In certain embodiments, C5 activity can be measured as a function of its cytolytic ability in the body fluid of a subject.C5 cytolytic ability or its reduction can be measured by methods well known in the art, for example, by conventional hemolysis assay, for example, the hemolysis assay described in Kabat and Mayer (eds.), Experimental Immunochemistry, 2nd ed., 135-240, Springfield, IL, CC Thomas (1961), pp. 135-139, or by a conventional modification of said assay, for example, chicken erythrocyte hemolysis assay, as described in Hillmen et al., N. Engl. J. Med. 350(6): 552-559 (2004).In certain embodiments, C5 activity or its inhibition is quantified using CH50eq assay.CH50eq assay is a method for measuring the total classical complement activity in serum. This test is a lysis assay that uses antibody-sensitized red blood cells as activators of the classical complement pathway and various dilutions of test serum to determine the amount required to give 50% lysis (CH50). 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, since the direct cause of the hemolysis measured is the TCC itself. Inhibition of C5 activation can also be detected and / or measured using the methods described and exemplified in the Examples. These or other suitable types of assays can be used to screen candidate antibodies that can inhibit C5 activation. In certain embodiments, inhibition of C5 activation includes at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% or more decrease in C5 activation in the assay compared to the effect of a negative control under similar conditions. In some embodiments, it refers to at least 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or more inhibition of C5 activation. In a preferred embodiment, the epitope of the anti-C5 antibody is different from the epitope of eculizumab.

[0032] In certain embodiments, the anti-C5 antibody according to the invention binds to an epitope within the beta chain of C5. In certain embodiments, the anti-C5 antibody binds to an epitope within the MG1-MG2 domain of the beta chain of C5. In certain embodiments, the anti-C5 antibody binds to an epitope within a fragment consisting of amino acids 19-180 of the beta chain of C5. In certain embodiments, the anti-C5 antibody binds to an epitope within the MG1 domain of the beta chain of C5 (amino acids 20-124 of SEQ ID NO:1). In certain embodiments, the anti-C5 antibody binds to an epitope within a fragment consisting of amino acids 33-124 of the beta chain of C5 (SEQ ID NO:1).

[0033] In certain embodiments, the anti-C5 antibody according to the present invention binds to an epitope in the beta chain of C5 consisting of the MG1 domain. In certain embodiments, the anti-C5 antibody binds to an epitope in the beta chain of C5 (SEQ ID NO:1) comprising at least one fragment selected from the group consisting of amino acids 47-57, 70-76, and 107-110. In certain embodiments, the anti-C5 antibody binds to an epitope in a fragment of the beta chain of C5 (SEQ ID NO:1) comprising at least one amino acid selected from the group consisting of Thr47, Glu48, Ala49, Phe50, Asp51, Ala52, Thr53, Lys57, His70, Val71, His72, Ser74, Glu76, Val107, Ser108, ​​Lys109, and His110. In certain embodiments, the anti-C5 antibody binds to an epitope within a fragment of the beta chain of C5 (SEQ ID NO:1) that includes at least one amino acid selected from the group consisting of Glu48, Asp51, His70, His72, Lys109, and His110. In certain embodiments, the binding of the anti-C5 antibody to a C5 mutant is reduced compared to its binding to wild-type C5, wherein the C5 mutant has at least one amino acid substitution at a position selected from the group consisting of Glu48, Asp51, His72, and Lys109. In another embodiment, the pH-dependent binding (described below) of the anti-C5 antibody to a C5 mutant is reduced compared to its pH-dependent binding to wild-type C5, wherein the C5 mutant has at least one amino acid substitution at a position selected from the group consisting of His70, His72, and His110. In a further embodiment, in the C5 variant, an amino acid at a position selected from Glu48, Asp51, and Lys109 is substituted with an alanine, and an amino acid at a position selected from His70, His72, and His110 is substituted with a tyrosine.

[0034] In another aspect, the anti-C5 antibody of the present invention may exhibit pH-dependent binding properties. The expression "pH-dependent binding" as used herein means that the antibody exhibits "reduced binding to C5 at acidic pH compared to binding to C5 at neutral pH" (for the purposes of this disclosure, both expressions can be used interchangeably). For example, an antibody with "pH-dependent binding properties" includes an antibody that binds to C5 with higher affinity at neutral pH compared to acidic pH. In certain embodiments, the antibody binds to C5 with at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10000 times or more higher affinity at neutral pH than at acidic pH. In some embodiments, the antibody binds to C5 with higher affinity at pH 7.4 compared to pH 5.8. In further embodiments, the antibody binds to C5 with at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10000 or more times higher affinity at pH 7.4 compared to pH 5.8.

[0035] The "affinity" of an antibody to C5 is, for the purposes of this disclosure, expressed as the KD of the antibody. The KD of an antibody refers to the equilibrium dissociation constant of antibody-antigen interaction. The higher the KD value for an antibody that binds to an antigen, the weaker its binding affinity to that particular antigen. Thus, as used herein, the expression "higher affinity at neutral pH than at acidic pH" (or the equivalent expression "pH-dependent binding") means that the KD of an antibody that binds to C5 at acidic pH is higher than the KD of an antibody that binds to C5 at neutral pH. For example, in the context of the present invention, if the KD of an antibody that binds to C5 at acidic pH is at least two times higher than the KD of an antibody that binds to C5 at neutral pH, the antibody is considered to bind to C5 with higher affinity at neutral pH than at acidic pH. Thus, anti-C5 antibodies according to the invention include antibodies that bind to C5 at acidic pH with a KD that is at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10000, or more times greater than the KD of the antibody that binds to C5 at neutral pH. -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 In another embodiment, the K value of the antibody at acidic pH is 10 -9 M, 10 -8 M, 10 -7 M, 10 -6 M, or even higher.

[0036] In further embodiments, an antibody is considered to bind C5 with higher affinity at neutral pH compared to acidic pH if the KD of the antibody that binds C5 at pH 5.8 is at least 2-fold greater than the KD of the antibody that binds C5 at pH 7.4. In some embodiments, an antibody binds C5 at pH 5.8 with a KD that is at least 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10000, or more times greater than the KD of the antibody that binds C5 at pH 7.4. In another embodiment, the KD value of the antibody at pH 7.4 is 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 In another embodiment, the K value of the antibody at pH 5.8 is 10 -9 M, 10 -8 M, 10 -7 M, 10 -6 M, or even higher.

[0037] The binding properties of an antibody for a particular antigen can also be expressed in terms of the antibody's kd. The kd of an antibody refers to the dissociation rate constant of the antibody for a particular antigen, and is expressed as the reciprocal of seconds (i.e., sec -1 The kd value is expressed in units of 1000 kd. An increased kd value means that the antibody binds weaker to its antigen. Thus, the present invention encompasses antibodies that bind to C5 with a higher kd value at acidic pH compared to neutral pH. Antibodies according to the present invention encompass antibodies that bind to C5 at acidic pH with a kd that is at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10000, or more times greater than the kd of the antibody that binds to C5 at neutral pH. In another embodiment, the kd value of the antibody at neutral pH is 10 -2 1 / s, 10 -3 1 / s, 10 -4 1 / s, 10 -51 / s, 10 -6 In another embodiment, the kd value of the antibody at acidic pH is 10 -3 1 / s, 10 -2 1 / s, 10 -1 1 / s, or more. Antibodies of the invention also include antibodies that bind to C5 with a higher kd value at pH 5.8 compared to pH 7.4. Antibodies of the invention include antibodies that bind to C5 at pH 5.8 with a kd that is at least 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10000, or more times greater than the kd of the antibody that binds to C5 at pH 7.4. In another embodiment, the kd value of the antibody at pH 7.4 is 10 -2 1 / s, 10 -3 1 / s, 10 -4 1 / s, 10 -5 1 / s, 10 -6 In another embodiment, the kd value of the antibody at pH 5.8 is 10 -3 1 / s, 10 -2 1 / s, 10 -1 It can be 1 / s, or even higher.

[0038] In certain examples, "reduced binding to C5 at acidic pH compared to binding to C5 at neutral pH" is expressed as the ratio of the KD value of the antibody that binds to C5 at acidic pH to the KD value of the antibody that binds to C5 at neutral pH (or vice versa). For example, if an antibody exhibits an acidic / neutral KD ratio of 2 or more, the antibody can be considered to exhibit "reduced binding to C5 at acidic pH compared to binding to C5 at neutral pH" for the purposes of the present invention. In certain exemplary embodiments, the pH5.8 / pH7.4 KD ratio of the antibody is 2 or more. In certain exemplary embodiments, the acidic / neutral KD ratio of the antibody can be 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10000, or more. In another embodiment, the KD value of the antibody at neutral pH is 10-7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 In another embodiment, the K value of the antibody at acidic pH is 10 -9 M, 10 -8 M, 10 -7 M, 10 -6 M, or more. In a further example, if an antibody exhibits a pH5.8 / pH7.4 KD ratio of 2 or more, for purposes of the present invention, the antibody can be considered to exhibit "reduced binding to C5 at acidic pH compared to binding to C5 at neutral pH." In certain exemplary embodiments, the pH5.8 / pH7.4 KD ratio of an antibody can be 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10000, or more. In another embodiment, the KD value of the antibody at pH 7.4 is 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 In another embodiment, the K value of the antibody at pH 5.8 is 10 -9 M, 10 -8 M, 10 -7 M, 10 -6 M, or even higher.

[0039] In certain examples, "reduced binding to C5 at acidic pH compared to binding to C5 at neutral pH" is expressed as the ratio of the kd value of the antibody that binds to C5 at acidic pH to the kd value of the antibody that binds to C5 at neutral pH (or vice versa). For example, if an antibody exhibits an acidic / neutral kd ratio of 2 or more, the antibody can be considered to exhibit "reduced binding to C5 at acidic pH compared to binding to C5 at neutral pH" for the purposes of the present invention. In certain exemplary embodiments, the pH5.8 / pH7.4 kd ratio of the antibody is 2 or more. In certain exemplary embodiments, the acidic / neutral kd ratio of the antibody can be 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10000, or more. In further exemplary embodiments, the pH 5.8 / pH 7.4 kd ratio of the antibody can be 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10000, or more. -2 1 / s, 10 -3 1 / s, 10 -4 1 / s, 10 -5 1 / s, 10 -6 1 / s, or less. In a further embodiment, the kd value of the antibody at pH 7.4 is 10 -2 1 / s, 10 -3 1 / s, 10 -4 1 / s, 10 -5 1 / s, 10 -6 In another embodiment, the kd value of the antibody at acidic pH is 10 -3 1 / s, 10 -2 1 / s, 10 -1 1 / s, or higher. In a further embodiment, the kd value of the antibody at pH 5.8 is 10 -3 1 / s, 10 -2 1 / s, 10 -1 It can be 1 / s, or even higher.

[0040] The expression "acidic pH" as used herein means a pH between 4.0 and 6.5. The expression "acidic pH" includes any one of the following pH values: 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, and 6.5. In a particular aspect, the "acidic pH" is 5.8.

[0041] The expression "neutral pH" as used herein means a pH of 6.7 to about 10.0. The expression "neutral pH" includes any one of the following pH values: 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, and 10.0. In a particular aspect, the "neutral pH" is 7.4.

[0042] The KD and kd values ​​expressed herein can be determined using a surface plasmon resonance-based biosensor to characterize antibody-antigen interactions. The KD and kd values ​​can be measured at 25°C or 37°C.

[0043] In another aspect, the anti-C5 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:2. In certain embodiments, the VH sequence is the amino acid sequence of SEQ ID NO:2. In certain embodiments, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but the anti-C5 antibody comprising the sequence retains the ability to bind to C5. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO:2. In certain embodiments, the substitutions, insertions, or deletions occur in the regions outside the HVRs (i.e., in the FRs). Optionally, the anti-C5 antibody comprises the VH sequence in SEQ ID NO:2, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:3, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:4, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:5.

[0044] As used herein, the term "HVR" stands for "hypervariable region" and the term "FR" stands for "framework."

[0045] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain typically consists of four FR domains: FR1, FR2, FR3, and FR4. Accordingly, the HVR and FR sequences typically appear in VH (or VL) in the following order: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0046] The term "hypervariable region" or "HVR" as used herein refers to each region of an antibody variable domain that is hypervariable in sequence (the "complementarity determining region" or "CDR") and / or forms structurally defined loops (the "hypervariable loops") and / or contains antigen contact residues (the "antigen contacts"). Typically, antibodies contain six HVRs: three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). Exemplary HVRs herein include the following: (a) hypervariable loops occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia, J. Mol. Biol. 196:901-917 (1987)); (b) CDRs occurring at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, NIH, Bethesda, MD (1991)); (c) antigenic contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262:732-745 (1996)); and (d) combinations of (a), (b), and / or (c), comprising HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (H1), 26-35b (H1), 49-65 (H2), 93-102 (H3), and 94-102 (H3). HVR residues and other residues in the variable domain (eg, FR residues) are numbered herein according to Kabat et al., supra.

[0047] In another aspect, the anti-C5 antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:6. In certain embodiments, the VL sequence is the amino acid sequence of SEQ ID NO:6. In certain embodiments, the VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but the anti-C5 antibody comprising the sequence retains the ability to bind to C5. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO:6. In certain embodiments, the substitutions, insertions, or deletions occur in the regions outside the HVR (i.e., in the FR). Optionally, the anti-C5 antibody comprises the VL sequence in SEQ ID NO:6, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:7, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:8, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:9.

[0048] In another embodiment, the antibody is a full length antibody, e.g., an IgG1, IgG2, IgG3, or IgG4 complete antibody, or an antibody that has been recombinantly engineered to have regions from two or more IgGs selected from IgG1, IgG2, IgG3, and IgG4 within the homologous regions among the IgG subclasses. The antibody may comprise any suitable Fc region, including human Fc region sequences (e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region).

[0049] Fc region variants In certain embodiments, the anti-C5 antibodies of the invention comprise an Fc region variant in which one or more amino acid modifications have been introduced into the native sequence Fc region of the antibody. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region) that contains an amino acid modification (e.g., substitution) at one or more amino acid positions.

[0050] In certain embodiments, antibody variants with some, but not all, effector functions are also contemplated by the present invention, which make the antibody a desirable candidate for applications where its in vivo half-life is important, but certain effector functions (such as complement and ADCC) are unnecessary or detrimental. In vitro and / or in vivo cytotoxicity assays can be performed to confirm the reduction / lack of CDC and / or ADCC activity. For example, Fc receptor (FcR) binding assays can be performed to confirm that the antibody lacks FcγR binding (and thus likely lacks ADCC activity) while retaining FcRn binding. NK cells, the primary cells mediating ADCC, express only FcγRIII, whereas monocytes express FcγRI, FcγRII, and FcγRIII. Expression of FcR on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest are described in U.S. Pat. No. 5,500,362 (see, e.g., Hellstrom et al., Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985); U.S. Pat. No. 5,821,337 (see, Bruggemann et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assays may be used (see, e.g., ACT1™ non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA); and CytoTox 96® non-radioactive cytotoxicity assays (Promega, Madison, WI)).Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells. Alternatively or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that described in Clynes et al., Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). C1q binding assays may also be performed to confirm that the antibody is unable to bind C1q and thus lacks CDC activity. See, e.g., C1q and C3c binding ELISAs in WO2006 / 029879 and WO2005 / 100402. CDC measurements may also be performed to assess complement activation (see, e.g., Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg et al., Blood 101:1045-1052 (2003); and Cragg et al., Blood 103:2738-2743 (2004)). In addition, FcRn binding and in vivo clearance / half-life determinations may also be performed using methods known in the art (see, e.g., Petkova et al., Int'l. Immunol. 18(12):1759-1769 (2006)).

[0051] Antibodies with reduced effector function include those with one or more substitutions at Fc region residues 238, 265, 269, 270, 297, 327, and 329 (U.S. Patent No. 6,737,056). Such Fc variants include Fc variants with substitutions at two or more amino acid positions 265, 269, 270, 297, and 327, including the so-called "DANA" Fc variant with substitutions of residues 265 and 297 to alanine (U.S. Patent No. 7,332,581).

[0052] Certain antibody variants with improved or diminished binding to FcRs have been described (see, e.g., U.S. Pat. No. 6,737,056; WO2004 / 056312, and Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001)).

[0053] In certain embodiments, the antibody variant comprises an Fc region with one or more amino acid substitutions that improve ADCC (e.g., substitutions at positions 298, 333, and / or 334 (residues in EU numbering) of the Fc region).

[0054] In some embodiments, modifications are made in the Fc region that result in altered (i.e., either improved or attenuated) C1q binding and / or complement dependent cytotoxicity (CDC), e.g., as described in U.S. Pat. No. 6,194,551, WO1999 / 51642, and Idusogie et al., J. Immunol. 164:4178-4184 (2000).

[0055] Antibodies with increased half-lives and improved binding to the neonatal Fc receptor (FcRn, responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)) have been described in U.S. Patent Application Publication No. 2005 / 0014934 (Hinton et al.). These antibodies comprise an Fc region with one or more substitutions therein that improve binding of the Fc region to FcRn. Such Fc variants include those with substitutions at one or more of Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, ​​413, 424, or 434 (e.g., substitution at Fc region residue 434 (U.S. Patent No. 7,371,826)).

[0056] For other examples of Fc region variants, see also Duncan, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821; and WO1994 / 29351.

[0057] In certain embodiments, an anti-C5 antibody according to the invention comprises a VH according to any of the above-mentioned embodiments and a heavy chain constant region comprising the amino acid sequence of any one of SEQ ID NOs: 10, 11, 12, 13, 14, and 15. In certain embodiments, an anti-C5 antibody comprises a VL according to any of the above-mentioned embodiments and a light chain constant region comprising the amino acid sequence of any one of SEQ ID NOs: 16, 17, and 18.

[0058] In certain embodiments, the anti-C5 antibody related to the present invention is any one of the antibodies described in WO2016 / 098356, WO2017 / 123636, and WO2017 / 132259.

[0059] In a particular embodiment, when the pharmaceutical composition is repeatedly administered to a subject by subcutaneous injection, the composition is administered once every 3 to 42 days. The appropriate administration interval of the subcutaneous injection can be determined within a suitable range according to the condition of the subject or patient. The specific administration interval of the subcutaneous injection is 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days. In a preferred embodiment, the administration interval is 4 to 35 days. In a more preferred embodiment, the administration interval is 5 to 31 days. In a most preferred embodiment, the administration interval is 7, 14, or 28 days, or 1 month. The pharmaceutical composition may be administered once a week (every week), once every two weeks (every two weeks or every other week), or once every four weeks (every four weeks or every month). Longer intervals can reduce the burden and pain of the patient.

[0060] In a particular embodiment, the pharmaceutical composition is administered subcutaneously at a dose of 17 to 6,000 mg of the antibody. The appropriate dose can be determined within a suitable range depending on the condition of the subject or patient. When the pharmaceutical composition is repeatedly administered subcutaneously to the subject, the dose does not necessarily have to be the same all the time, and can be determined arbitrarily as long as the dose is within a suitable range. For example, the dose may be gradually decreased. In a preferred embodiment, the dose range is 25 to 4,000 mg of the antibody. In a more preferred embodiment, the dose range is 50 to 2,000 mg of the antibody. In a most preferred embodiment, the dose range is 75 to 1,000 mg of the antibody. Particularly preferred doses are 100 mg, 170 mg, 340 mg, 600 mg, and 680 mg. More preferred doses are 170 mg, 340 mg, 600 mg, and 680 mg. When the pharmaceutical composition is administered weekly (at about 7-day intervals), the preferred dose is 170 mg. When the pharmaceutical composition is administered every 2 weeks (about 14 days apart), the preferred dose is 340 mg. When the pharmaceutical composition is administered every 4 weeks (about 28 days apart), the preferred dose is 600 mg or 680 mg. The dosing regimen of 600 mg or 680 mg every 4 weeks is particularly preferred because it can reduce the burden and pain of the patient.

[0061] In certain embodiments, any pharma- ceutically acceptable carrier that can be used for a general composition for subcutaneous injection can be included in the pharmaceutical composition. Certain carriers used for subcutaneous injection can be suitably selected from carriers generally known in the art.

[0062] In certain embodiments, the formulation of the pharmaceutical composition can be any one selected from the group consisting of liquid, semi-solid, and solid.Solid compositions are usually made by lyophilization from liquid formulations.Lyophilized compositions are usually reconstituted with water or saline immediately before subcutaneous injection.

[0063] When the composition is administered subcutaneously, the concentration of anti-C5 antibody in the liquid formulation of the composition is determined within the range generally known in the art. In certain embodiments, the amount of the composition for subcutaneous injection is determined within the range generally known in the art.

[0064] In certain embodiments, the C5-related disease is a complement-mediated disease or condition that involves excessive or uncontrolled activation of C5.In certain embodiments, the C5-related disease is at least one selected from the group consisting of: rheumatoid arthritis (RA); lupus nephritis; ischemia-reperfusion injury; paroxysmal nocturnal hemoglobinuria (PNH); atypical hemolytic uremic syndrome (aHUS); dense deposit disease (DDD); macular degeneration; HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome; thrombotic thrombocytopenic purpura (TTP); spontaneous fetal loss; oligoimmune vasculitis; epidermolysis bullosa; recurrent abortion; multiple sclerosis (MS); traumatic brain injury; and injury resulting from myocardial infarction, cardiopulmonary bypass or hemodialysis; refractory generalized myasthenia gravis (gMG); neuromyelitis optica (NMO). In a preferred embodiment, the C5-associated disease is at least one selected from the group consisting of PNH, aHUS, gMG, and NMO.

[0065] In certain aspects, the first dose of the composition for subcutaneous injection is administered after a dose of another pharmaceutical composition is administered intravenously. The pharmaceutical composition for intravenous injection is the same as that described below.

[0066] In certain embodiments, the composition for subcutaneous injection is subcutaneously administered on the same day as the dose of the composition for intravenous injection is intravenously administered, or one or more days later.One or more doses of the composition for intravenous injection may be administered to the subject or patient before the first dose of the composition for subcutaneous injection is administered.In a preferred embodiment, the first dose of the composition for subcutaneous injection is administered after the last dose of the composition for intravenous injection.

[0067] In a particular embodiment, the first dose of the composition for subcutaneous injection is administered on the same day as the dose of the composition for intravenous injection or 1 to 28 days thereafter. The specific interval between the dose of the composition for intravenous injection and the first dose of the composition for subcutaneous injection is 0 days (i.e., within 24 hours), 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, or 28 days. In a preferred embodiment, the interval is 1 to 14 days. In a further preferred embodiment, the interval is 3 to 10 days. In a most preferred embodiment, the interval is 5 to 8 days.

[0068] III. Pharmaceutical Compositions for Intravenous Injection The pharmaceutical composition formulated for intravenous injection in the present invention is for treating or preventing C5-related diseases, contains anti-C5 antibody, and is administered intravenously. Intravenous injection can be performed using a general device and method for administering pharmaceutical compositions into a vein by injection. Alternatively, a device and method specifically for intravenous injection can be selected.

[0069] The anti-C5 antibody used for intravenous injection can be any antibody described above for the pharmaceutical composition for subcutaneous injection.The pharmaceutical composition for intravenous injection and the pharmaceutical composition for subcutaneous injection can contain the same anti-C5 antibody or different anti-C5 antibodies.In a preferred embodiment, the anti-C5 antibody used for intravenous injection is the same antibody as that described above for subcutaneous injection.

[0070] In certain embodiments, the pharmaceutical composition is administered intravenously at a dose of 50 to 5,000 mg of antibody. The appropriate dose can be determined within a suitable range depending on the condition of the subject or patient. When the pharmaceutical composition is repeatedly administered intravenously to the subject, the dose does not necessarily have to be the same all the time, and can be determined arbitrarily as long as the dose is within a suitable range. For example, the dose may be gradually decreased. In a preferred embodiment, the dose range is 55 to 4,000 mg of antibody. In a further preferred embodiment, the dose range is 60 to 2,500 mg of antibody. In a most preferred embodiment, the dose range is 70 to 1,500 mg of antibody. Particularly preferred doses are 75 mg, 125 mg, 150 mg, 300 mg, 375 mg, 500 mg, and 1,000 mg. More preferred doses are 375 mg, 500 mg, and 1,000 mg, and most preferred is 1,000 mg.

[0071] In a specific embodiment, the number of times that the pharmaceutical composition is administered by intravenous injection is not particularly limited, and can be one or more times. In a preferred embodiment, the number of times is one, two, or three times. In a more preferred embodiment, the number of times is one or two times. In the most preferred embodiment, the number of times is one time. Fewer times can reduce the burden and pain of the patient.

[0072] In certain embodiments, when the pharmaceutical composition is repeatedly administered intravenously to a subject or patient, the composition is administered once every hour to once every 14 days. The appropriate administration interval of intravenous injection can be determined within a suitable range depending on the condition of the subject or patient. Specific dosing intervals for intravenous injection are 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 ​​hours, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days. In a preferred embodiment, the administration interval is 24 hours to 10 days. In a more preferred embodiment, the administration interval is 48 hours to 7 days. In a most preferred embodiment, the administration interval is 3 to 5 days.

[0073] In certain embodiments, any pharma- ceutically acceptable carrier available for a general composition for intravenous injection can be included in the composition. Certain carriers used for intravenous injection can be suitably selected from carriers generally known in the art.

[0074] In certain embodiments, the formulation of the pharmaceutical composition can be any selected from the group consisting of liquid, semi-solid, and solid. A solid composition is usually made by lyophilization from a liquid formulation. A lyophilized composition is usually reconstituted with water or saline immediately before intravenous injection. The formulation of the pharmaceutical composition for intravenous injection can be the same or different from the formulation of the pharmaceutical composition for subcutaneous injection. In a preferred embodiment, the formulation of the pharmaceutical composition for intravenous injection is the same as the formulation of the pharmaceutical composition for subcutaneous injection to reduce production costs.

[0075] When the composition is administered intravenously, the concentration of the anti-C5 antibody in the liquid formulation of the composition is determined within the range generally known in the art. In certain embodiments, the amount of the composition for intravenous injection is determined within the range generally known in the art.

[0076] In certain aspects, a dose of the composition for intravenous injection is administered before a first dose of another pharmaceutical composition is administered subcutaneously. The pharmaceutical composition for subcutaneous injection is the same as described above.

[0077] In certain embodiments, the composition for intravenous injection is intravenously administered on the same day as the first dose of the composition for subcutaneous injection is administered subcutaneously, or one or more days before that.One or more doses of the composition for intravenous injection may be administered to the subject or patient before the first dose of the composition for subcutaneous injection is administered.In a preferred embodiment, the final dose of the composition for intravenous injection is administered before the first dose of the composition for subcutaneous injection.

[0078] In a particular embodiment, a dose of the composition for intravenous injection is administered on the same day as the first dose of the composition for subcutaneous injection or 1 to 28 days before. The specific interval between the dose of the composition for intravenous injection and the first dose of the composition for subcutaneous injection is 0 days (i.e., within 24 hours), 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, or 28 days. In a preferred embodiment, the interval is 1 to 14 days. In a further preferred embodiment, the interval is 3 to 10 days. In a most preferred embodiment, the interval is 5 to 8 days.

[0079] IV. Switching from other medicines In another aspect, the above-mentioned pharmaceutical composition for subcutaneous injection or intravenous injection is useful for treating or preventing C5-related disease in a subject who has been treated once or multiple times with at least one pharmaceutical for treating or preventing the disease.For example, the pharmaceutical composition of the present invention can be useful for treating a patient with a disease who has previously been treated with at least one pharmaceutical for treating or preventing C5-related disease, but is expected to respond better to treatment with the pharmaceutical composition of the present invention.In such a case, the drug therapy can be switched from the pharmaceutical to the pharmaceutical composition of the present invention.In a preferred embodiment, the first dose of the composition for intravenous injection of the present invention is administered after the final dose of the pharmaceutical used in the previous treatment.

[0080] In certain embodiments, the pharmaceutical product comprises an agent different from the anti-C5 antibody in the above composition for subcutaneous injection and intravenous injection.In some embodiments, the agent of the pharmaceutical product is an siRNA targeting C5 mRNA, or an anti-C5 antibody different from the anti-C5 antibody contained in the above composition for subcutaneous injection and intravenous injection.In a preferred embodiment, the pharmaceutical product comprises an antibody that is different from the antibody in the above composition for subcutaneous injection and intravenous injection.In the most preferred embodiment, the antibody contained in the pharmaceutical product used in the above treatment is eculizumab or its derivative.

[0081] In a particular embodiment, the first dose of the intravenous composition of the present invention is administered on the same day as the last dose of the drug or one or more days later. The specific interval between the last dose of the drug and the first dose of the intravenous composition of the present invention is 0 days (meaning that the first dose of the intravenous composition is administered on the same day as the last dose of the drug), 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In a preferred embodiment, the intravenous composition of the present invention is administered three or more days after the last dose of the drug. In a more preferred embodiment, the intravenous composition of the present invention is administered seven or more days after the last dose of the drug. In a further preferred embodiment, the intravenous composition of the present invention is administered 14 or more days after the last dose of the drug. In a most preferred embodiment, the intravenous composition of the present invention is administered 21 or more days after the last dose of the drug.

[0082] V. Methods for Treatment or Prevention In another aspect, the invention includes a method for treating or preventing a C5-related disease.

[0083] In one embodiment, the method comprises intravenously administering a first pharmaceutical composition formulated for intravenous injection and comprising an anti-C5 antibody, and, after administration of the first composition, subcutaneously administering a second pharmaceutical composition formulated for subcutaneous injection and comprising an anti-C5 antibody.

[0084] The conditions and target diseases of the pharmaceutical composition for subcutaneous or intravenous injection used in this method are the same as those mentioned in the above chapters "II. Pharmaceutical Composition for Subcutaneous Injection" and "III. Pharmaceutical Composition for Intravenous Injection".

[0085] VI. Vaccination In the subject administered with anti-C5 antibody, infectious diseases such as meningococcal infections may occur.To prevent such infectious diseases, the subject may be immunized with a vaccine known to treat or prevent such diseases before, after, or during administration of the above-mentioned composition for subcutaneous and intravenous injection.

[0086] VII. Manufactured products In another aspect of the present invention, an article of manufacture or product is provided that includes materials useful for treating or preventing the above-mentioned C5-related diseases. The article of manufacture or product includes one or more containers and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, SC solution syringes, and the like. The containers can be formed from a variety of materials, such as glass or plastic. The container holds the composition alone or in combination with another composition effective for treating or preventing the condition, and may have a sterile access port (e.g., the container may be an intravenous solution bag or vial with a stopper pierceable by a hypodermic needle). At least one active agent in the composition is an anti-C5 antibody as described above. The label, package insert, or such information indicates that the composition is to be used to treat the selected condition.

[0087] In certain embodiments, the composition contained in the article of manufacture or container of product is formulated for subcutaneous injection. The article of manufacture or product in this embodiment of the invention may further comprise a package insert indicating that the composition should be administered after intravenous administration of a dose of another pharmaceutical composition. The other pharmaceutical composition in this embodiment of the invention comprises an anti-C5 antibody and is formulated for intravenous injection.

[0088] In certain embodiments, the composition contained in the article of manufacture or container of product is formulated for intravenous injection. The article of manufacture or product of this embodiment of the invention may further comprise a package insert indicating that the composition should be administered before a first dose of another pharmaceutical composition is administered subcutaneously. The other pharmaceutical composition of this embodiment of the invention comprises an anti-C5 antibody and is formulated for subcutaneous injection.

[0089] In yet certain other embodiments, the article of manufacture or product may include (a) a first container having contained therein a first composition comprising an anti-C5 antibody and formulated for intravenous injection; and (b) a second container having contained therein a second composition comprising an anti-C5 antibody and formulated for subcutaneous injection. The article of manufacture in this embodiment of the invention may further include a package insert indicating that the compositions can be used to treat a particular condition, such as a C5-related disease, and further indicating that administration of the first and second pharmaceutical compositions is in the following order: one or more intravenous administrations of the first pharmaceutical composition for intravenous injection and one or more subcutaneous administrations of the second pharmaceutical composition for subcutaneous injection.

[0090] The article of manufacture or product may further comprise an additional container having a composition therein comprising an additional cytotoxic or otherwise therapeutic agent. The article of manufacture in this aspect of the invention may further comprise a package insert indicating that the composition can be used to treat a particular condition. Alternatively, or in addition, the article of manufacture may further comprise another additional container comprising a pharma- ceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution, and dextrose solution. It may further include other equipment desirable from a commercial or user standpoint, such as other buffers, diluents, filters, needles, and syringes. EXAMPLES

[0091] The following are examples of the methods and compositions of the present invention. In light of the general description above, it will be understood that various other embodiments may be practiced.

[0092] Example 1 Generation of anti-C5 antibodies 305LO15, an anti-C5 antibody in WO2016 / 098356, was prepared by a general method. Briefly, the gene encoding the heavy chain variable domain (VH) of 305LO15 was combined with the gene encoding the modified human IgG1 heavy chain constant domain (CH) mutant SG115 (SEQ ID NO: 13). The gene encoding the light chain variable domain (VL) of 305LO15 was combined with the gene encoding the human light chain constant domain (CL) (SK1, SEQ ID NO: 18). The antibody was expressed in HEK293 cells co-transfected with a combination of heavy and light chain expression vectors and purified by protein A.

[0093] Example 2 Protein drugs, such as antibody drugs, are typically administered intravenously because it is difficult to concentrate proteins. In fact, eculizumab, the only approved antibody that can be used for treatment at present, is administered intravenously. If subcutaneous injection becomes available, self-injection is possible, so it is expected that the burden on patients, such as outpatient treatment for intravenous injection and long-term hospitalization, will be reduced.

[0094] To investigate the feasibility of subcutaneous administration of anti-C5 antibodies, 305LO15 disclosed in WO2016 / 098356 was selected due to its high solubility. Higher solubility was thought to provide the possibility that protein pharmaceuticals could be administered in smaller volumes, enabling subcutaneous injection.

[0095] To compare the pharmacokinetics of 305LO15 after subcutaneous or intravenous injection, cynomolgus monkeys were divided into two groups: subcutaneous injection group and intravenous injection group. 305LO15 was administered subcutaneously to the animals in the first group (3 males and 3 females) once a week for a total of 22 doses, with 40 mg antibody / kg for each dose. The plasma 305LO15 concentrations of these animals were measured using ELISA analysis at the time points shown in Figure 1a. 305LO15 was administered intravenously to the animals in the second group (6 males and 6 females) once a week for a total of 5 doses, with 40 mg antibody / kg for each dose. The plasma 305LO15 concentrations of the animals were measured by ELISA analysis at the time points shown in Figure 1b.

[0096] As shown in Figure 1a, plasma 305LO15 concentrations in cynomolgus monkeys were increased by subcutaneous injection, demonstrating that 305LO15 can be administered by subcutaneous injection for therapeutic purposes. The initial rate of increase in plasma concentration after the first dose was lower with subcutaneous administration (Figure 1a) compared to intravenous injection (Figure 1b).

[0097] Example 3 We next investigated whether the relatively slow rate of rise in plasma concentrations after subcutaneous injection of the initial dose could be compensated for by intravenous injection of 305LO15. Five male and five female cynomolgus monkeys were given a single intravenous initial dose of 305LO15 at a dose of 100 mg / kg of antibody. One week after the initial intravenous dose, subcutaneous injections of 305LO15 were started. A total of 26 subcutaneous injections were given weekly at a dose of 40 mg / kg of antibody for each dose.

[0098] As shown in Figure 2, the rate of increase in plasma concentration of 305LO15 was faster when the initial dose of antibody was administered as an intravenous injection prior to the subcutaneous maintenance dose than when the initial dose was not administered intravenously. The plasma concentration of 305LO15 reached and was maintained at levels comparable to those shown in Figure 1a. This more rapid increase in plasma concentration of 305LO15 was believed to contribute to the more rapid achievement of the therapeutic effect of the drug.

[0099] Example 4 To estimate the effective plasma concentration of 305LO15, the relationship between plasma concentrations of free antigen (C5) or complement activity and plasma concentrations of antibody (305LO15) was determined in cynomolgus monkeys. 305LO15 was administered intravenously (0.8 mg / kg, 4 mg / kg, or 20 mg / kg) or subcutaneously (4 mg / kg). Plasma concentrations of antibody and free C5 were measured by ELISA. Complement activity was measured by RBC hemolysis assay. As shown in Figure 3, when plasma concentrations of 305LO15 were maintained above 40 μg / mL 305LO15 (Figure 3a), free C5 concentrations were suppressed below subμg / mL levels, and plasma concentrations of 305LO15 at or above 40 μg / mL inhibited complement activity (hemolysis) to less than 20% of baseline (i.e., without antibody application) (Figure 3b). It was estimated that sustained concentrations of 305LO15 in plasma of 40 μg / mL or greater would suppress complement activity to less than 20% of baseline (i.e., without antibody injection).

[0100] Example 5 To determine the optimal dose of 305LO15 to maintain an effective plasma 305LO15 concentration for clinical trials, we performed simulations to predict the time course of plasma 305LO15 concentration in humans. First, cynomolgus monkeys were administered the antibody at 0.8, 4, and 20 mg / kg for each dose, and the plasma 305LO15 concentration was measured over time. The PK parameters for cynomolgus monkeys were estimated by analyzing the data using a two-compartment model. The PK parameters for humans were estimated based on the PK parameters for cynomolgus monkeys using allometric scaling. Estimated PK parameters in humans are shown in Table 1 (abbreviations for parameters in Table 1: BW, body weight; CL, total clearance of drug; F, bioavailability, i.e., the fraction of an administered dose of drug that becomes systemically available; Ka, absorption rate constant; mAb, monoclonal antibody; PK, pharmacokinetics; Q, intercompartmental clearance; SC, subcutaneous; Vc, volume of distribution of the central compartment; Vp, volume of distribution of the peripheral compartment).

[0101] [Table 1]

[0102] Human PK profiles were estimated for each cohort planned for the Phase 1 / 2 study (Figure 4). The first part of the study was designed to include three groups of subjects. Group 1 was a group of subjects who received a single intravenous dose of 305LO15 at a dose of 75 mg / body. Group 2 was a group of subjects who received a single intravenous dose of 305LO15 at a dose of 150 mg / body. Group 3 was a group of subjects who received a single subcutaneous dose of 305LO15 at a dose of 170 mg / body. Plasma 305LO15 concentrations in subjects receiving any one of the doses were predicted not to be maintained above the threshold (40 μg / mL) for more than one week (Figure 4a).

[0103] The second part of the study was designed to include one group of subjects who received three doses of 305LO15 intravenously (at a dose of 300 mg / body, then at 500 mg / body one week after the first dose, and finally at 1000 mg / body two weeks after the second dose), and then, starting two weeks after the last intravenous dose, received weekly subcutaneous doses of 305LO15 at a dose of 170 mg / body. The dosing regimen in the second part of the study predicted that 305LO15 concentrations would be maintained above the PD threshold (40 μg / mL) ( FIG. 4 b).

[0104] The third part of the study was designed to include three groups of subjects. First, all subjects in the group were administered 305LO15 intravenously once at a dose of 500 mg / body. From the day after the first dose, 305LO15 was administered subcutaneously once a week at a dose of 170 mg / body to subjects in group 1, once every two weeks at a dose of 340 mg / body to subjects in group 2, and once every four weeks at a dose of 600 mg / body to subjects in group 3. 305LO15 concentrations were predicted to remain higher than the PD threshold (40 μg / mL) in all three groups in the third part of the study (Figure 4c).

[0105] Example 6 Eculizumab is used to treat patients with PNH or aHUS. If 305LO15 is expected to have a more favorable effect on PNH or aHUS patients than eculizumab, the drug therapy for the patient may be switched from eculizumab to 305LO15. On the other hand, since the epitope of 305LO15 is different from that of eculizumab, i.e., eculizumab binds to the α chain of C5 while 305LO15 binds to the β chain of C5, 305LO15 may form an immune complex with C5 and eculizumab in the body. The formation of such an immune complex may cause abnormal activation, and therefore it is desirable to prevent this as much as possible.

[0106] To investigate whether 305LO15 forms immune complexes with eculizumab (ECZ, heavy chain sequence shown in SEQ ID NO:19 and light chain sequence shown in SEQ ID NO:20) and human C5 (hC5, SEQ ID NO:21), an in vitro analysis using size exclusion chromatography (SEC) was performed. hC5 was prepared according to the method disclosed in WO2016 / 098356. For buffer exchange, ECZ, hC5, and 305LO15 were dialyzed against DPBS pH 7.4. ECZ and hC5 were then mixed and incubated at 37°C for 3-4 hours. After incubation, 305LO15 was added to this mixture containing ECZ and hC5. The final concentrations of ECZ and hC5 were adjusted to 200 μg / mL, and the 305LO15 concentrations were adjusted to 0, 25, 125, 250, or 1250 μg / mL. These mixtures were incubated at 37°C for 3 to 4 hours, and then SEC analysis was performed at pH 7.4 and pH 6.0. The specific SEC conditions are shown below. HPLC system: Waters Alliance e2695 HPLC system Column: TSKgel G4000SWXL Column temperature: 25℃ Elution solution: 50 mM Na-PB / 300 mM NaCl, pH 7.4 or pH 6.0 Flow rate: 0.5 mL / min Detection: 220 nm UV absorption Injection: 10μL

[0107] As a result, 305LO15 at concentrations of 125-1250 μg / mL did not affect the SEC profile at pH 6.0, but did affect it at pH 7.4. More specifically, when 305LO15 was mixed with ECZ and hC5, a large ECZ / hC5 / 305LO15 immune complex peak was detected at pH 7.4 (see the peaks indicated by the arrows in Figure 5, top) in addition to the small complex peaks (see peaks "2Ag+Ab" and "Ag+Ab" in Figure 5, top). At pH 6.0, only the small complex peak was detected (see peaks in Figure 5, bottom, corresponding to "2Ag+Ab" and "Ag+Ab" in Figure 5, top). This means that 305LO15 binds to the ECZ / hC5 complex at pH 7.4 but not at pH 6.0, consistent with the binding properties of 305LO15 (which binds to hC5 at pH 7.4 but not at pH 6.0). These results suggest that co-administration of 305LO15 and ECZ to subjects may result in the formation of large immune complexes in plasma.

[0108] Example 7 Study BP39144, an adaptive Phase I / II trial, evaluated the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of 305LO15 in healthy volunteers and patients with paroxysmal nocturnal hemoglobinuria (PNH).

[0109] The first part of study BP39144 (a randomized, double-blind, adaptive, placebo-controlled, parallel-group study) evaluated the safety and tolerability of a single dose of 305LO15 in healthy volunteers. A total of five healthy volunteers in each dose level / cohort were randomized to receive a single intravenous (IV; cohorts 1 and 2) or subcutaneous (SC; cohort 3) dose of 305LO15 or placebo. The study had an adaptive design, with ongoing evaluation of available safety, tolerability, PK, and PD data before initiating the next dose. The planned dose levels for cohorts 1, 2, and 3 were 75 mg IV, 150 mg IV, and 170 mg SC, respectively (Figure 4a). Based on preliminary examination of PK and PD data from cohort 1, the dose was reduced in cohorts 2 and 3 to 125 mg IV (cohort 2) and 100 mg SC (cohort 3).

[0110] For IV infusion, blood samples were taken pre-dose, at the end of IV infusion (1 hour), 2, 6, 12, 24, 48, 72, 96, and 144 hours post-dose, and on days 14, 21, 28, 35, 42, 56, 84, and 91. For SC administration, blood samples were taken pre-dose, 12, 24, 48, 72, 96, and 144 hours post-dose, and on days 14, 21, 28, 35, 42, 56, 84, and 91.

[0111] Preliminary safety results from the first part of Study BP39144 indicate that 305LO15 was well tolerated at all dose levels evaluated (75 and 125 mg IV and 100 mg SC). Available clinical safety information did not raise any significant safety concerns or provide any evidence of any patterns of adverse events or laboratory abnormalities. No notable findings or trends were noted in vital signs or 12-lead ECGs in any of the treatment groups.

[0112] Preliminary serum PK results and concentration-time simulated profiles for 305LO15 are shown in Figures 6, 7, and 8. Based on these data, the PK of 305LO15 in healthy subjects was consistent with initial predictions of human PK based on the cynomolgus monkey PK data (Example 5). After an IV dose, exposure appeared to be dose proportional from 75 to 125 mg. The terminal half-life (t 1 / 2 ) was estimated to be approximately 25 days. After SC administration, preliminary PK results indicated that exposure to 305LO15 peaked at approximately day 7 and bioavailability was approximately 90%. After absorption, t 1 / 2 is the t of IV injection 1 / 2 was equivalent to.

[0113] A preliminary assessment of the exposure-response relationship confirmed the initial prediction, namely that approximately 40 μg of 305LO15 per mL of blood was required to achieve complete complement inhibition (Figure 9).

[0114] Example 8 The second part of study BP39144 (an open-label, multiple-dose, multicenter, intra-individual dose-escalation study) evaluated the safety and tolerability over a total duration of 5 months, as well as the pharmacodynamic effects of multiple doses of 305LO15 on complement activity in treatment-naïve patients with PNH. Six patients with PNH were enrolled in the study. Patients enrolled had never been treated with any complement inhibitor or had been previously treated but discontinued due to ineffectiveness based on a single missense C5 heterozygous mutation, and had elevated serum LDH levels (>1.5 x ULN) at screening (ULN: upper limit of normal).

[0115] One of the six patients (Patient X) had PNH and was a candidate for treatment with complement inhibitors. Patient X received three single ascending IV doses; a single injection of 375 mg of 305LO15 on day 1, followed by a single injection of 500 mg of 305LO15 on day 8, and further followed by a single injection of 1000 mg of 305LO15 on day 22. The first SC dose (170 mg) was initiated on day 36, followed by weekly (QW) SC injections of 305LO15 (170 mg) continued for a total treatment period of 5 months.

[0116] Preliminary pharmacodynamic results from Patient X are shown in Table 2 and Figure 10. LDH levels, as a pharmacodynamic marker of hemolysis, decreased to levels within the normal range limits by day 15, further decreased by day 36, and were maintained at normalized levels by day 43 (Table 2 and Figure 10a). As shown in Table 2 and Figure 10b, liposome immunoassay (LIA) results showed that complement activity was completely inhibited at the end of infusion on day 1, the start of the study. A dose of 375 mg 305LO15 on day 1 maintained complete complement inhibition until the next dose of 500 mg 305LO15 on day 8. A dose of 500 mg 305LO15 on day 8 maintained complete complement inhibition until the next dose of 1000 mg 305LO15 on day 22. A dose of 1000 mg 305LO15 on day 22 maintained complete complement inhibition until the next SC dose of 170 mg 305LO15 on day 36. The SC dose on day 36 maintained complete complement inhibition on day 43.

[0117] 305LO15 was well tolerated with only mild abdominal pain unrelated to treatment.

[0118] [Table 2]

[0119] Example 9 The third part of study BP39144 (an open-label, multiple-dose, multicenter study) evaluated the safety and tolerability over a total period of 5 months, as well as the pharmacodynamic effects of multiple doses of 305LO15 on complement activity in PNH patients currently treated with eculizumab. Eighteen PNH patients are expected to participate in the study. Patients enrolled in the study had been continuously treated with eculizumab for at least 3 months immediately prior to enrollment, and were required to receive regular infusions of eculizumab.

[0120] One of the 18 patients (Patient Y) was a PNH patient treated with eculizumab, which was last administered 14 days prior to the first IV infusion of 305LO15. Patient Y received a single IV loading dose; a single infusion of 1000 mg of 305LO15 on day 1. The first SC dose (680 mg) was given on day 8, followed by SC injections of 305LO15 (680 mg) every 4 weeks (Q4W) for a total treatment duration of 5 months.

[0121] Preliminary pharmacodynamic results from patient Y are shown in Table 3. LDH levels, as a pharmacodynamic marker of hemolysis, remained at baseline levels from dose 1 through day 43 (Table 3). As shown in Table 3, liposome immunoassay (LIA) results showed complete inhibition of complement activity at the end of infusion on day 1, the start of the study. The 1000 mg 305LO15 dose on day 1 maintained complete complement inhibition up to the 680 mg 305LO15 SC dose on day 8. The SC dose on day 8 maintained complete complement inhibition on day 43.

[0122] [Table 3]

Claims

1. A pharmaceutical composition for treating or preventing a C5-related disease, comprising: The composition is formulated for subcutaneous injection, comprises an anti-C5 antibody, and is administered subcutaneously; a first dose of the composition is administered after a dose of another pharmaceutical composition is administered intravenously; The other pharmaceutical composition is formulated for intravenous administration and comprises the anti-C5 antibody.

2. A pharmaceutical composition for treating or preventing a C5-related disease, comprising: The composition is formulated for intravenous injection, comprises an anti-C5 antibody, and is administered intravenously; a dose of said composition is administered before a first dose of another pharmaceutical composition is administered subcutaneously; The other pharmaceutical composition is formulated for subcutaneous injection and comprises the anti-C5 antibody.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the first dose of the composition for subcutaneous injection is administered on the same day as the dose of the composition for intravenous injection, or 1 to 28 days thereafter.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein said composition for subcutaneous injection is given once every 3 to 42 days.

5. 5. The pharmaceutical composition according to any one of claims 1 to 4, wherein said composition for intravenous injection is administered in two or more doses, given from once an hour to once every 14 days.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein said composition for subcutaneous injection is given in a single dose of 17 to 6,000 mg of said antibody.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein said composition for intravenous injection is given in a single dose of 50 to 5,000 mg of said antibody.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the composition is for the treatment or prevention of a C5-related disease in a subject who has been treated with at least one medicinal product for the treatment or prevention of the disease, and the first dose of the composition for intravenous injection is administered after the last dose of the medicinal product.

9. 9. The pharmaceutical composition of claim 8, wherein the first dose of said composition for intravenous injection is administered 3 days or more after the last dose of the pharmaceutical agent.

10. The pharmaceutical composition of claim 8 or 9, wherein the pharmaceutical comprises an siRNA targeting C5 mRNA or an anti-C5 antibody different from the anti-C5 antibody contained in the composition.

11. The pharmaceutical composition according to any one of claims 8 to 10, wherein the medicament comprises eculizumab or a derivative thereof.

12. A pharmaceutical composition for treating or preventing a C5-related disease, comprising: The pharmaceutical composition is formulated for subcutaneous injection and comprises an anti-C5 antibody, the pharmaceutical composition being administered subcutaneously in a single dose of 17 to 6,000 mg of said antibody.

13. A pharmaceutical composition for treating or preventing a C5-related disease, comprising: The pharmaceutical composition is formulated for intravenous injection and comprises an anti-C5 antibody, the pharmaceutical composition being administered intravenously in a single dose of 50-5,000 mg of said antibody.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the C5-related disease is any one selected from the group consisting of rheumatoid arthritis (RA); lupus nephritis; ischemia-reperfusion injury; paroxysmal nocturnal hemoglobinuria (PNH); atypical hemolytic uremic syndrome (aHUS); dense deposit disease (DDD); macular degeneration; hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; thrombotic thrombocytopenic purpura (TTP); spontaneous fetal loss; oligoimmune vasculitis; epidermolysis bullosa; recurrent abortion; multiple sclerosis (MS); traumatic brain injury; and injury resulting from myocardial infarction, cardiopulmonary bypass, or hemodialysis.

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