Agent for improving or supressing hemosiderin deposition and / or synovial membrane thickening

Abstract

[Problem] To provide: an agent that is used for the improvement or suppression of hemosiderin deposition and / or synovial membrane thickening or the like; a use of an antigen-binding molecule for the above-mentioned improvement or suppression; and others. [Solution] It has been found that a multispecific antigen-binding molecule capable of recognizing blood coagulation factor IX and / or activated blood coagulation factor IX and also capable of recognizing blood coagulation factor X and / or activated blood coagulation factor X is effective for the improvement and / or suppression of hemosiderin deposition and / or synovial membrane thickening or the like in joints. The present invention provides: an agent that is used for the improvement or suppression of hemosiderin deposition and / or synovial membrane thickening or the like, the agent comprising the multispecific antigen-binding molecule; a use of the molecule for the above-mentioned improvement or suppression; and others.

Description

Agent for improving or inhibiting hemosiderin deposition and / or synovial hyperplasia The present invention relates to an agent for use in ameliorating or suppressing hemosiderin deposition and / or synovial thickening, and the like, and to use of an antigen-binding molecule for such amelioration or suppression. Congenital hemophilia A (hemophilia A) is a bleeding disorder characterized by congenital underproduction or dysfunction of blood clotting factor VIII (FVIII), a protein essential for blood clotting. Congenital deficiency or dysfunction of FVIII in hemophilia A patients results in a lifelong tendency to bleed. Common clinical signs include easy bruising, prolonged bleeding after trauma or surgery, spontaneous bleeding in joints / muscles / soft tissues, and intracranial bleeding. The main bleeding sites are intra-articular, intramuscular, subcutaneous, oral, intracranial, gastrointestinal, and nasal, but joint bleeding can cause inflammation and destruction of the joint, ultimately leading to hemophilic arthropathy, a serious complication in hemophilia patients. Recurrent intra-articular bleeding can cause hemosiderin accumulation, inflammatory changes in the synovial membrane, synovial hypertrophy, and cartilage degradation, and in the end stage, joint destruction may require joint replacement surgery (Non-Patent Documents 1, 2). These disease-related problems are associated with increased pain, unemployment, school absenteeism, and impaired physical health and quality of life (HRQoL) (non-patent literature 3-7). Treatment of hemophilia A is divided into two types: hemostatic therapy for bleeding episodes and planned replacement therapy to prevent bleeding episodes. In replacement therapy, therapeutic agents are administered periodically to maintain hemostatic ability to prevent bleeding, especially joint bleeding that may lead to arthropathy and physical disability. With replacement therapy, hemophilia patients should be able to lead healthy and active lives similar to those of the non-hemophilia population, including the ability to participate in most physical and social activities (at home, school, work, and in the community) (Non-Patent Document 8). The standard treatment for patients with severe hemophilia A without inhibitors is replacement therapy with recombinant FVIII (rFVIII) or plasma-derived FVIII concentrates administered intravenously. In recent years, the usefulness of replacement therapy for joint disorders has been demonstrated (Non-Patent Documents 7, 9), and the rate of replacement therapy with FVIII agents in severe hemophilia A has increased, reaching 94% in Japan (Non-Patent Document 10). It has been reported that patients with FVIII trough levels of 10% or more are still at risk for spontaneous joint bleeding, which only resolves at levels of 15% or more (Non-Patent Document 11). Furthermore, recent recommendations from the European Directorate-General for Medicines and Healthcare Quality and the World Federation of Hemophilia suggest a minimum target level of 3% to 5% to maintain joint function (Non-Patent Documents 28, 29). While prophylaxis maintains joint function and slows the progression of hemophilic arthropathy, it may not be sufficient to prevent progression (Non-Patent Document 27). Acute intra-articular bleeding, which causes hemophilic arthropathy, may be transient and asymptomatic, and acute synovitis, which is a risk factor for rebleeding and chronicity, may also be asymptomatic. These asymptomatic joint bleeding and synovitis are thought to be related to the onset and progression of arthropathy (Non-Patent Document 15). Standard routine replacement therapy requires intravenous administration three times a week, which is expensive, cumbersome to administer frequently, and difficult to obtain blood vessels for administration (Non-Patent Document 12). Even with the recently released FVIII preparations with extended half-lives aimed at reducing the frequency of administration, intravenous administration once or twice a week is still required (Non-Patent Documents 13, 14). Emicizumab is a recombinant humanized bispecific immunoglobulin G4 (IgG4) monoclonal antibody that binds to activated factor IX (FIXa) and factor X (FX) with moderate affinity, mimicizing the cofactor function of activated blood coagulation factor VIII (FVIIIa) (Patent Documents 1 and 2). Furthermore, emicizumab has no sequence homology with FVIII, so hemostatic ability is restored even in hemophilia A patients who express FVIII inhibitors. Emicizumab can be administered subcutaneously, eliminating the need for venous access. In addition, the pharmacokinetic (PK) properties of this agent allow for a significant extension of the dosing interval, allowing it to be administered once a week (QW), once every two weeks (Q2W), or once every four weeks (Q4W), dramatically changing the treatment strategy for hemophilia A patients with or without FVIII inhibitors who require effective, safe, and low-burden prophylactic therapy. Emicizumab has demonstrated efficacy and safety in children and adults with and without FVIII inhibitors through phase III clinical trials conducted both globally and domestically (Non-Patent Documents 16-22). In the international phase III HAVEN 2 clinical trial, emicizumab led to a low annualized bleeding rate of treated bleeds (0.3, 95% CI 0.17-0.50) in 65 children with hemophilia A and FVIII inhibitors, with 76.9% having no treated bleeds. In 23 patients who received emicizumab for ≥52 weeks and had target joints at baseline (joints with ≥3 bleeds in the 24 weeks prior to emicizumab treatment), all 45 evaluable target joints improved during the study period. Furthermore, 20 of the 23 patients (87.0%) had no target joint bleeds during emicizumab treatment. Two of these patients had three and five target joints at baseline, respectively (Non-Patent Document 23). In the HOHOEMI study, a domestic phase III clinical trial targeting children with hemophilia A without FVIII inhibitors, 53.8% of the 13 patients did not experience bleeding requiring treatment (Non-Patent Document 16). In both studies, no thrombotic microangiopathy (TMA), thromboembolic events (TE), or deaths were reported, confirming a favorable safety profile. While there is extensive evidence on the efficacy and safety of emicizumab, data on its long-term impact on joint health in patients with hemophilia A are lacking. Currently, MRI is considered the most suitable method for early detection of joint damage in joint evaluation. Furthermore, it has been reported that synovial hyperplasia confirmed by MRI is a risk factor for future bleeding (Non-Patent Documents 25, 26). Based on the evidence in children to date, a clinical trial (AOZORA study) was planned to evaluate the long-term safety and impact on joint health of emicizumab in patients with hemophilia A aged 12 years or younger without FVIII inhibitors (Non-Patent Document 24). WO 2012 / 067176WO 2018 / 047813 van Vulpen LFD, Holstein K, Martinoli C. Joint disease in haemophilia: pathophysiology, pain and imaging. Haemophilia. 2018;24(S6):44-49. doi:10.1111 / hae.13449Rodriguez-Merchan EC. Musculo-skeletal manifestations of haemophilia. Blood Rev. 2016;30(5):401-409. doi:10.1016 / j.blre.2016.04.008Chen CM, Huang KC, Chen CC, et al. The impact of joint range of motion limitations on health-related quality of life in patients with haemophilia A: a prospective study. Haemophilia. 2015;21(3):e176-e184. doi:10.1111 / hae.12644Holstein K, von Mackensen S, Bokemeyer C, Langer F. The impact of social factors on outcomes in patients with bleeding disorders. Haemophilia. 2016;22(1):46-53. doi:10.1111 / hae.12760Khair K, Holland M, Bladen M, Griffioen A, McLaughlin P, von Mackensen S. Study of physical function in adolescents with haemophilia: the SO-FIT study. Haemophilia. 2017;23(6):918-925. doi:10.1111 / hae.13323O'Hara J, Walsh S, Camp C, et al.The impact of severe haemophilia and the presence of target joints on health-related quality-of-life. Health Qual Life Outcomes. 2018;16(1):84. doi:10.1186 / s12955-018-0908-9Rodriguez-Merchan EC. Treatment of musculo-skeletal pain in haemophilia. Blood Rev. 2018;32(2):116-121. doi:10.1016 / j.blre.2017.09.004Alok S, Elena S, Alison D, et al. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia. 2020 Aug;26 Suppl 6:1-158. doi: 10.1111 / hae.14046.Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357: 535-44.National Survey of Blood Coagulation Disorders, Japan AIDS Prevention Foundation, FY2023 ReportDen Uijl IEM, Fischer K., van der Bom JG, Grobbee DE, Rosendaal FR, Plug I., Haemophilia, 17 (2011), 41-44Geraghty S, Dunkley T, Harrington C, Lindvall K, Maahs J, Sek J. Practice patterns in haemophilia A therapy - global progress towards optimal care. Haemophilia. 2006; 12: 75-81.Adynovate IV Package Insert February 2018 (6th Edition)Eloctate IV Package Insert February 2017 (3rd Edition)Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007 Aug 9; 357 (6): 535-44.Shima M, Nogami K, Nagami S, et al. A multicentre, open-label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors. Haemophilia 2019;25:979-87.doi:10.1111 / hae.13848Mahlangu J, Oldenburg J, Paz-Priel I, et al. Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. N Engl J Med 2018;379:811-22.doi:10.1056 / NEJMoa1803550Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med 2017;377:809-18.doi:10.1056 / NEJMoa1703068Young G, Liesner R, Chang T, et al. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood 2019;134:2127-38.doi:10.1182 / blood.2019001869Pipe SW, Shima M, Lehle M, et al. Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (Haven 4): a multicentre, open-label, non-randomised phase 3 study. Lancet Haematol 2019;6:e295-305.doi:10.1016 / S2352-3026(19)30054-7Uchida N, Sambe T, Yoneyama K, et al. A first-in-human phase 1 study of ACE910, a novel factor VIII-mimetic bispecific antibody, in healthy subjects. Blood 2016;127:1633-41.doi:10.1182 / blood-2015-06-650226Shima M, Hanabusa H, Taki M, et al. Long-Term safety and efficacy of emicizumab in a phase 1 / 2 study in patients with hemophilia A with or without inhibitors. Blood Adv 2017;1:1891-9.doi:10.1182 / bloodadvances.2017006684Young G, Liesner R, Chang T, et al. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood 2019;134:2127-38.doi:10.1182 / blood.2019001869Shima M, Takedani H, Kitsukawa K, et al.AOZORA: long-term safety and joint health in paediatric persons with haemophilia A without factor VIII inhibitors receiving emicizumab - protocol for a multicentre, open-label, phase IV clinical study. BMJ Open. 2022 Jun 13;12(6):e059667. doi: 10.1136 / bmjopen-2021-059667.Roberta Gualtierotti, Luigi Piero Solimeno, Flora Peyvandi. Hemophilic arthropathy: Current knowledge and future perspectives. J Thromb Haemost. 2021 Sep;19(9):2112-2121. doi: 10.1111 / jth.15444. Epub 2021 Jul 27.Wouter F, Irene C, Frederik J, et al. MRI predicts 5-year joint bleeding and development of arthropathy on radiographs in hemophilia. Blood Adv. 2020 Jan 14;4(1):113-121. doi: 10.1182 / bloodadvances.2019001238.Hanley J、 McKernan A、 Creagh MD、 et al. Guidelines for the management of acute joint bleeds and chronic synovitis in haemophilia. Haemophilia. 2017;23(4):511-520.Peyvandi F., Berger K., Seitz R., Haematologica, 105 (8) (2020), 2038-2043Srivastava A., Santagostino E., Dougall A., et al.Haemophilia, 26 (S6) (2020), 1-158. The present invention has been made in view of the above-mentioned circumstances, and an objective of the present invention is to provide a drug for use in improving or suppressing hemosiderin deposition and / or synovial thickening, use of the drug, use of an antigen-binding molecule in the production of the drug, use of the antigen-binding molecule in improving or suppressing hemosiderin deposition and / or synovial thickening, etc. In order to test the safety of long-term administration of emicizumab and its effect on joints, the present inventors administered emicizumab continuously to hemophilia patients and evaluated the following items. Adverse events Adverse events leading to discontinuation of study drug Adverse events of particular interest Physical examination findings Abnormal laboratory test results -FVIII inhibitor occurrence status - Magnetic resonance imaging (MRI) knee and ankle scores (International Prophylaxis Study Group MRI scale) Hemophilia Joint Health Score (HJHS) 2.1 combined elbow, knee, ankle and gait scores As a result, good safety was confirmed for the first time with long-term administration of emicizumab. In addition, effusion / intra-articular bleeding was observed in 21 joints (18.1%) at Week 1 and in 31 joints (29.8%) at Week 145, whereas the score remained 0 in 42.3% (11 of 26) of joints at the start of emicizumab administration (Week 1) and Week 145 (Table 2). In contrast, with regard to synovial thickening and hemosiderin deposition, although synovial thickening and hemosiderin deposition were newly observed in one joint at Week 145, of the 10 joints (8.6%) in which synovial thickening and hemosiderin deposition were observed at Week 1, the scores improved in all joints by Week 145, and the findings of synovial thickening and hemosiderin deposition had disappeared in nine joints. Thus, this three-year emicizumab administration study demonstrated the safety of long-term administration of emicizumab, and for the first time demonstrated that emicizumab inhibits and improves synovial thickening and hemosiderin deposition in long-term administration. Inhibition and improvement of synovial thickening and hemosiderin deposition is thought to be particularly useful in preventing the progression of irreversible joint destruction, such as cartilage degradation, and in improving the long-term quality of life of patients. Specifically, the present invention provides a drug for use in improving or suppressing hemosiderin deposition and / or synovial thickening, and the like, and use of an antigen-binding molecule for the improvement or suppression, and more specifically, relates to the following inventions: [1] A drug for use in improving and / or inhibiting hemosiderin deposition in joints and / or synovial thickening, comprising as active ingredients (a) blood coagulation factor IX and / or activated blood coagulation factor IX, and (b) a bispecific antigen-binding molecule that binds to blood coagulation factor X and / or activated blood coagulation factor X. [2] The drug described in [1] for use in improving and / or inhibiting hemosiderin deposition and / or synovial thickening in the joints of a patient suffering from a disease whose onset and / or progression is caused by a decrease or deficiency in the activity of blood coagulation factor VIII and / or activated blood coagulation factor VIII (FVIIIa). [3] The drug according to [2], wherein the disease is hemophilia. [4] The drug according to [2] or [3], wherein the patient also suffers from hemophilic arthropathy. [5] The drug according to [2], wherein the patient is a patient confirmed to have hemophilic arthropathy. [6] The drug according to any one of [2] to [5], wherein the patient has been confirmed to have hemophilic arthropathy by MRI. [7] The drug according to any one of [2] to [6], wherein the patient is a patient in whom hemosiderin deposition and / or synovial thickening in joints has been confirmed by MRI. [8] The agent according to any one of [1] to [7], wherein the antigen-binding molecule is a bispecific antibody. [9] The agent according to any of [1] to [8], wherein the antigen-binding molecule is emicizumab.

[10] The agent according to any one of [1] to [9], wherein the antigen-binding molecule is a bispecific antibody in which a first polypeptide is associated with a third polypeptide and a second polypeptide is associated with a fourth polypeptide, and the bispecific antibody is any one of the following bispecific antibodies (a) to (c): (a) a bispecific antibody comprising a first polypeptide which is a heavy chain comprising a heavy chain variable region comprising the amino acid sequences of CDRs 1, 2, and 3 of SEQ ID NOs: 1, 2, and 3, respectively; a second polypeptide which is a heavy chain comprising a heavy chain variable region comprising the amino acid sequences of CDRs 1, 2, and 3 of SEQ ID NOs: 6, 7, and 8, respectively; and third and fourth polypeptides which are shared light chains comprising light chain variable regions comprising the amino acid sequences of CDRs 1, 2, and 3 of SEQ ID NOs: 11, 12, and 13, respectively; (b) a bispecific antibody comprising a first polypeptide, which is a heavy chain comprising the heavy chain variable region amino acid sequence of SEQ ID NO:4; a second polypeptide, which is a heavy chain comprising the heavy chain variable region amino acid sequence of SEQ ID NO:9; and third and fourth polypeptides, which are a shared light chain comprising the light chain variable region amino acid sequence of SEQ ID NO:14; or (c) A bispecific antibody comprising a first polypeptide, which is a heavy chain comprising the amino acid sequence of SEQ ID NO:5; a second polypeptide, which is a heavy chain comprising the amino acid sequence of SEQ ID NO:10; and third and fourth polypeptides, which are shared light chains comprising the amino acid sequence of SEQ ID NO:15.

[11] The drug according to any of [2] to

[10] , wherein the disease is selected from the group consisting of hemophilia A, acquired hemophilia A, von Willebrand disease, and hemophilia A accompanied by the appearance of inhibitors to blood coagulation factor VIII and / or activated blood coagulation factor VIII.

[12] The drug according to any one of [2] to

[11] , wherein the disease is congenital hemophilia A.

[13] The agent according to any one of [3] to

[12] , wherein the hemophilia patient does not have an inhibitor to FVIII.

[14] The drug according to any one of [3] to

[13] , wherein the hemophilia patient is a pediatric patient with congenital hemophilia A aged 12 years or younger.

[15] The agent according to any one of [1] to

[14] , which is administered to a subject who has developed hemosiderin deposition in joints and / or synovial thickening and / or a subject who is at risk of developing such hemosiderin deposition and / or synovial thickening.

[16] The drug according to any one of [1] to

[15] , wherein the improvement is exhibited upon long-term administration.

[17] The drug according to any one of [1] to

[16] , wherein the drug is administered for 145 weeks or more.

[18] The drug according to any one of [1] to

[17] , wherein the drug is administered for 300 weeks or more.

[19] The agent according to any one of [1] to

[18] , wherein the antigen-binding molecule is administered at a dose of 1 to 4.5 mg / kg per week.

[20] The drug according to any one of [1] to

[19] , which is administered at intervals of once a week to once a month.

[21] The drug according to any one of [1] to

[20] , wherein the administration of the loading dose is followed by administration of a maintenance dose, and the weekly dose of the loading dose is greater than that of the maintenance dose.

[22] The agent of any of [1] to

[21] , wherein a loading dose of 3 mg / kg of the antigen-binding molecule is administered four times at weekly intervals, and after completion of the loading dose administration, a maintenance dose of 6 mg / kg of the antigen-binding molecule is administered once or in multiple divided doses every four weeks.

[23] The drug according to

[21] or

[22] , wherein the maintenance dose is selected from the following (a) to (c): (a) the maintenance dose is administered once every 4 weeks at a single dose of 6 mg / kg of antibody; (b) two maintenance doses of 3 mg / kg each of the antibody are administered every four weeks, wherein one maintenance dose of 3 mg / kg of the antibody is administered every two weeks; (c) a maintenance dose is administered every four weeks for four doses of 1.5 mg / kg each of the antibody, wherein one maintenance dose of 1.5 mg / kg of the antibody is administered once per week; The present invention also relates to the following inventions. [A1] A method for improving and / or inhibiting hemosiderin deposition and / or synovial thickening in joints, comprising the step of administering effective amounts of (a) blood coagulation factor IX and / or activated blood coagulation factor IX, and (b) a bispecific antigen-binding molecule that binds to blood coagulation factor X and / or activated blood coagulation factor X. [A2] The method according to [A1], which comprises administering the compound to a joint of a patient suffering from a disease whose onset and / or progression is caused by a decrease in or deficiency in the activity of blood coagulation factor VIII and / or activated blood coagulation factor VIII (FVIIIa), thereby improving and / or inhibiting hemosiderin deposition and / or synovial thickening in the joint. [A3] The method according to [A2], wherein the disease is hemophilia. [A4] The method according to [A2] or [A3], wherein the patient also suffers from hemophilic arthropathy. [A5] The method according to [A2], wherein the patient is a patient confirmed to have hemophilic arthropathy. [A6] The method according to any one of [A2] to [A5], wherein the patient has been confirmed to have hemophilic arthropathy by MRI. [A7] The method according to any one of [A2] to [A6], wherein the patient is a patient in whom hemosiderin deposition and / or synovial thickening in joints has been confirmed by MRI. [A8] The method according to any one of [A1] to [A7], wherein the antigen-binding molecule is a bispecific antibody. [A9] The method according to any one of [A1] to [A8], wherein the antigen-binding molecule is emicizumab. [A10] The method according to any one of [A1] to [A9], wherein the antigen-binding molecule is a bispecific antibody in which a first polypeptide is associated with a third polypeptide and a second polypeptide is associated with a fourth polypeptide, and the bispecific antibody is any one of the following bispecific antibodies (a) to (c): (a) a bispecific antibody comprising a first polypeptide which is a heavy chain comprising a heavy chain variable region comprising the amino acid sequences of CDRs 1, 2, and 3 of SEQ ID NOs: 1, 2, and 3, respectively; a second polypeptide which is a heavy chain comprising a heavy chain variable region comprising the amino acid sequences of CDRs 1, 2, and 3 of SEQ ID NOs: 6, 7, and 8, respectively; and third and fourth polypeptides which are shared light chains comprising light chain variable regions comprising the amino acid sequences of CDRs 1, 2, and 3 of SEQ ID NOs: 11, 12, and 13, respectively; (b) a bispecific antibody comprising a first polypeptide, which is a heavy chain comprising the heavy chain variable region amino acid sequence of SEQ ID NO:4; a second polypeptide, which is a heavy chain comprising the heavy chain variable region amino acid sequence of SEQ ID NO:9; and third and fourth polypeptides, which are a shared light chain comprising the light chain variable region amino acid sequence of SEQ ID NO:14; or (c) A bispecific antibody comprising a first polypeptide, which is a heavy chain comprising the amino acid sequence of SEQ ID NO:5; a second polypeptide, which is a heavy chain comprising the amino acid sequence of SEQ ID NO:10; and third and fourth polypeptides, which are shared light chains comprising the amino acid sequence of SEQ ID NO:15. [A11] The method according to any of [A2] to [A10], wherein the disease is selected from the group consisting of hemophilia A, acquired hemophilia A, von Willebrand disease, and hemophilia A accompanied by the appearance of inhibitors to blood coagulation factor VIII and / or activated blood coagulation factor VIII. [A12] The method according to any one of [A2] to [A11], wherein the disease is congenital hemophilia A. [A13] The method according to any one of [A3] to [A12], wherein the hemophilia patient does not have an inhibitor to FVIII. [A14] The method according to any one of [A3] to [A13], wherein the hemophilia patient is a pediatric patient with congenital hemophilia A aged less than 12 years. [A15] The method according to any one of [A1] to [A14], which is administered to a subject who has developed hemosiderin deposition in joints and / or synovial thickening and / or a subject who is at risk of developing such hemosiderin deposition and / or synovial thickening. [A16] The method according to any one of [A1] to [A15], wherein the improvement is exhibited upon long-term administration. [A17] The method according to any one of [A1] to [A16], wherein the drug is administered for 145 weeks or more. [A18] The method according to any one of [A1] to [A17], wherein the drug is administered for 300 weeks or more. [A19] The method according to any one of [A1] to [A18], wherein the antigen-binding molecule is administered at a dose of 1 to 4.5 mg / kg per week. [A20] The method according to any one of [A1] to [A19], wherein the antigen-binding molecule is administered at intervals of once a week to once a month. [A21] The method according to any one of [A1] to [A20], wherein the administration of a loading dose is followed by administration of a maintenance dose, and the weekly dose of the loading dose is greater than that of the maintenance dose. [A22] The method of any of [A1] to [A21], wherein a loading dose of 3 mg / kg of the antigen-binding molecule is administered four times at weekly intervals, and after completion of the loading dose administration, a maintenance dose of 6 mg / kg of the antigen-binding molecule is administered once or in multiple divided doses every four weeks. [A23] The method according to [A21] or [A22], wherein the maintenance dose is selected from the following (a) to (c): (a) the maintenance dose is administered once every 4 weeks at a single dose of 6 mg / kg of antibody; (b) two maintenance doses of 3 mg / kg each of the antibody are administered every four weeks, wherein one maintenance dose of 3 mg / kg of the antibody is administered every two weeks; (c) a maintenance dose is administered every four weeks for four doses of 1.5 mg / kg each of the antibody, wherein one maintenance dose of 1.5 mg / kg of the antibody is administered once per week; The above-mentioned [A5] may include a step of confirming that the patient has hemophilic arthropathy. The above-mentioned [A6] may include a step of confirming that the patient has hemophilic arthropathy by MRI. The above-mentioned [A7] may include a step of confirming that the patient has hemosiderin deposition in joints and / or synovial hyperplasia by MRI. The above-mentioned [A17] may include a step of administering the drug for 145 weeks or more.The above-mentioned [A18] may include a step of administering the drug for 300 weeks or more. The above-mentioned method [A22] may further comprise a step of administering 3 mg / kg of the antigen-binding molecule four times at weekly intervals as a loading dose, and, after completion of the loading dose administration, administering 6 mg / kg of the antigen-binding molecule once or in multiple divided doses every four weeks as a maintenance dose.The above-mentioned method [A22] may further comprise a step of administering the maintenance dose selected from the above-mentioned (a) to (c). The present invention also relates to the following inventions. [B1] Use of a bispecific antigen-binding molecule that binds to (a) blood coagulation factor IX and / or activated blood coagulation factor IX and (b) blood coagulation factor X and / or activated blood coagulation factor X for improving and / or inhibiting hemosiderin deposition and / or synovial thickening in joints. [B2] The use described in [B1] for improving and / or inhibiting hemosiderin deposition and / or synovial thickening in the joints of patients suffering from a disease whose onset and / or progression is caused by a decrease or deficiency in the activity of blood coagulation factor VIII and / or activated blood coagulation factor VIII (FVIIIa). [B3] The use according to [B2], wherein the disease is hemophilia. [B4] The use described in [B2] or [B3], wherein the patient also suffers from hemophilic arthropathy. [B5] The use according to [B2], wherein the patient is a patient confirmed to have hemophilic arthropathy. [B6] The use according to any one of [B2] to [B5], wherein the patient has been confirmed to have hemophilic arthropathy by MRI. [B7] The use according to any one of [B2] to [B6], wherein the patient has hemosiderin deposition and / or synovial thickening in the joints confirmed by MRI. [B8] The use according to any one of [B1] to [B7], wherein the antigen-binding molecule is a bispecific antibody. [B9] The use according to any one of [B1] to [B8], wherein the antigen-binding molecule is emicizumab. [B10] The use according to any one of [B1] to [B9], wherein the antigen-binding molecule is a bispecific antibody in which a first polypeptide is associated with a third polypeptide and a second polypeptide is associated with a fourth polypeptide, and the bispecific antibody is any one of the following bispecific antibodies (a) to (c): (a) a bispecific antibody comprising a first polypeptide which is a heavy chain comprising a heavy chain variable region comprising the amino acid sequences of CDRs 1, 2, and 3 of SEQ ID NOs: 1, 2, and 3, respectively; a second polypeptide which is a heavy chain comprising a heavy chain variable region comprising the amino acid sequences of CDRs 1, 2, and 3 of SEQ ID NOs: 6, 7, and 8, respectively; and third and fourth polypeptides which are shared light chains comprising light chain variable regions comprising the amino acid sequences of CDRs 1, 2, and 3 of SEQ ID NOs: 11, 12, and 13, respectively; (b) a bispecific antibody comprising a first polypeptide, which is a heavy chain comprising the heavy chain variable region amino acid sequence of SEQ ID NO:4; a second polypeptide, which is a heavy chain comprising the heavy chain variable region amino acid sequence of SEQ ID NO:9; and third and fourth polypeptides, which are a shared light chain comprising the light chain variable region amino acid sequence of SEQ ID NO:14; or (c) A bispecific antibody comprising a first polypeptide, which is a heavy chain comprising the amino acid sequence of SEQ ID NO:5; a second polypeptide, which is a heavy chain comprising the amino acid sequence of SEQ ID NO:10; and third and fourth polypeptides, which are shared light chains comprising the amino acid sequence of SEQ ID NO:15. [B11] The use according to any of [B2] to [B10], wherein the disease is selected from the group consisting of hemophilia A, acquired hemophilia A, von Willebrand disease, and hemophilia A accompanied by the appearance of inhibitors against blood coagulation factor VIII and / or activated blood coagulation factor VIII. [B12] The use according to any one of [B2] to [B11], wherein the disease is congenital hemophilia A. [B13] The use according to any one of [B3] to [B12], wherein the hemophilia patient does not have an inhibitor to FVIII. [B14] The use according to any one of [B3] to [B13], wherein the hemophilia patient is a pediatric patient with congenital hemophilia A aged less than 12 years. [B15] The use according to any one of [B1] to [B14], which is administered to a subject who has developed hemosiderin deposition in joints and / or synovial thickening and / or a subject who is at risk of developing such a condition. [B16] The use according to any one of [B1] to [B15], wherein the improvement is exhibited upon long-term administration. [B17] The use according to any one of [B1] to [B16], wherein the drug is administered for 145 weeks or more. [B18] The use according to any one of [B1] to [B17], wherein the drug is administered for 300 weeks or more. [B19] The use according to any one of [B1] to [B18], wherein the antigen-binding molecule is administered at a dose of 1 to 4.5 mg / kg per week. [B20] The use according to any one of [B1] to [B19], wherein the antigen-binding molecule is administered at intervals of once a week to once a month. [B21] The use according to any one of [B1] to [B20], wherein the administration of a loading dose is followed by administration of a maintenance dose, and the weekly dose of the loading dose is greater than that of the maintenance dose. [B22] The use of any of [B1] to [B21], wherein a loading dose of 3 mg / kg of the antigen-binding molecule is administered four times at weekly intervals, and after completion of the loading dose administration, a maintenance dose of 6 mg / kg of the antigen-binding molecule is administered once or in multiple divided doses every four weeks. [B23] The use according to [B21] or [B22], wherein the maintenance dose is selected from the following (a) to (c): (a) the maintenance dose is administered once every 4 weeks at a single dose of 6 mg / kg of antibody; (b) two maintenance doses of 3 mg / kg each of the antibody are administered every four weeks, wherein one maintenance dose of 3 mg / kg of the antibody is administered every two weeks; (c) a maintenance dose is administered every four weeks for four doses of 1.5 mg / kg each of the antibody, wherein one maintenance dose of 1.5 mg / kg of the antibody is administered once per week; The present invention also relates to the following inventions. [C1] Use of a bispecific antigen-binding molecule that binds to (a) blood coagulation factor IX and / or activated blood coagulation factor IX and (b) blood coagulation factor X and / or activated blood coagulation factor X in the manufacture of a medicament for use in improving and / or inhibiting hemosiderin deposition and / or synovial thickening in joints. [C2] The use according to [C1], wherein the drug is for use in improving and / or inhibiting hemosiderin deposition and / or synovial thickening in the joints of a patient suffering from a disease whose onset and / or progression is caused by a decrease or deficiency in the activity of blood coagulation factor VIII and / or activated blood coagulation factor VIII (FVIIIa). [C3] The use according to [C2], wherein the disease is hemophilia. [C4] The use described in [C2] or [C3], wherein the patient also suffers from hemophilic arthropathy. [C5] The use according to [C2], wherein the patient is confirmed to have hemophilic arthropathy. [C6] The use according to any one of [C2] to [C5], wherein the patient has been confirmed to have hemophilic arthropathy by MRI. [C7] The use according to any one of [C2] to [C6], wherein the patient has hemosiderin deposition and / or synovial thickening in the joints confirmed by MRI. [C8] The use according to any one of [C1] to [C7], wherein the antigen-binding molecule is a bispecific antibody. [C9] The use according to any one of [C1] to [C8], wherein the antigen-binding molecule is emicizumab. [C10] The use according to any one of [C1] to [C9], wherein the antigen-binding molecule is a bispecific antibody in which a first polypeptide is associated with a third polypeptide and a second polypeptide is associated with a fourth polypeptide, and the bispecific antibody is any one of the following bispecific antibodies (a) to (c): (a) a bispecific antibody comprising a first polypeptide which is a heavy chain comprising a heavy chain variable region comprising the amino acid sequences of CDRs 1, 2, and 3 of SEQ ID NOs: 1, 2, and 3, respectively; a second polypeptide which is a heavy chain comprising a heavy chain variable region comprising the amino acid sequences of CDRs 1, 2, and 3 of SEQ ID NOs: 6, 7, and 8, respectively; and third and fourth polypeptides which are shared light chains comprising light chain variable regions comprising the amino acid sequences of CDRs 1, 2, and 3 of SEQ ID NOs: 11, 12, and 13, respectively; (b) a bispecific antibody comprising a first polypeptide, which is a heavy chain comprising the heavy chain variable region amino acid sequence of SEQ ID NO:4; a second polypeptide, which is a heavy chain comprising the heavy chain variable region amino acid sequence of SEQ ID NO:9; and third and fourth polypeptides, which are a shared light chain comprising the light chain variable region amino acid sequence of SEQ ID NO:14; or (c) A bispecific antibody comprising a first polypeptide, which is a heavy chain comprising the amino acid sequence of SEQ ID NO:5; a second polypeptide, which is a heavy chain comprising the amino acid sequence of SEQ ID NO:10; and third and fourth polypeptides, which are shared light chains comprising the amino acid sequence of SEQ ID NO:15. [C11] The use according to any of [C2] to [C10], wherein the disease is selected from the group consisting of hemophilia A, acquired hemophilia A, von Willebrand disease, and hemophilia A accompanied by the appearance of inhibitors to blood coagulation factor VIII and / or activated blood coagulation factor VIII. [C12] The use according to any one of [C2] to [C11], wherein the disease is congenital hemophilia A. [C13] The use according to any one of [C3] to [C12], wherein the hemophilia patient does not have an inhibitor to FVIII. [C14] The use according to any one of [C3] to [C13], wherein the hemophilia patient is a pediatric patient with congenital hemophilia A aged less than 12 years. [C15] The use according to any one of [C1] to [C14], wherein the drug is administered to a subject who has developed hemosiderin deposition in joints and / or synovial thickening and / or a subject who is at risk of developing the same. [C16] The use according to any one of [C1] to [C15], wherein the improvement is exhibited upon long-term administration. [C17] The use according to any one of [C1] to [C16], wherein the drug is administered for 145 weeks or more. [C18] The use according to any one of [C1] to [C17], wherein the drug is administered for 300 weeks or more. [C19] The use according to any one of [C1] to [C18], wherein the antigen-binding molecule is administered at a dose of 1 to 4.5 mg / kg per week. [C20] The use according to any one of [C1] to [C19], wherein the antigen-binding molecule is administered at intervals of once a week to once a month. [C21] The use of any of [C1] to [C20], wherein the antigen-binding molecule is administered in a loading dose followed by a maintenance dose, and the weekly dosage of the loading dose is greater than that of the maintenance dose. [C22] The use of any of [C1] to [C21], wherein a loading dose of 3 mg / kg of the antigen-binding molecule is administered four times at weekly intervals, and after completion of the loading dose administration, a maintenance dose of 6 mg / kg of the antigen-binding molecule is administered once or in multiple divided doses every four weeks. [C23] The use according to [C21] or [C22], wherein the maintenance dose is selected from the following (a) to (c): (a) the maintenance dose is administered once every 4 weeks at a single dose of 6 mg / kg of antibody; (b) two maintenance doses of 3 mg / kg each of the antibody are administered every four weeks, wherein one maintenance dose of 3 mg / kg of the antibody is administered every two weeks; (c) a maintenance dose is administered every four weeks for four doses of 1.5 mg / kg each of the antibody, wherein one maintenance dose of 1.5 mg / kg of the antibody is administered once per week; According to the present invention, it has been found that a bispecific antigen-binding molecule that binds to (a) blood coagulation factor IX and / or activated blood coagulation factor IX and (b) blood coagulation factor X and / or activated blood coagulation factor X is effective in improving and / or inhibiting hemosiderin deposition and / or synovial thickening in joints. Therefore, the molecule is considered to be promising as a drug for improving and / or inhibiting hemosiderin deposition and / or synovial thickening in joints. The present invention relates to a drug for use in improving and / or inhibiting hemosiderin deposition in joints and / or synovial thickening, the drug comprising as active ingredients a bispecific antigen-binding molecule that binds to (a) blood coagulation factor IX (also referred to as FIX) and / or activated blood coagulation factor IX (also referred to as FIXa), and (b) blood coagulation factor X (also referred to as FX) and / or activated blood coagulation factor X (also referred to as FXa), and the use of the drug and the production thereof, etc. A bispecific antigen-binding molecule comprises a binding site capable of specifically binding to at least two different types of antigens, i.e., a first antigen-binding site and a second antigen-binding site. The first antigen-binding site and the second antigen-binding site of the bispecific antigen-binding molecule of the present invention are not particularly limited as long as they have the activity of binding to (a) FIX and / or FIXa and (b) FX and / or FXa, respectively. Examples include sites required for binding to antigens such as antibodies, scaffold molecules (antibody-like molecules), and peptides, as well as fragments containing such sites. The scaffold molecule is a molecule that exhibits its function by binding to a target molecule, and any polypeptide may be used as long as it is a conformationally stable polypeptide capable of binding to at least one target antigen. Examples of such polypeptides include antibody variable regions, fibronectin (WO2002 / 032925), protein A domains (WO1995 / 001937), LDL receptor A domains (WO2004 / 044011, WO2005 / 040229), ankyrin (WO2002 / 020565), and the like, as well as molecules described in Nygren et al. (Current Opinion in Structural Biology, 7: 463-469 (1997); and Journal of Immunol Methods, 290: 3-28 (2004)), Binz et al. (Nature Biotech 23: 1257-1266 (2005)), and Hosse et al. (Protein Science 15: 14-27 (2006)). Furthermore, peptide molecules capable of binding to target antigens may also be used, as described in Curr Opin Mol Ther. 2010 Aug; 12(4): 487-95 and Drugs. 2008; 68(7): 901-12. Bispecific antigen-binding molecules include aptamers composed of nucleic acid molecules and peptides, and may be single molecules or polymers thereof. In the present invention, a bispecific antigen-binding molecule may further bind to a target other than the above, so long as it binds to, for example, (a) FIX and / or FIXa and (b) FX and / or FXa. That is, in the present invention, a bispecific antigen-binding molecule may contain an additional antigen-binding site. Such a molecule is also referred to as a bispecific antigen-binding molecule in the present invention. Furthermore, the bispecific antigen-binding molecule may be, for example, an antibody, in which case the antibody is, for example, a complete antibody. Bispecific antibodies are a preferred embodiment of the bispecific antigen-binding molecule of the present invention. Bispecific antibodies include human antibodies, mouse antibodies, rat antibodies, etc., and their origins are not limited. They may be genetically modified antibodies such as chimeric antibodies and humanized antibodies. In the present invention, the term "antigen-binding molecule" is used in the broadest sense, and includes monoclonal antibodies, polyclonal antibodies, chimeric antibodies, humanized antibodies, multispecific antibodies, antibody analogs (minimum antibody variants (including antibody fragments to which other molecules may be added), etc.), antibody derivatives, and modified antibodies, so long as they exhibit the desired antigen-binding activity and biological activity (Miller K et al. J Immunol. 2003, 170(9), 4854-61). For example, an "antigen-binding molecule" in the present invention may be a molecule in which an HAS-binding scaffold is added to Fab (only the Fab portion is a normal antibody). In addition, in the present invention, an "antigen-binding molecule" may be either a polypeptide or a heterologous multimer. Preferred antigen-binding molecules are monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, Fc-fusion antibodies, and minimolecular antibody analogs such as antibody fragments. In the present invention, an antibody can be any type (e.g., IgG, IgE, IgM, IgD, and IgA), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass of immunoglobulin molecule. The immunoglobulin can be from any species (e.g., human, mouse, or rabbit). The terms "antibody," "immunoglobulin," and "immunoglobulin" are used interchangeably and in a broad sense. For example, an antibody comprises an antibody antigen-binding site. The term "binding site" or "antigen-binding site" as used herein denotes the region of an antibody molecule where an antigen actually binds. The term "antigen-binding site" comprises an antibody heavy chain variable domain (VH) and an antibody light chain variable domain (VL) (VH / VL pair). Additionally, the terms "full length antibody," "complete antibody," and "whole antibody" are used interchangeably herein and refer to an antibody having a structure substantially similar to a native antibody structure or having a heavy chain that includes an Fc region as defined herein. "Native antibodies" refer to immunoglobulin molecules with various structures that occur in nature. For example, native IgG antibodies are heterotetrameric glycoproteins of about 150,000 daltons composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also called the variable heavy domain or the heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also called the variable light domain or the light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody may be assigned to one of two types, called kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain. For example, the antigen-binding molecule of the present invention may be an antibody analogue, such as a fragment of a complete antibody, a derivative derived from a complete antibody, or a low molecular weight antibody derivative. Antibody fragments and low molecular weight antibody derivatives refer to molecules other than a complete antibody that contain a portion of the complete antibody that binds to the antigen to which the complete antibody binds. An "antibody derivative" includes a portion of an antibody, preferably a variable domain of an antibody, or at least an antigen-binding region of an antibody. Examples of antibody fragments and derivatives include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2, linear antibody molecules, and single-chain antibody (hereinafter also referred to as scFv) molecules, sc(Fv)2, Fab3, domain antibody (dAb) molecules (WO 2004 / 058821, WO 2003 / 002609), diabodies (Db), triabodies, tetrabodies, and multispecific antibody-like molecules formed from minibodies. These are not classified as antibodies in the present invention, but as antibody analogues or antibody derivatives. Antibody analogs and derivatives also include multispecific molecules formed from antibody fragments, which do not take the form of an antibody. Here, "Fab" is composed of one light chain and one heavy chain CH1 region and variable region. "Fv" is a fragment containing the variable region of an antibody but not the constant region, and contains a complete antigen recognition region and antigen binding region. The antibody derivative may also be a fusion with, for example, the Fc of an IgG antibody. See, e.g., U.S. Pat. No. 5,641,870, Example 2; Zapata G et al. Protein Eng. 1995, 8(10), 1057-1062; Olafsen T et al. Protein Eng. Design & Sel. 2004, 17(4):315-323; Holliger P et al. Nat. Biotechnol. 2005, 23(9);1126-36; Fischer N et al. Pathobiology. 2007, 74(1):3-14; Shen J et al. J Immunol Methods. 2007, 318, 65-74; Wu et al. Nat Biotechnol. 2007, 25(11), 1290-7. A diabody refers to a bivalent low molecular weight antibody derivative constructed by gene fusion (Holliger P et al., Proc.Natl.Acad.Sci.USA 1993;90:6444-6448, EP404,097, WO93 / 11161, etc.). A diabody is a dimer composed of two polypeptide chains, and each polypeptide chain is linked by a linker that is short enough that the L chain variable region (VL) and the H chain variable region (VH) cannot bind to each other in the same chain, for example, preferably 2 to 12 residues, more preferably 3 to 10 residues, and particularly about 5 residues. The VL and VH encoded on the same polypeptide chain cannot form a single chain variable region fragment because the linker between them is short, and therefore the diabody has two antigen binding sites. Antibody analogs, such as single chain antibodies or scFv antibody fragments, contain the VH and VL regions of an antibody, which are present in a single polypeptide chain. In general, the Fv polypeptide further contains a polypeptide linker between the VH and VL regions, which allows the scFv to form the structure required for antigen binding (for a review of scFv, see Pluckthun, The Pharmacology of Monoclonal Antibodies, Vol. 113 (Rosenburg and Moore ed. (Springer Verlag, New York) pp. 269-315, 1994)). The linker in the present invention is not particularly limited as long as it does not inhibit the expression of the antibody variable region linked to both ends. Bispecific antibody analogs can also be prepared by chemically crosslinking Fab'. For example, Fab' prepared from one antibody is maleimidized with ortho-phenylenedi-maleimide (o-PDM) and reacted with Fab' prepared from the other antibody to crosslink Fab's derived from different antibodies to prepare bispecific F(ab')2 (Keler T et al. Cancer Research 1997;57:4008-4014). In addition, a method of chemically binding antibody fragments such as Fab'-thionitrobenzoic acid (TNB) derivatives and Fab'-thiol (SH) is also known (Brennan M et al. Science 1985;229:81-83). Instead of chemical crosslinking, leucine zippers derived from Fos, Jun, etc. can be used. Fos and Jun can also form homodimers, but the fact that they preferentially form heterodimers is utilized. Fab' with the Fos leucine zipper and another Fab' with the Jun leucine zipper are expressed and prepared. Bispecific F(ab')2 can be formed by mixing and reacting monomeric Fab'-Fos and Fab'-Jun reduced under mild conditions (Kostelny SA et al. J of Immunology, 1992;148:1547-53). This method is not limited to Fab', but can also be applied to scFv, Fv, etc. In addition, IgG-scFv (Protein Eng Des Sel. 2010;23(4):221-8), sc(Fv)2 such as BiTE (Drug Discov Today 2005;15;10(18):1237-44), DVD-Ig (Nat Biotechnol 2007;25(11):1290-7. Epub 2007 Oct 14, MAbs 2009;1(4):339-47. Epub 2009 Jul 10) and other antibodies (IDrugs 2010;13:698-700), two-in-one antibodies (Science 2009;20;323(5921):1610-4, Immunotherapy 2009;20;323(5921):1610-4, 2009;1(5):749-51), and bispecific antibody analogues such as Tri-Fab, tandem scFv, and diabodies are also known (MAbs 2009;1(6):539-547.). Furthermore, even when using molecular forms such as scFv-Fc and scaffold-Fc, heterogeneous combinations of Fc are preferentially secreted (Ridgway JB et al. Protein Engineering 1996;9:617-621, Merchant AM et al. Nature Biotechnology 1998;16:677-681, WO2006 / 106905, Davis JH et al. Protein Eng Des Sel 2010;4:195-202), bispecific antibody derivatives can be efficiently produced. Bispecific antibody analogs can also be produced using diabodies. Bispecific diabodies are heterodimers of two cross-over scFv fragments. In other words, they can be produced by forming heterodimers using VH (A)-VL (B) and VH (B)-VL (A) that are produced by linking the VH and VL from two types of antibodies A and B with a relatively short linker of about 5 residues (Holliger P et al. Proc of the National Academy of Sciences of the USA 1993;90:6444-6448). In this case, the desired composition can be promoted by linking the two types of scFv with a flexible, relatively long linker of about 15 residues (single-chain diabody: Kipriyanov SM et al. J of Molecular Biology 1999;293:41-56) or by making appropriate amino acid substitutions (knobs-into-holes: Zhu Z et al. Protein Science 1997;6:781-788, VH / VL interface engineering: Igawa T et al. Protein Eng Des Sel 2010;8:667-77). sc(Fv)2, which can be prepared by linking two types of scFv with a flexible, relatively long linker of about 15 residues, can also be a bispecific antibody analogue (Mallender WD et al. J of Biological Chemistry 1994;269:199-206). In the present invention, the antibody may be modified. Examples of modified antibodies include antibodies bound to various molecules such as polyethylene glycol (PEG). The antibodies of the present invention also include these modified antibodies. There is no limitation on the substance bound to the modified antibodies of the present invention. Such modified antibodies can be obtained by chemically modifying the obtained antibodies. These methods have already been established in this field. In addition, the amino acids contained in the amino acid sequences described in the present invention may be modified after translation (for example, modification of N-terminal glutamine to pyroglutamic acid by pyroglutamylation is a modification well known to those skilled in the art), and even if an amino acid is modified after translation in this way, it is of course included in the amino acid sequences described in the present invention. The antibody may also include appropriate mutations. That is, in certain embodiments, amino acid sequence variants of the antibodies provided herein are also contemplated. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody. Amino acid sequence variants of the antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions from and / or insertions into and / or substitutions of residues in the amino acid sequence of the antibody. Any combination of deletions, insertions, and substitutions may be made to arrive at the final construct, provided that the final construct has the desired characteristics (e.g., antigen binding). Amino acid sequence insertions include fusions ranging in length from one residue to polypeptides containing 100 or more residues at the amino and / or carboxyl termini, as well as single or multiple amino acid residue insertions within the sequence. An example of a terminal insertion includes an antibody with a methionyl residue at the N-terminus. Other insertional variants of the antibody molecule include the fusion to the N- or C-terminus of the antibody of an enzyme (e.g., for ADEPT) or a polypeptide which increases the plasma half-life of the antibody. In certain embodiments, the antibodies provided herein have been modified to increase or decrease the extent to which the antibody is glycosylated. Adding or deleting glycosylation sites to an antibody can be conveniently accomplished by modifying the amino acid sequence to create or remove one or more glycosylation sites. If the antibody comprises an Fc region, the carbohydrate attached thereto may be modified. Natural antibodies produced by mammalian cells typically comprise branched, biantennary oligosaccharides, which are usually attached by N-linkage to Asn297 in the CH2 domain of the Fc region. See, e.g., Wright et al. TIBTECH 15:26-32 (1997). Oligosaccharides include, for example, various carbohydrates such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose attached to the GlcNAc in the "stem" of the biantennary oligosaccharide structure. In some embodiments, modification of the oligosaccharides in the antibodies of the invention may be performed to generate modified antibodies with specific improved properties. In certain embodiments, one or more amino acid modifications may be introduced into the Fc region of the antibody provided herein to generate an Fc region variant. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region) that comprises an amino acid modification (e.g., substitution) at one or more amino acid positions. The antibodies of the present invention also include those that comprise such mutant Fc regions. See, for example, U.S. Patent No. 6,737,056; WO2004 / 056312; Shields et al., J. Biol. Chem. 9(2): 6591-6604 (2001); U.S. Patent No. 7,371,826, Duncan & Winter, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821; and WO94 / 29351. Chimeric antibodies are antibodies that contain fragments derived from two or more different antibodies, and can be prepared, for example, as described in U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984). In one example, the chimeric antibody contains a non-human variable region (e.g., a variable region derived from a non-human primate such as a mouse, rat, hamster, rabbit, or monkey) and a human constant region. In a further example, the chimeric antibody is a "class-switched" antibody whose class or subclass has been changed from that of the parent antibody. The chimeric antibody also includes its antigen-binding fragment. A "human antibody" is an antibody with an amino acid sequence that corresponds to that of an antibody produced by a human or human cell, or an antibody derived from a non-human source using a human antibody repertoire or other human antibody coding sequence. This definition of a human antibody excludes humanized antibodies, which contain non-human antigen-binding residues. Human antibodies can be produced by a variety of techniques known in the art. Human antibodies are reviewed in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008). A "humanized" antibody refers to a chimeric antibody that contains amino acid residues from non-human HVRs and amino acid residues from human FRs. A humanized antibody usually contains one or more variable domains, in which the HVRs (e.g., CDRs (or portions thereof)) are derived from a non-human antibody and the FRs (or portions thereof) are derived from a human antibody sequence. A humanized antibody optionally contains at least a portion of a human constant region. In some embodiments, a humanized antibody contains substantially all of at least one, and typically two, variable domains, in which all or substantially all HVRs (e.g., CDRs) correspond to those of a non-human antibody and all or substantially all FRs correspond to those of a human antibody. A humanized antibody may optionally contain at least a portion of an antibody constant region derived from a human antibody. In some embodiments, some FR residues in a humanized antibody are replaced with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve antibody specificity or affinity. A "humanized form" of an antibody (eg, a non-human antibody) refers to an antibody that has undergone humanization. Methods for obtaining human antibodies are known.For example, transgenic animals carrying a full repertoire of human antibody genes can be immunized with an antigen of interest to obtain the human antibody of interest (see International Publication Nos. WO93 / 12227, WO92 / 03918, WO94 / 02602, WO94 / 25585, WO96 / 34096, and WO96 / 33735).For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See also, for example, U.S. Patent Nos. 6,075,181 and 6,150,584, which describe XENOMOUSE™ technology; U.S. Patent No. 5,770,429, which describes HUMAB® technology; U.S. Patent No. 7,041,870, which describes KM MOUSE® technology; and U.S. Patent Application Publication No. 2007 / 0061900, which describes VELOCIMOUSE® technology. The human variable regions from intact antibodies generated by such animals may be further modified, for example, by combining with different human constant regions. Human antibodies can also be produced by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described (see, e.g., Kozbor J. Immunol., 133: 3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp.51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147: 86 (1991). Human antibodies generated via human B-cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Additional methods include those described, for example, in U.S. Patent No. 7,189,826 (describing production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing human-human hybridomas). Human hybridoma technology (trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005). Human antibodies can also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. The bispecific antibody of the present invention has an activity of binding to (a) blood coagulation factor IX and / or activated blood coagulation factor IX and (b) blood coagulation factor X and / or activated blood coagulation factor X. The bispecific antibody can be produced, for example, using a genetic recombination technique (see, for example, Borrebaeck CAK and Larrick JW, THERAPEUTIC MONOCLONAL ANTIBODIES, Published in the United Kingdom by MACMILLAN PUBLISHERS LTD, 1990). A recombinant antibody can be obtained by cloning the DNA encoding it from an antibody-producing cell, such as a hybridoma or an antibody-producing sensitized lymphocyte, incorporating it into a vector, and introducing this into a host (host cell) to allow production of the antibody. The antibody may be of any origin, including human, mouse, and rat antibodies, and may also be a genetically modified antibody, such as a chimeric antibody or a humanized antibody. Methods for obtaining human antibodies are already known. For example, as described above, a transgenic animal having a full repertoire of human antibody genes can be immunized with an antigen of interest to obtain a human antibody of interest (see International Patent Application Publication Nos. WO 93 / 12227, WO 92 / 03918, WO 94 / 02602, WO 94 / 25585, WO 96 / 34096, and WO 96 / 33735). Genetically modified antibodies can be produced using known methods. Specifically, for example, a chimeric antibody is an antibody consisting of the variable regions of the H and L chains of an antibody from an immunized animal and the constant regions of the H and L chains of a human antibody. A chimeric antibody can be obtained by linking DNA encoding the variable region of an antibody derived from an immunized animal to DNA encoding the constant region of a human antibody, incorporating this into an expression vector, and introducing it into a host for production. A humanized antibody is a modified antibody also called a reshaped human antibody. A humanized antibody is constructed by transplanting the CDR of an antibody derived from an immunized animal into the complementarity determining region of a human antibody. General gene recombination techniques are also known (see European Patent Application Publication No. EP 239400, International Patent Application Publication No. WO 96 / 02576, Sato K et al, Cancer Research 1993, 53: 851-856, International Patent Application Publication No. WO 99 / 51743). A bispecific antibody is an antibody that has specificity for two different antigens. Bispecific antibodies are not limited to IgG type antibodies, but for example, IgG type bispecific antibodies can be secreted by hybrid hybridomas (quadromas) produced by fusing two types of hybridomas that produce IgG antibodies (Milstein C et al. Nature 1983, 305: 537-540). In addition, the genes for the L and H chains constituting the two types of IgG of interest, a total of four types of genes, can be introduced into cells to be coexpressed and secreted. In this case, by making appropriate amino acid substitutions in the CH3 region of the H chain, it is possible to preferentially secrete IgG with a heterogeneous combination of H chains (Ridgway JB et al. Protein Engineering 1996, 9: 617-621; Merchant AM et al. Nature Biotechnology 1998, 16: 677-681; WO2006 / 106905; Davis JH et al. Protein Eng Des Sel. 2010, 4: 195-202.). Regarding L chains, since the diversity of the L chain variable region is lower than that of the H chain variable region, it is expected that a common L chain capable of imparting binding ability to both H chains will be obtained, and the antibody of the present invention may be an antibody having a common L chain. By expressing IgG by introducing this common L chain and the genes for both H chains into cells, it becomes possible to efficiently express bispecific IgG. Bispecific antigen-binding molecules of the present invention can include bispecific antibodies (BsAbs) (sometimes called bispecific antibodies) that bind to FIX and / or FIXa and FX and / or FXa. Such antigen-binding molecules that recognize (a) FIX and / or FIXa and (b) FX and / or FXa can be obtained, for example, according to the methods described in WO2005 / 035756, WO2006 / 109592, and WO2012 / 067176, WO2018 / 141863, WO2020 / 025672, WO2021 / 152066. Specifically, the antigen-binding molecules can be generated, for example, based on the sequences of antibodies against FIX and / or FIXa and antibodies against FX and / or FXa using genetic recombination techniques known to those skilled in the art. Based on the sequences of antibodies against FIX and / or FIXa and antibodies against FX and / or FXa, polynucleotides encoding the antibodies can be constructed and inserted into expression vectors, which can then be expressed in suitable host cells (see, for example, Co, MS et al., J. Immunol. (1994) 152, 2968-2976; Better, M. and Horwitz, AH, Methods Enzymol. (1989) 178, 476-496; Pluckthun, A. and Skerra, A., Methods Enzymol. (1989) 178, 497-515; Lamoyi, E., Methods Enzymol. (1986) 121, 652-663; Rousseaux, J. et al., Methods Enzymol. (1986) 121, 663-669; and Bird, RE and Walker, See BW, Trends Biotechnol. (1991) 9, 132-137). Such bispecific antigen-binding molecules can be isolated from inside or outside of host cells (e.g., medium) and purified as substantially pure and homogeneous molecules.Isolation and purification of antigen-binding molecules can be carried out using commonly used methods for isolation and purification.The method is not limited to, but can be selected and combined appropriately to isolate and purify antigen-binding molecules, for example, column chromatography column, filter, ultrafiltration, salting out, solvent precipitation, solvent extraction, distillation, immunoprecipitation, SDS polyacrylamide gel electrophoresis, isoelectric focusing, dialysis, recrystallization, etc. Bispecific antigen-binding molecules of the present invention include, for example, the antibodies described in WO2005 / 035756, WO2006 / 109592, WO2012 / 067176, WO2018 / 141863, WO2020 / 025672, and WO2021 / 152066. The L chains of the antibodies that serve as bispecific antigen-binding molecules of the present invention may be different, or may share a common L chain. In the present invention, a "common L chain" is an L chain that can associate with two or more different H chains and exhibit binding ability to each antigen. Here, "different H chains" preferably refers to, but is not limited to, H chains of antibodies against different antigens, and refers to H chains whose amino acid sequences are different from each other. The common L chain can be obtained, for example, according to the method described in WO2006 / 109592. The bispecific antigen-binding molecule of the present invention is a molecule consisting of an antibody or an antibody fragment having specificity for two or more different antigens, and is preferably a molecule containing an antibody having specificity for two or more different antigens (bispecific antibody). The antibody of the present invention is not particularly limited, but is preferably monoclonal or derived from a monoclonal antibody. In one embodiment of the present invention, the bispecific antigen-binding molecule recognizes FIX and / or FIXa, and FX and / or FXa, and has a function of substituting for the function of FVIII. The antigen-binding molecule of the present invention generally has a structure comprising a variable region of an anti-FIXa antibody and a variable region of an anti-FX antibody. In one embodiment of the present invention, the bispecific antigen-binding molecule comprises a first polypeptide and a third polypeptide comprising an antigen-binding site recognizing FIX and / or FIXa, and a second polypeptide and a fourth polypeptide comprising an antigen-binding site recognizing FX and / or FXa. The first polypeptide and the third polypeptide, and the second polypeptide and the fourth polypeptide, respectively comprise an antigen-binding site of an antibody heavy chain and an antigen-binding site of an antibody light chain. For example, in the bispecific antigen-binding molecule of the present invention, the first and third polypeptides each contain an antigen-binding site of an antibody H chain or L chain against FIX or FIXa, and the second and fourth polypeptides each contain an antigen-binding site of an antibody H chain or L chain against FX and / or FXa, in which case the antigen-binding sites of the antibody L chain contained in the first and third polypeptides, and the second and fourth polypeptides, may be a common L chain. A polypeptide comprising an antigen-binding site of an antibody L chain in the present invention preferably comprises all or a part of the sequence of an antibody L chain that binds to FIX, FIXa, FX, and / or FXa. A preferred embodiment of the substance having an activity substituting for the function of FVIII according to the present invention is a bispecific antibody that binds to (a) FIX and / or FIXa, and (b) FX and / or FXa. Such an antibody can be obtained according to the methods described in, for example, WO2005 / 035756, WO2006 / 109592, WO2012 / 067176, WO2018 / 141863, WO2020 / 025672, WO2021 / 152066, etc. The bispecific antibody of the present invention includes the antibodies described in these documents. A preferred bispecific antibody is ACE910 (Emicizumab), a bispecific antibody that binds to FIX and / or FIXa and FX and / or FXa, which is described in the patent literature (WO 2012 / 067176). More specifically, for example, the bispecific antigen-binding molecule of the present invention is a bispecific antibody in which a first polypeptide is associated with a third polypeptide and a second polypeptide is associated with a fourth polypeptide, and is preferably an antibody as shown below. More preferably, the bispecific antigen-binding molecule of the present invention is emicizumab (ACE910, RO5534262): (a) a bispecific antibody comprising a first polypeptide which is a heavy chain containing a heavy chain variable region containing the amino acid sequences of CDRs 1, 2, and 3 of SEQ ID NOs: 1, 2, and 3, respectively; a second polypeptide which is a heavy chain containing a heavy chain variable region containing the amino acid sequences of CDRs 1, 2, and 3 of SEQ ID NOs: 6, 7, and 8, respectively; and third and fourth polypeptides which are shared light chains containing light chain variable regions containing the amino acid sequences of CDRs 1, 2, and 3 of SEQ ID NOs: 11, 12, and 13, respectively; (b) a bispecific antibody comprising a first polypeptide, which is a heavy chain containing the heavy chain variable region amino acid sequence of SEQ ID NO:4; a second polypeptide, which is a heavy chain containing the heavy chain variable region amino acid sequence of SEQ ID NO:9; and third and fourth polypeptides, which are a shared light chain containing the light chain variable region amino acid sequence of SEQ ID NO:14; (c) A bispecific antibody (Q499-z121 / J327-z119 / L404-k), comprising a first polypeptide which is a heavy chain comprising the amino acid sequence of SEQ ID NO:5; a second polypeptide which is a heavy chain comprising the amino acid sequence of SEQ ID NO:10; and third and fourth polypeptides which are shared light chains comprising the amino acid sequence of SEQ ID NO:15. (d) a bispecific antibody comprising a first polypeptide which is a heavy chain comprising a heavy chain variable region comprising the amino acid sequences of CDRs 1, 2, and 3 of SEQ ID NOs: 16, 17, and 18; a second polypeptide which is a heavy chain comprising a heavy chain variable region comprising the amino acid sequences of CDRs 1, 2, and 3 of SEQ ID NOs: 21, 22, and 23; a third polypeptide which is a light chain comprising a light chain variable region comprising the amino acid sequences of CDRs 1, 2, and 3 of SEQ ID NOs: 26, 27, and 28; and a fourth polypeptide which is a light chain comprising a light chain variable region comprising the amino acid sequences of CDRs 1, 2, and 3 of SEQ ID NOs: 31, 32, and 33; (e) a bispecific antibody comprising: a first polypeptide, which is a heavy chain containing the heavy chain variable region amino acid sequence of SEQ ID NO:19; a second polypeptide, which is a heavy chain containing the heavy chain variable region amino acid sequence of SEQ ID NO:24; a third polypeptide, which is a light chain containing the light chain variable region amino acid sequence of SEQ ID NO:29; and a fourth polypeptide, which is a light chain containing the light chain variable region amino acid sequence of SEQ ID NO:34; or (f) A bispecific antibody comprising a first polypeptide, which is an H chain containing the amino acid sequence of SEQ ID NO:20; a second polypeptide, which is an H chain containing the amino acid sequence of SEQ ID NO:25; a third polypeptide, which is an L chain containing the amino acid sequence of SEQ ID NO:30; and a fourth polypeptide, which is an L chain containing the amino acid sequence of SEQ ID NO:35. In the bispecific antibodies exemplified above, the first polypeptide and the third polypeptide associate with each other to exert binding activity to FIX and / or FIXa, and the second polypeptide and the fourth polypeptide associate with each other to exert binding activity to FX and / or FXa. Methods for producing antibodies The antibody of the present invention can be produced by a method known to those skilled in the art. Specifically, DNA encoding the antibody of interest is incorporated into an expression vector. In this case, the DNA is incorporated into the expression vector so that it is expressed under the control of an expression control region, such as an enhancer or promoter. Next, a host cell is transformed with this expression vector to express the antibody. In this case, a suitable combination of a host and an expression vector can be used. Examples of vectors include M13 vectors, pUC vectors, pBR322, pBluescript, pCR-Script, etc. Furthermore, for the purpose of subcloning or excision of cDNA, in addition to the above vectors, for example, pGEM-T, pDIRECT, pT7, etc. can be used. When vectors are used for the purpose of producing antibodies, expression vectors are particularly useful. For example, when the host is Escherichia coli such as JM109, DH5α, HB101, or XL1-Blue, it is essential that the expression vector has a promoter capable of efficient expression in Escherichia coli, such as the lacZ promoter (Ward et al., Nature (1989) 341, 544-546; FASEB J. (1992) 6, 2422-2427), the araB promoter (Better et al., Science (1988) 240, 1041-1043), or the T7 promoter. In addition to the above vectors, such vectors include pGEX-5X-1 (Pharmacia), "QIAexpress system" (QIAGEN), pEGFP, or pET (in this case, the host is preferably BL21, which expresses T7 RNA polymerase). The vector may also contain a signal sequence for polypeptide secretion. When the polypeptide is produced in the periplasm of E. coli, for example, the pelB signal sequence (Lei, SP et al. J. Bacteriol. (1987) 169, 4397) may be used as the signal sequence for polypeptide secretion. The vector can be introduced into the host cell by, for example, the calcium chloride method or the electroporation method. In addition to E. coli expression vectors, examples of vectors for producing the antibodies of the present invention include mammalian expression vectors (e.g., pcDNA3 (Invitrogen), pEGF-BOS (Nucleic Acids. Res. 1990, 18(17), p5322), pEF, and pCDM8), insect cell-derived expression vectors (e.g., "Bac-to-BAC baculovairus expression system" (GIBCO BRL), pBacPAK8), plant-derived expression vectors (e.g., pMH1 and pMH2), animal virus-derived expression vectors (e.g., pHSV, pMV, and pAdexLcw), retrovirus-derived expression vectors (e.g., pZIPneo), yeast-derived expression vectors (e.g., "Pichia Expression Kit" (Invitrogen), pNV11, and SP-Q01), and Bacillus subtilis-derived expression vectors (e.g., pPL608 and pKTH50). When the objective is to express the vector in animal cells such as CHO cells, COS cells, and NIH3T3 cells, it is essential to have a promoter necessary for intracellular expression, such as the SV40 promoter (Mulligan et al., Nature (1979) 277, 108), the MMTV-LTR promoter, the EF1α promoter (Mizushima et al., Nucleic Acids Res. (1990) 18, 5322), the CAG promoter (Gene. (1991) 108, 193), or the CMV promoter, and it is even more preferable to have a gene for selecting transformed cells. An example of a gene for selecting transformed cells is a drug resistance gene that can be distinguished by a drug (neomycin, G418, etc.). Examples of vectors having such characteristics include pMAM, pDR2, pBK-RSV, pBK-CMV, pOPRSV, and pOP13. Furthermore, when the aim is to stably express a gene and to amplify the copy number of the gene in the cell, a method can be used in which a vector (e.g., pCHOI, etc.) having a DHFR gene that complements the nucleic acid synthesis pathway is introduced into a CHO cell lacking the nucleic acid synthesis pathway and the vector is amplified with methotrexate (MTX). When the aim is to express a gene transiently, a method can be used in which a COS cell having a gene expressing SV40 T antigen on its chromosome is transformed with a vector (e.g., pcD) having an SV40 replication origin. Replication origins can also be derived from polyoma virus, adenovirus, bovine papilloma virus (BPV), etc. Furthermore, in order to amplify the copy number of the gene in the host cell system, the expression vector can contain, as a selection marker, an aminoglycoside transferase (APH) gene, a thymidine kinase (TK) gene, an Escherichia coli xanthine guanine phosphoribosyltransferase (Ecogpt) gene, a dihydrofolate reductase (dhfr) gene, etc. The antibody of the present invention thus obtained can be isolated from inside or outside the host cell (such as the medium) and purified as a substantially pure and homogeneous antibody. Separation and purification of the antibody can be performed using any separation and purification method that is commonly used in the purification of antibodies, and is not limited in any way. For example, the antibody can be separated and purified by appropriately selecting and combining a chromatography column, a filter, ultrafiltration, salting out, solvent precipitation, solvent extraction, distillation, immunoprecipitation, SDS-polyacrylamide gel electrophoresis, isoelectric focusing, dialysis, recrystallization, and the like. Examples of chromatography include affinity chromatography, ion exchange chromatography, hydrophobic chromatography, gel filtration, reversed-phase chromatography, and adsorption chromatography (Strategies for Protein Purification and Characterization: A Laboratory Course Manual. Ed Daniel R. Marshak et al., Cold Spring Harbor Laboratory Press, 1996). These chromatographies can be performed using liquid-phase chromatography, such as HPLC and FPLC. Examples of columns used in affinity chromatography include Protein A columns and Protein G columns. For example, columns using Protein A include Hyper D, POROS, and Sepharose FF (GE Amersham Biosciences). The present invention also includes antibodies highly purified using these purification methods. The obtained antibody can be purified to homogeneity. As described above, the antibody can be separated and purified by the same separation and purification methods used for ordinary proteins. For example, the antibody can be separated and purified by appropriately selecting and combining a chromatography column such as affinity chromatography, a filter, ultrafiltration, salting out, dialysis, SDS polyacrylamide gel electrophoresis, isoelectric focusing, etc. (Antibodies: A Laboratory Manual. Ed Harlow and David Lane, Cold Spring Harbor Laboratory, 1988), but is not limited thereto. Examples of columns used for affinity chromatography include Protein A columns and Protein G columns. The medicament and pharmaceutical composition of the present invention contain the bispecific antigen-binding molecule as described above as an active ingredient. Here, the terms "medicament" and "pharmaceutical composition" are used interchangeably herein. The medicament and pharmaceutical composition of the present invention can be prepared by mixing with a suitable pharma- ceutical acceptable carrier, medium, etc., if necessary, and can be made into a lyophilized formulation or a solution formulation. Examples of suitable pharma- ceutically acceptable carriers and vehicles include sterile water, physiological saline, stabilizers, excipients, antioxidants (such as ascorbic acid), buffers (such as phosphate, citric acid, histidine, and other organic acids), preservatives, surfactants (such as PEG and Tween), chelating agents (such as EDTA), and binders. They may contain other low molecular weight polypeptides, proteins such as serum albumin, gelatin, and immunoglobulins, amino acids such as glycine, glutamine, asparagine, glutamic acid, aspartic acid, methionine, arginine, and lysine, sugars and carbohydrates such as polysaccharides and monosaccharides, and sugar alcohols such as mannitol and sorbitol. When preparing an aqueous solution for injection, for example, isotonic solutions containing physiological saline, glucose and other auxiliary agents, such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride, may be used, and suitable solubilizers such as alcohol (e.g., ethanol), polyhydric alcohols (e.g., propylene glycol and PEG), and non-ionic surfactants (e.g., polysorbate 80, polysorbate 20, poloxamer 188, and HCO-50) may be used in combination. By mixing hyaluronidase in the formulation, a larger volume of liquid can be administered subcutaneously (Expert Opin Drug Deliv. 2007 July; 4(4): 427-40). In addition, the medicaments and pharmaceutical compositions of the present invention may be preloaded into a syringe. Meanwhile, solution formulations can be prepared according to the method described in WO2011 / 090088. If necessary, the antigen-binding molecules of the present invention can be encapsulated in microcapsules (e.g., made of hydroxymethylcellulose, gelatin, and poly(methyl methacrylate)) or prepared as colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) (see, e.g., "Remington's Pharmaceutical Science 16th edition", Oslo Ed. (1980)). Methods for preparing drugs as controlled release drugs are also well known, and such methods can be applied to the antigen-binding molecules of the present invention (Langer et al., J. Biomed. Mater. Res. 15: 267-277 (1981); Langer, Chemtech. 12: 98-105 (1982); U.S. Patent No. 3,773,919; European Patent Application Publication No. EP 58,481; Sidman et al., Biopolymers 22: 547-556 (1983); EP 133,988). A preferred liquid formulation is as follows: 20mg / ml to 180mg / ml emicizumab; Poloxamer 188 at 0.2mg / ml to 1mg / ml; histidine-aspartate buffer, where the concentration of histidine is 10 mM to 40 mM; A liquid formulation containing 100 mM to 300 mM arginine and having a pH of 4.5 to 6.5. A more preferred liquid formulation is as follows: 20mg / ml to 180mg / ml emicizumab; 0.5mg / ml Poloxamer 188, histidine-aspartate buffer (wherein the concentration of histidine is 20 mM); A liquid formulation containing 150 mM arginine and having a pH between 4.5 and 6.5. The agents and pharmaceutical compositions of the present invention may be administered to a patient via any suitable route, for example, intravenously by bolus injection or continuous infusion over a period of time, intramuscularly, intraperitoneally, intracerebrospinally, transdermally, subcutaneously, intraarticularly, sublingually, intrasynovially, orally, by inhalation, topically, or topically. Intravenous or subcutaneous administration is preferred. The drug comprising the bispecific antigen-binding molecule of the present invention can be used alone or in combination with other drugs in therapy. For example, the drug of the present invention can be co-administered with at least one additional therapeutic agent. In a specific embodiment, the additional therapeutic agent is, for example, FVIII, FVII, FIX, TFPI inhibitor, siRNA targeting antithrombin, more specifically Advate, Adynovate, Feiba, NovoSeven, NovoEight, N8-GP, N9-GP, Concizumab, Elocta, Fitusiran. In addition, FVIII, FVII and FIX can be Fc fusion or PEG fusion. Combination therapy as described above includes combined administration (two or more therapeutic agents in the same or separate formulations) and separate administration, where administration of an agent of the invention may precede, be concurrent with, and / or be subsequent to administration of the additional therapeutic agent. In one embodiment, administration of an agent of the invention and administration of the additional therapeutic agent occur within about 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months, or within about 1, 2, or 3 weeks, or within about 1, 2, 3, 4, 5, or 6 days of each other. The agents of the invention (and any additional therapeutic agents) can be administered by any suitable means, including parenteral, pulmonary, and nasal administration, and, if desired for localized treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Dosing can be by any suitable route, such as by injection, e.g., intravenous or subcutaneous injection, depending in part on whether administration is brief or chronic. Various dosing schedules are contemplated herein, including, but not limited to, single or repeated administration over various time periods, bolus administration, and pulse infusion. The agents of the present invention are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the schedule of administration, and other factors known to medical practitioners. The agents of the present invention are optionally, but not necessarily, formulated with one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents depends on the amount of bispecific antigen-binding molecule present in the formulation, the type of disorder or treatment, and other factors discussed above. These are typically used in the same dosages and routes of administration as described herein, or about 1 to 99% of the dosages described herein, or in any dosage and by any route that is empirically / clinically deemed appropriate. For the prevention or treatment of a disease, the appropriate dose of the agent of the present invention (when used alone or in combination with one or more other additional therapeutic agents) will depend on the type of disease being treated, the type of bispecific antigen-binding molecule or agent contained as an active ingredient, the severity and course of the disease, whether the agent of the present invention is administered for prophylactic or therapeutic purposes, medical history, the patient's clinical history and response to the agent of the present invention, and the discretion of the attending physician. The agent of the present invention is suitably administered to the patient at one time or over a series of treatments. Depending on the type and severity of the disease, for example, about 1 μg / kg to 15 mg / kg (e.g., 0.1 mg / kg to 10 mg / kg) of the bispecific antigen-binding molecule may be an initial candidate dose for administration to a patient, whether by one or more separate administrations or by continuous infusion. A typical daily dose may range from about 1 μg / kg to 100 mg / kg or more, depending on the factors mentioned above. In the case of repeated administration over several days or longer, depending on the circumstances, treatment is usually maintained until a desired suppression of disease symptoms occurs. One exemplary dose of the bispecific antigen-binding molecule is in the range of about 0.05 mg / kg to about 10 mg / kg. Thus, one or more doses of about 0.5 mg / kg, 2.0 mg / kg, 4.0 mg / kg, or 10 mg / kg (or any combination thereof) may be administered to the patient. Such doses may be administered intermittently, for example, every week or every three weeks (e.g., such that the patient receives about 2 to about 20, or, for example, about 6 doses of the bispecific antigen-binding molecule). A high initial loading dose may be administered followed by one or more lower doses. However, other dosing regimens may also be useful. The progress of this therapy is easily monitored by conventional techniques and measurements. The agent of the present invention is administered for the purpose of improving and / or inhibiting hemosiderin deposition in joints and / or synovial thickening. The subject of administration may be a subject who has hemosiderin deposition in joints and / or synovial thickening and / or a subject who is concerned about such deposition. Such subjects include subjects with reduced or deficient activity of blood coagulation factor VIII and / or activated blood coagulation factor VIII, and such diseases include hemophilia and von Willebrand's disease. Among them, congenital hemophilia and acquired hemophilia, particularly congenital hemophilia A and acquired hemophilia A, are included. These hemophilia A include hemophilia A accompanied by the appearance of inhibitors against blood coagulation factor VIII and / or activated blood coagulation factor VIII, and hemophilia A without the appearance of such inhibitors. In particular, among patients suffering from such diseases, subjects with hemosiderin deposition and / or synovial thickening in joints and / or subjects with concerns about such are suitable as subjects for administration, and the drug of the present invention can be administered selectively to such subjects. The drug of the present invention can also be administered suitably in a regimen that includes a step of selecting subjects with hemosiderin deposition and / or synovial thickening in joints and / or subjects with concerns about such. For example, subjects with hemosiderin deposition and / or synovial thickening in joints, subjects with hemophilic arthropathy, particularly subjects with hemosiderin deposition and / or synovial thickening, and subjects with hemophilic arthropathy are subjects for administration of the drug of the present invention. Hemosiderin deposition, synovial thickening, and hemophilic arthropathy can be confirmed by MRI. One embodiment of the subjects to which the agents of the present invention are administered may be patients confirmed to have hemophilic arthropathy by MRI, and patients confirmed to have hemosiderin deposition in joints and / or synovial thickening by MRI. There is no particular limit to the age of the subject of administration, but in a preferred embodiment, the agent of the present invention may be particularly applicable to children. Children generally refer to children from newborns to adolescents, and specifically refer to subjects under 18, 17, or 16 years of age. In some preferred embodiments, the agent of the present invention is administered to subjects under 18, 17, 16, 15, 14, 13, or 12 years of age. For example, the agent may be intended for children aged 0 to 17 years, 0 to 16 years, 0 to 15 years, 0 to 14 years, 0 to 13 years, 0 to 12 years, 0 to 11 years, 1 to 17 years, 1 to 16 years, 1 to 15 years, 1 to 14 years, 1 to 13 years, 1 to 12 years, or 1 to 11 years. For example, subjects under 12 years of age are preferred subjects of administration in the present invention. The administration regimen for the agent of the present invention may be appropriately selected, and preferred embodiments are described in detail below. As used herein, the terms "4 weeks" or "monthly" are used interchangeably, and as used herein, the terms "every 4 weeks," "4-weekly," "every month," or "monthly" are used interchangeably. As used herein, the terms "every 2 weeks," "2-weekly," or "bi-weekly" are used interchangeably. As used herein, a "maintenance" dose refers to one or more doses of a drug administered to a patient over a treatment and / or prophylaxis period. Different maintenance doses can be combined with different administration intervals. In one aspect, the maintenance dose is between 0.3 mg / kg and 24 mg / kg of the antigen binding molecule (eg, antibody). In one aspect, the dosing interval is from 1 week to 24 weeks or 6 months. In one aspect, the maintenance dose is 6 mg / kg of an antigen-binding molecule (e.g., an antibody). A maintenance dose of 6 mg / kg refers to, for example, a total of 6 mg / kg administered once or in multiple divided doses over a 4-week or monthly period. In a particular embodiment, the maintenance dose is 6 mg / kg of an antigen-binding molecule (e.g., an antibody), which is administered once and is spaced 4 weeks apart (monthly). In this case, one administration is administered every month or every 4 weeks. In another embodiment, the maintenance dose is 6 mg / kg of the antigen-binding molecule (e.g., antibody), administered in two divided doses each containing 3 mg / kg of the antigen-binding molecule, with two doses spaced apart (every two weeks). In this case, two doses are administered within a one month or four week period. In another embodiment, the maintenance dose is 6 mg / kg of the antigen-binding molecule (e.g., antibody), administered in four divided doses each containing 1.5 mg / kg of the antigen-binding molecule, with one week (weekly) between doses, in this case four doses administered over a one month or four week period. In certain embodiments, the maintenance dose is 6 mg / kg of antigen binding molecule (e.g., antibody) per dose, with a 4 week (monthly) interval between doses, in which case one dose is administered per month or every 4 weeks. In another embodiment, the maintenance dose is 3 mg / kg of antigen binding molecule (e.g., antibody) per dose, with a dosing interval of 2 weeks (every 2 weeks), in this case two doses administered within a 1 month or 4 week period. In another embodiment, the maintenance dose is 1.5 mg / kg of the antigen binding molecule (e.g., antibody) per dose, with a weekly (every week) interval between doses, in this case four doses over a one month or four week period. In another aspect, the maintenance dose is 9mg / kg of antigen-binding molecule (e.g., antibody).A maintenance dose of 9mg / kg refers to, for example, administering a total of 9mg / kg of antigen-binding molecule once or in multiple doses every 4 weeks or once a month.This may be applicable for pediatric patients or such special patient populations where exposure is expected to be lower. In a particular embodiment, the maintenance dose is 9 mg / kg of the antigen-binding molecule (e.g., antibody), administered in two divided doses each containing 4.5 mg / kg of the antigen-binding molecule, with two doses spaced apart (every two weeks). In this case, two doses are administered within a one month or four week period. In another embodiment, the maintenance dose is 9 mg / kg of the antigen-binding molecule (e.g., antibody), administered in four divided doses each containing 2.25 mg / kg of the antigen-binding molecule, with one week (weekly) between doses, in this case four doses administered over a one month or four week period. In another specific embodiment, the maintenance dose is 4.5 mg / kg of antigen binding molecule (e.g., antibody) per dose, with a dosing interval of 2 weeks (every 2 weeks), in this case two doses administered within a 1 month or 4 week period. In another embodiment, the maintenance dose is 2.25 mg / kg of antigen binding molecule (e.g., antibody) per dose with a weekly (every week) interval between doses, in this case four doses over a one month or four week period. In another aspect, the maintenance dose is 12 mg / kg of an antigen-binding molecule (e.g., an antibody). A maintenance dose of 12 mg / kg refers to, for example, administering a total of 12 mg / kg once or in multiple doses every 4 weeks or once a month. This may be applicable for pediatric patients or for such special patient populations where exposure is expected to be lower. In a particular embodiment, the maintenance dose is 12 mg / kg of an antigen-binding molecule (e.g., an antibody), administered in two divided doses each containing 6 mg / kg of the antigen-binding molecule, with two doses spaced apart (every two weeks). In this case, two doses are administered within a one-month or four-week period. In another embodiment, the maintenance dose is 12 mg / kg of the antigen-binding molecule (e.g., antibody), administered in four divided doses each containing 3 mg / kg of the antigen-binding molecule, with one week (weekly) between doses, in this case four doses administered over a one month or four week period. In certain embodiments, the maintenance dose is a single dose of 6 mg / kg of antigen binding molecule (e.g., antibody) with a dosing interval of 2 weeks (every 2 weeks), in this case two doses administered within a 1 month or 4 week period. In another embodiment, the maintenance dose is 3 mg / kg of antigen binding molecule (e.g., antibody) per dose, with a weekly (every week) interval between doses, in this case four doses over a one month or four week period. In other aspects, different or alternative maintenance doses and dosing intervals may be applicable. In certain embodiments, different or alternative maintenance doses and dosing intervals may be applicable after the first maintenance dose and dosing interval. More specifically, the maintenance dosing regimen of 6mg / kg every 4 weeks, the maintenance dosing regimen of 9mg / kg every 4 weeks, and / or the maintenance dosing regimen of 12mg / kg every 4 weeks may be modified to apply different, alternative, or modified maintenance doses and dosing intervals. For example, after carrying out administration of any of the maintenance dosing regimens of 6mg / kg every 4 weeks, the maintenance dosing regimen of 9mg / kg every 4 weeks, and the maintenance dosing regimen of 12mg / kg every 4 weeks, the administration of the maintenance dose may be evaluated as to whether it is sufficient to treat the subject. If the administration of the maintenance dose is found to be insufficient or to cause no or insufficient therapeutic and / or prophylactic effect, the administration of the maintenance dose may be stopped, and the administration of the modified maintenance dose may be started. The effect of administration of the maintenance dose can be evaluated at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 60 weeks, or more after the start of administration of the maintenance dose. The number of times that the maintenance dose can be changed is not particularly limited. The change in the maintenance dose can be made several times, for example, 1 to 4 times. In other words, one to several, e.g., one to five, different maintenance doses may be applied sequentially, such as: (0) administration of one maintenance dose, (1) discontinuing administration of that maintenance dose and beginning administration of a first modified maintenance dose, (2) discontinuing administration of the first modified maintenance dose and beginning administration of a second modified maintenance dose, (3) discontinuing administration of the second modified maintenance dose and beginning administration of a third modified maintenance dose, (4) discontinuing administration of the third modified maintenance dose and beginning administration of a fourth modified maintenance dose. In some embodiments, the modified maintenance dose may be applied from the outset without using the aforementioned 6 mg / kg every 4 weeks maintenance dosing regimen, 9 mg / kg every 4 weeks maintenance dosing regimen, and / or 12 mg / kg every 4 weeks maintenance dosing regimen. In certain aspects, the modified maintenance dose is 6 mg / kg of an antigen-binding molecule (e.g., an antibody). A modified maintenance dose of 6 mg / kg refers to, for example, a total of 6 mg / kg administered in one or multiple doses over a two-week period or every two weeks. In a particular embodiment, the modified maintenance dose is 6 mg / kg of the antigen binding molecule, which is administered once, and the modified administration interval is 2 weeks (every 2 weeks). In this case, one administration is administered every 2 weeks. In another embodiment, the modified maintenance dose is 6 mg / kg of the antigen-binding molecule, administered in two divided doses each containing 3 mg / kg of the antigen-binding molecule, and the modified dosing interval is one week (every week). In this case, two doses are administered over a two-week period. In a particular embodiment, the modified maintenance dose is 6 mg / kg of the antigen binding molecule as a single dose and the modified dosing interval is 2 weeks (every 2 weeks), in this case 2 doses are administered within a 1 month or 4 week period, in other words, 1 dose is administered within a 2 week period. In another embodiment, the modified maintenance dose is 3 mg / kg of the antigen binding molecule as a single dose and the modified dosing interval is 1 week (every week), in this case two doses are administered within a 2 week period. In certain embodiments, the modified maintenance dose is 9mg / kg of the antigen-binding molecule.The modified maintenance dose of 9mg / kg refers to, for example, administering a total of 9mg / kg of the antigen-binding molecule in one or multiple doses for 2 weeks or every 2 weeks.This may be applicable for pediatric patients or such special patient populations where exposure is expected to be lower. In another embodiment, the modified maintenance dose is 9 mg / kg of the antigen-binding molecule, administered in two divided doses each containing 4.5 mg / kg of the antigen-binding molecule, and the modified dosing interval is one week (every week). In this case, two doses are administered over a two-week period. In another embodiment, the modified maintenance dose is 4.5 mg / kg of the antigen binding molecule as a single dose and the modified dosing interval is 1 week (every week), in which case 4 doses are administered over a period of 1 month or 4 weeks, in other words 2 doses are administered over a period of 2 weeks. In certain embodiments, the modified maintenance dose is 12 mg / kg of the antigen-binding molecule. The modified maintenance dose of 12 mg / kg refers to, for example, administering a total of 12 mg / kg of the antigen-binding molecule in one or multiple doses for 2 weeks or every 2 weeks. This may be applicable for pediatric patients or such special patient populations where exposure is expected to be lower. In another embodiment, the modified maintenance dose is 12 mg / kg of the antigen-binding molecule, administered in two divided doses each containing 6 mg / kg of the antigen-binding molecule, and the modified dosing interval is one week (every week). In this case, two doses are administered over a two-week period. In another embodiment for each divided dose as a modified maintenance dose, the modified maintenance dose is 6 mg / kg of the antigen binding molecule as a single dose and the modified dosing interval is 1 week (every week), in which case 4 doses are administered over a period of 1 month or 4 weeks, in other words 2 doses are administered over a period of 2 weeks. In one preferred embodiment, the maintenance dose is 1 to 4.5 mg / kg per week. The administration interval may be one week, two weeks, three weeks, four weeks, five weeks, one month, or other intervals. More preferably, the maintenance dose may be 1 to 3 mg / kg, 1 to 2 mg / kg, 1.5±0.5 mg / kg, 1.5±0.4 mg / kg, 1.5±0.3 mg / kg, 1.5±0.2 mg / kg, 1.5±0.1 mg / kg, about 1.5 mg / kg, or 1.5 mg / kg per week. For example, the maintenance dose may be 1.5 mg / kg QW, 3 mg / kg Q2W, or 6 mg / kg Q4W, but is not limited thereto. These doses can be changed as appropriate, for example, when administered at 1.5 mg / kg QW, this may be changed to 3 mg / kg Q2W or 6 mg / kg Q4W, when administered at 3 mg / kg Q2W, this may be changed to 1.5 mg / kg QW or 6 mg / kg Q4W, when administered at 6 mg / kg Q4W, this may be changed to 1.5 mg / kg QW or 3 mg / kg Q2W. Of course, it can also be changed to other modes. There is no particular limit to the administration period, but it is preferable to administer for a period sufficient to obtain the effect of improving hemosiderin deposition and / or synovial thickening in joints.In particular, the drug of the present invention can be effective when administered for a long period of time.The administration period of long-term administration is not limited thereto, but may be, for example, at least 70 weeks, for example, 80 weeks or more, 85 weeks or more, 90 weeks or more, 95 weeks or more, 100 weeks or more, 110 weeks or more, 120 weeks or more, 130 weeks or more, 135 weeks or more, 140 weeks or more, 145 weeks or more, 150 weeks or more, 180 weeks or more, 190 weeks or more, 200 weeks or more, 230 weeks or more, 250 weeks or more, 280 weeks or more, or 300 weeks or more. For example, administration for 90 weeks or more, preferably 100 weeks or more, more preferably 120 weeks or more, more preferably 145 weeks or more, more preferably 300 weeks or more, or longer, is expected to satisfactorily improve hemosiderin deposition in joints and / or synovial thickening. There is no particular upper limit to the administration period, and administration can be continued as long as no adverse effects that require interruption of administration are observed. The number of times that the maintenance dose is administered is not particularly limited, and the number of times can be, for example, at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 15, at least 20, at least 25, at least 35, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 500, at least 1000, at least 10,000, or more. As used herein, a "loading" dose generally includes an initial dose of a therapeutic agent administered to a patient, followed by one or more maintenance doses. In one aspect, the loading dose refers to the amount given in each individual administration, which may be administered 0 to 24 times, preferably at least 1, at least 2, at least 3, at least 4, or more, preferably 2 or 4 times. Generally, the loading dose is administered at treatment intervals of 1 to 4 weeks, preferably about every week, about every 2 weeks, about every 3 weeks, or about every 4 weeks (monthly). In one aspect, the loading dose is 0.3 mg / kg to 30 mg / kg, preferably 3 mg / kg, 4.5 mg / kg, or 6 mg / kg of the antigen-binding molecule. The loading dose is intended to achieve steady-state therapeutic plasma concentrations as quickly as possible. In a particular embodiment, the loading dose is 3 mg / kg, the dosing interval is one week (every week), and the dosing is repeated four times. In another embodiment, the loading dose is 4.5 mg / kg, the dosing interval is one week (every week), and the dose is repeated two or four times. In another embodiment, the loading dose is 6 mg / kg, the dosing interval is one week (every week), and the dose is repeated four times. In another embodiment, the loading dose is 6 mg / kg, the dosing interval is 2 weeks (every 2 weeks), and the dose is repeated twice. The "dosing interval" (the interval between individual doses) refers to the interval between the nth (n is an integer of 1 or more) loading dose and the (n+1)th loading dose, and the interval between the nth (n is an integer of 1 or more) maintenance dose and the (n+1)th maintenance dose. For example, administration of 3 mg / kg four times at one-week intervals is a preferred example of administration in the loading dose. Following administration of the loading dose, administration of the maintenance dose is started. An appropriate interval may be provided between administration of the loading dose and administration of the maintenance dose. The interval may be, for example, from one day to one month, or from 3 days to 4 weeks, for example, from 5 days to 3 weeks, for example, one week. For example, administration of 3 mg / kg four times at one-week intervals (administration in the loading dose) may be performed, and administration in the maintenance dose may be performed from the fifth administration one week later (4 weeks after the first administration). In certain embodiments, the antigen binding molecule is administered as follows. Regimen A: A loading dose of 3 mg / kg once weekly for 4 weeks, followed (e.g., 1 week later) by a maintenance dose of 1.5 mg / kg once weekly (every week). Regimen B: A loading dose of 3 mg / kg weekly for 4 weeks, followed (e.g., 1 week later) by a maintenance dose of 3 mg / kg every 2 weeks. Regimen C: A loading dose of 3 mg / kg weekly for 4 weeks, followed (e.g., 1 week later) by a maintenance dose of 6 mg / kg every 4 weeks. Of course, other regimens may be used, and the maintenance dose may be changed to a modified maintenance dose, if appropriate. For example, in dosage forms with a loading dose, the present invention relates to the following invention: [1] A method for improving and / or inhibiting hemosiderin deposition and / or synovial thickening in a joint, comprising the steps of: (a) administering to a subject a bispecific antibody that recognizes blood coagulation factor IX and / or activated blood coagulation factor IX and (b) blood coagulation factor X and / or activated blood coagulation factor X at a weekly loading dose of 3 mg / kg or 4.5 mg / kg of antibody for one week or more, or at a biweekly loading dose of 6 mg / kg of antibody for two weeks or more; administering one or more maintenance doses of the antibody to the subject after the loading dose is completed, wherein the maintenance dose is 6 mg / kg of antibody; [2] The method of [1], wherein a maintenance dose of 6 mg / kg of the antibody is administered to the subject in one or multiple divided doses every four weeks or every month; [3] The method of [1] or [2], wherein the antibody is administered at a weekly loading dose of 3 mg / kg of antibody for 4 weeks, followed by a maintenance dose; [4] The method of [1] or [2], wherein the antibody is administered at a weekly loading dose of 4.5 mg / kg of antibody for two weeks, followed by a maintenance dose; [5] The method of [1] or [2], wherein the antibody is administered at a loading dose of 6 mg / kg of antibody every other week for 4 weeks, followed by a maintenance dose; [6] Any one of the methods [1] to [5], wherein the maintenance dose is administered once every month or every four weeks at a single dose of 6 mg / kg of antibody; [7] Any one of the methods of [1] to [5], wherein the maintenance dose is administered monthly or every four weeks, for two doses of 3 mg / kg of antibody each, wherein one maintenance dose of 3 mg / kg of antibody is administered every two weeks; [8] any one of the methods of [1]-[5], wherein the maintenance dose is administered monthly or every four weeks for four doses of 1.5 mg / kg of antibody each, wherein one of the maintenance doses of 1.5 mg / kg of antibody is administered once a week; [9] Any one of the methods of [1] to [8], further comprising the step of discontinuing administration of the antibody at a maintenance dose and starting administration of an alternative maintenance dose of the antibody to the subject in cases where the effect of administration of the antibody at a maintenance dose (improvement and / or inhibition of hemosiderin deposition in joints and / or synovial thickening) cannot be confirmed or is insufficient, wherein the alternative maintenance dose is a weekly dose of 3 mg / kg of the antibody or a biweekly dose of 6 mg / kg of the antibody;

[10] A method for improving and / or inhibiting hemosiderin deposition and / or synovial hyperplasia in a joint, comprising the steps of: (a) administering to a subject a bispecific antibody that recognizes blood coagulation factor IX and / or activated blood coagulation factor IX and (b) blood coagulation factor X and / or activated blood coagulation factor X at a weekly loading dose of 4.5 mg / kg of antibody for four weeks; thereafter, administering one or more maintenance doses of the antibody to the subject, the maintenance dose being 9 mg / kg of antibody administered in two or four divided doses every four weeks or every month;

[11] A method for improving and / or inhibiting hemosiderin deposition and / or synovial hyperplasia in a joint, comprising the steps of: (a) administering to a subject a bispecific antibody that recognizes blood coagulation factor IX and / or activated blood coagulation factor IX and (b) blood coagulation factor X and / or activated blood coagulation factor X at a weekly loading dose of 6 mg / kg of antibody for four weeks; thereafter, administering one or more maintenance doses of the antibody to the subject, the maintenance dose being 12 mg / kg of antibody administered in two or four divided doses every four weeks or every month;

[12] In cases where the effect of administration of a maintenance dose of the antibody (improvement and / or inhibition of hemosiderin deposition in joints and / or synovial thickening) cannot be confirmed or is insufficient, the method further comprises the step of discontinuing administration of the antibody at the maintenance dose and starting administration of an alternative maintenance dose of the antibody to the subject, the alternative maintenance dose being a weekly dose of 4.5 mg / kg of the antibody.

[0010] Method of

[13] In cases where the effect of administration of a maintenance dose of the antibody (improvement and / or inhibition of hemosiderin deposition in joints and / or synovial thickening) cannot be confirmed or is insufficient, the method further comprises the step of discontinuing administration of the antibody at the maintenance dose and starting administration of an alternative maintenance dose of the antibody to the subject, the alternative maintenance dose being a weekly dose of 6 mg / kg of the antibody.

[0011] Method of

[14] Any one of the methods according to [1] to

[0013] , wherein the antibody is emicizumab; and

[15] Any one of the methods according to [1] to

[0014] , wherein the subject to be administered the therapeutic agent is a subject suffering from a disease selected from the group consisting of hemophilia A, acquired hemophilia A, von Willebrand disease, hemophilia A accompanied by the appearance of inhibitors against blood coagulation factor VIII and / or activated blood coagulation factor VIII, and hemophilia A without the appearance of such inhibitors. Furthermore, the present invention relates to:

[16] A pharmaceutical composition comprising (a) a bispecific antibody recognizing blood coagulation factor IX and / or activated blood coagulation factor IX and (b) blood coagulation factor X and / or activated blood coagulation factor X for use in ameliorating and / or inhibiting hemosiderin deposition in joints and / or synovial thickening, wherein the bispecific antibody is administered at a weekly loading dose of 3 mg / kg or 4.5 mg / kg of antibody for one week or more, or at a biweekly loading dose of 6 mg / kg of antibody for two weeks or more, and after completion of the loading dose administration, one or more maintenance doses of 6 mg / kg of antibody are administered;

[17] A pharmaceutical composition comprising (a) a bispecific antibody recognizing blood coagulation factor IX and / or activated blood coagulation factor IX and (b) blood coagulation factor X and / or activated blood coagulation factor X for use in ameliorating and / or inhibiting hemosiderin deposition in joints and / or synovial thickening, wherein the bispecific antibody is administered at a weekly loading dose of 4.5 mg / kg of antibody for 4 weeks, followed by one or more maintenance doses of 9 mg / kg of antibody administered in 2 or 4 divided doses every 4 weeks or every month;

[18] A pharmaceutical composition for use in ameliorating and / or inhibiting hemosiderin deposition in joints and / or synovial thickening, comprising (a) a bispecific antibody recognizing blood coagulation factor IX and / or activated blood coagulation factor IX and (b) blood coagulation factor X and / or activated blood coagulation factor X, wherein the bispecific antibody is administered at a weekly loading dose of 6 mg / kg of antibody for 4 weeks, followed by one or more maintenance doses of 12 mg / kg of antibody administered in 2 or 4 divided doses every 4 weeks or every month;

[19] A product comprising: (i) a container; (ii) a pharmaceutical composition therein comprising a bispecific antibody that recognizes (a) blood coagulation factor IX and / or activated blood coagulation factor IX and (b) blood coagulation factor X and / or activated blood coagulation factor X; and (iii) a document instructing a patient to (a) administer the bispecific antibody at a weekly loading dose of 3 mg / kg or 4.5 mg / kg of antibody for one week or more, or at a biweekly loading dose of 6 mg / kg of antibody for two weeks or more, and (b) administer one or more maintenance doses of the bispecific antibody after the loading dose is completed, wherein the maintenance dose is 6 mg / kg of antibody, and the document describes an effect of the bispecific antibody in improving and / or inhibiting hemosiderin deposition in joints and / or synovial hyperplasia;

[20] A product comprising: (i) a container; (ii) a pharmaceutical composition therein comprising a bispecific antibody that recognizes (a) blood coagulation factor IX and / or activated blood coagulation factor IX and (b) blood coagulation factor X and / or activated blood coagulation factor X; and (iii) a written instruction to (a) administer the bispecific antibody at a weekly loading dose of 4.5 mg / kg of antibody for four weeks, and (b) administer one or more maintenance doses of the bispecific antibody after the loading dose is completed, the maintenance dose being 9 mg / kg of antibody administered in two or four divided doses every four weeks or monthly, the written instruction describing the effect of the product in improving and / or inhibiting hemosiderin deposition in joints and / or synovial hyperplasia;

[21] A product comprising: (i) a container; (ii) a pharmaceutical composition therein comprising a bispecific antibody that recognizes (a) blood coagulation factor IX and / or activated blood coagulation factor IX and (b) blood coagulation factor X and / or activated blood coagulation factor X; and (iii) a written instruction to (a) administer the bispecific antibody at a weekly loading dose of 6 mg / kg of antibody for four weeks, and (b) administer one or more maintenance doses of the bispecific antibody after completion of the loading dose, the maintenance dose being 12 mg / kg of antibody administered in two or four divided doses every four weeks or every month, the written instruction describing the effect of the product in improving and / or inhibiting hemosiderin deposition in joints and / or synovial hyperplasia;

[22] A bispecific antibody recognizing (a) blood coagulation factor IX and / or activated blood coagulation factor IX and (b) blood coagulation factor X and / or activated blood coagulation factor X for use in ameliorating and / or inhibiting hemosiderin deposition in joints and / or synovial thickening, wherein the bispecific antibody is administered at a weekly loading dose of 3 mg / kg or 4.5 mg / kg of antibody for at least one week, or at a biweekly loading dose of 6 mg / kg of antibody for at least two weeks, and after completion of the loading dose administration, one or more maintenance doses of 6 mg / kg of antibody are administered;

[23] A bispecific antibody recognizing (a) blood coagulation factor IX and / or activated blood coagulation factor IX and (b) blood coagulation factor X and / or activated blood coagulation factor X for use in ameliorating and / or inhibiting hemosiderin deposition in joints and / or synovial thickening, wherein the bispecific antibody is administered at a weekly loading dose of 4.5 mg / kg of antibody for 4 weeks, followed by one or more maintenance doses of 9 mg / kg of antibody administered in 2 or 4 divided doses every 4 weeks or every month;

[24] A bispecific antibody recognizing (a) blood coagulation factor IX and / or activated blood coagulation factor IX and (b) blood coagulation factor X and / or activated blood coagulation factor X for use in ameliorating and / or inhibiting hemosiderin deposition in joints and / or synovial thickening, wherein the bispecific antibody is administered at a weekly loading dose of 6 mg / kg of antibody for 4 weeks, followed by one or more maintenance doses of 12 mg / kg of antibody administered in 2 or 4 divided doses every 4 weeks or every month;

[25] Use of a bispecific antibody that recognizes (a) blood coagulation factor IX and / or activated blood coagulation factor IX and (b) blood coagulation factor X and / or activated blood coagulation factor X in the manufacture of a pharmaceutical composition for use in ameliorating and / or inhibiting hemosiderin deposition and / or synovial thickening in joints, wherein the bispecific antibody is administered at a weekly loading dose of 3 mg / kg or 4.5 mg / kg of antibody for one week or more, or at a biweekly loading dose of 6 mg / kg of antibody for two weeks or more, and after completion of the loading dose administration, one or more maintenance doses of 6 mg / kg of antibody are administered;

[26] Use of a bispecific antibody that recognizes (a) blood coagulation factor IX and / or activated blood coagulation factor IX and (b) blood coagulation factor X and / or activated blood coagulation factor X in the manufacture of a pharmaceutical composition for use in improving and / or inhibiting hemosiderin deposition in joints and / or synovial thickening, wherein the bispecific antibody is administered at a weekly loading dose of 4.5 mg / kg of antibody for 4 weeks, followed by one or more maintenance doses of 9 mg / kg of antibody administered in 2 or 4 divided doses every 4 weeks or every month; and

[27] Use of a bispecific antibody recognizing (a) blood coagulation factor IX and / or activated blood coagulation factor IX and (b) blood coagulation factor X and / or activated blood coagulation factor X in the manufacture of a pharmaceutical composition for use in ameliorating and / or inhibiting hemosiderin deposition in joints and / or synovial thickening, wherein the bispecific antibody is administered at a weekly loading dose of 6 mg / kg of antibody for 4 weeks, followed by one or more maintenance doses of 12 mg / kg of antibody administered in 2 or 4 divided doses every 4 weeks or every month. In some preferred embodiments, the agents and regimens of the present invention may be applicable for subjects (patients) with hemosiderin deposition and / or synovial thickening or for subjects (patients) concerned about hemosiderin deposition and / or synovial thickening. The agents and regimens of the present invention may be applicable in methods for preventing (suppressing) and / or treating (improving) hemosiderin deposition and / or synovial thickening in such patients. As used herein, "prevention" or "treatment" of hemosiderin deposition and / or synovial thickening refers to reducing the incidence of hemosiderin deposition and / or synovial thickening in a subject (patient), reducing the likelihood of hemosiderin deposition and / or synovial thickening, or improving hemosiderin deposition and / or synovial thickening. In certain embodiments, the hemosiderin deposition and / or synovial thickening in such subjects (patients) is caused by a disease that develops and / or progresses due to reduced or deficient activity of FVIII and / or FVIIIa. In certain embodiments, the subjects (patients) with hemosiderin deposition and / or synovial thickening have hemophilia, which may be hemophilia A. The agents, methods, uses, etc. of the present invention may be agents, methods, uses, etc. for selecting subjects (patients) with hemosiderin deposition and / or synovial thickening and administering to these subjects (patients). In the present invention, "improvement" and "suppression" do not mean complete improvement or suppression, but may mean at least improvement and suppression, respectively, compared to before treatment, and may also mean at least improvement and suppression, respectively, compared to the absence of treatment. In some embodiments, the agents and regimens of the present invention may be applicable for patients with hemophilia A, preferably for patients with hemophilia A with FVIII inhibitors and / or patients with hemophilia A without FVIII inhibitors. In some embodiments, the medicaments and regimens of the present invention may be applicable for patients with severe hemophilia A. In some embodiments, the agents and regimens of the present invention may be applicable for adult patients and / or pediatric patients and / or such special patient populations where exposure is expected to be lower. In some preferred embodiments, the medicament of the present invention may be applicable for children, as described above. Children generally refer to children from newborns to adolescents, and specifically refer to subjects under 18, 17, or 16 years of age. In some preferred embodiments, the medicament of the present invention is administered to subjects under 18, 17, 16, 15, 14, 13, or 12 years of age. For example, the medicament may be intended for children aged 0-17, 0-16, 0-15, 0-14, 0-13, 0-12, 0-11, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, or 1-11. For example, subjects under 12 years of age are suitable subjects for administration in the present invention. Dosage regimen is determined, for example, by considering efficacy and safety.Furthermore, dosing regimen is determined by considering patient convenience within the range that does not impair efficacy and safety.For example, dosing regimen for hemophilia A patients can be determined by considering the effect of preventing hemosiderin deposition and / or synovial thickening in patients and clinically acceptable safety. The disease to which the therapeutic agent is administered may include diseases whose onset and / or progression is due to a decrease or deficiency in the activity of FVIII and / or FVIIIa. Diseases that develop and / or progress due to reduced or deficient activity of FVIII and / or FVIIIa include, for example, hemophilia A, hemophilia A with or without the appearance of inhibitors to FVIII / FVIIIa, congenital hemophilia A, acquired hemophilia A, and von Willebrand's disease, but are not particularly limited to these. In some embodiments, the medicaments and regimens of the present invention may be applicable to prevent, treat, and / or reduce the incidence of hemosiderin deposition and / or synovial thickening in congenital FVIII-deficient patients with inhibitors. In some embodiments, the medicaments and regimens of the present invention may be applicable to prevent, treat, and / or reduce the incidence of hemosiderin deposition and / or synovial thickening in non-inhibitor congenital FVIII-deficient patients. In some embodiments, the agents and regimens of the invention may be applicable to prevent, treat, and / or reduce the incidence of hemosiderin deposition and / or synovial thickening in acquired FVIII-deficient patients with inhibitors. In some embodiments, the medicaments and regimens of the invention may be applicable to prevent, treat, and / or reduce the incidence of hemosiderin deposition and / or synovial thickening in non-inhibitor acquired FVIII-deficient patients. In some embodiments, the agents and regimens of the present invention may be applicable to prevent, treat, and / or reduce the incidence of hemosiderin deposition and / or synovial thickening in patients with congenital von Willebrand factor deficiency. In some embodiments, the agents and regimens of the present invention may be applicable to prevent, treat, and / or reduce the incidence of hemosiderin deposition and / or synovial thickening in patients with acquired von Willebrand factor deficiency. As used herein, the term "inhibitor patient" refers to a patient with hemophilia A who has a FVIII inhibitor. As used herein, the term "non-inhibitor patient" refers to a patient with hemophilia A who does not have FVIII inhibitors. The present invention provides a product comprising at least (i) a container, (ii) a pharmaceutical composition in the container, comprising (a) FIX and / or FIXa and (b) a multispecific antigen-binding molecule that recognizes FX and / or FXa, and (iii) a document that describes that the product can be used in an application that inhibits and / or improves hemosiderin deposition and / or synovial thickening. In addition, a label, a syringe, a needle, a pharma- ceutical acceptable medium, alcohol-soaked cotton, a gauze bandage, etc. may be packaged in the product. The container may be, for example, a bottle, a glass bottle, or a syringe, and may be made of various materials such as glass or plastic. A device that assists administration may be included with the product. The pharmaceutical composition is stored in the container, and the mouth of the container is sealed by a rubber stopper or the like. The document in (iii) may include instructions (e.g., a package insert) that specify the loading dose, maintenance dose, frequency or interval of administration according to the above-mentioned dosing regimen. The term "package insert" is used herein to refer to instructions typically included in commercial packaging for therapeutic products that contain information about the indications, usage, dosage, methods of administration, concomitant therapy, contraindications, and / or warnings regarding the use of such therapeutic product. Inhibition and / or amelioration of hemosiderin deposition and / or synovial thickening refers to, but is not limited to, for example, inhibiting and / or ameliorating the symptoms of hemosiderin deposition and / or synovial thickening by administering the composition to a patient who actually shows the symptoms, and / or reducing the frequency of occurrence by administering the composition to a patient who has previously shown the symptoms in order to prevent the onset of the symptoms in advance. Treatment and prevention may be understood to have the same meaning in certain cases, and such treatment and prevention are also referred to as prophylactic therapy or regular administration therapy of a therapeutic agent (the bispecific antigen-binding molecule of the present invention). Prevention of hemosiderin deposition and / or synovial thickening refers, for example, to reducing the incidence or likelihood of hemosiderin deposition and / or synovial thickening. As used herein, the term "coagulation factor preparations" refers to, for example, FVIII preparations and bypass preparations (activated prothrombin complex preparations, recombinant FVIIa preparations, etc.). The present invention provides a pharmaceutical composition comprising a bispecific antigen binding molecule that recognizes (a) FIX and / or FIXa and (b) FX and / or FXa, or a dosing regimen thereof, as a more effective pharmaceutical composition for the prevention and / or treatment of hemosiderin deposition and / or synovial thickening, diseases associated with such deposition and / or thickening, or diseases caused by such deposition and / or thickening, including those whose onset and / or progression is due to reduced or deficient activity of FVIII and / or FVIIIa. All prior art documents cited herein are hereby incorporated by reference. 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. Although the foregoing invention has been described in detail by way of illustration and example for purposes of facilitating a clear understanding, the descriptions and illustrations herein should not be construed as limiting the scope of the invention. Example 1 The AOZORA study is a multicenter, open-label, single-arm study designed to evaluate the long-term safety and effects on joints of emicizumab administered subcutaneously within the approved dosage regimen in children with hemophilia A under the age of 12 without FVIII inhibitors. Approximately 30 subjects enrolled in the study will continue to receive emicizumab subcutaneously for 313 weeks from the first dose of emicizumab, or until the study is discontinued (for any reason) or the criteria described in the study protocol (the occurrence of unacceptable adverse effects) are met. In addition, subjects who were participating in the HOHOEMI study were allowed to transition to this study. Subjects were allowed to choose the emicizumab administration regimen within the approved dosage regimen. Number of subjects enrolled: Thirty cases were enrolled, including subjects transferring from the HOHOEMI study. Target population: Subjects were required to be those who were starting emicizumab treatment for the first time in the HOHOEMI study or AOZORA study. Test drugs: In this study, the commercially available subcutaneous injection of Hemlibra (registered trademark) was used as the test drug and was administered in accordance with the package insert. Specifically, in the HOHOEMI study, the loading dose of emicizumab was 3 mg / kg QW for 4 weeks, followed by a maintenance dose of 3 mg / kg Q2W or 6 mg / kg Q4W. In the AOZORA study, subjects starting emicizumab for the first time received a loading dose of 3 mg / kg QW for 4 weeks, followed by a maintenance dose of 1.5 mg / kg QW, 3 mg / kg Q2W, or 6 mg / kg Q4W. Primary endpoint: The long-term safety of emicizumab administered subcutaneously according to the approved dosage regimen to pediatric patients with hemophilia A without FVIII inhibitors was comprehensively evaluated with respect to the following items: Adverse events Adverse events leading to discontinuation of study drug Adverse events of particular interest Physical examination findings Abnormal laboratory test results -FVIII inhibitor occurrence status In addition, the effects of emicizumab on joints when administered subcutaneously according to the approved dosage regimen in pediatric patients with hemophilia A without FVIII inhibitors were evaluated at specified time points for the following items: - Magnetic resonance imaging (MRI) knee and ankle scores (International Prophylaxis Study Group MRI scale) Hemophilia Joint Health Score (HJHS) 2.1 combined elbow, knee, ankle and gait scores result: The cutoff was the last day of Week 145 for each subject. Ten subjects were enrolled from the HOHOEMI study, and 20 subjects were newly enrolled. Including patients from the HOHOEMI study, the start of treatment in the HOHOEMI study was defined as Week 1. The median age (range) was 4.2 years (0.7-11.1), all subjects were male, and 27 subjects (93.1%) were receiving FVIII prophylaxis before study enrollment. One subject had one target joint (knee) at week 1. A target joint is a joint that had had three or more bleeds in the 24 weeks prior to emicizumab administration. [Table 1] AOZORA study subject characteristics (FVIII, factor VIII; ITI, immune tolerance induction) MRI evaluation of the joints was performed in 29 cases (116 joints) at Week 1 and in 26 cases (104 joints) at Week 145 using the IPSG MRI scale (Haemophilia. 2012 Nov;18(6):962-70. doi: 10.1111 / j.1365-2516.2012.02883.x. Epub 2012 Jul 5.). Of 10 joints (8.6%) that had synovial thickening and hemosiderin deposition at Week 1, the scores improved in all joints by Week 145, and the findings of synovial thickening and hemosiderin deposition disappeared in 9 joints. At Week 145, synovial thickening and hemosiderin deposition were newly observed in 1 joint. Effusion / intra-articular bleeding was observed in 21 joints (18.1%) at Week 1 and in 31 joints (29.8%) at Week 145. In 11 of 26 cases (42.3%), the score was 0 at Week 1 and Week 145, confirming that the condition of the joint was maintained. In this study, 5 patients (16.7%) had 7 emicizumab-related adverse events (AEs) (6 injection site reactions in 5 patients, 1 anemia in 1 patient). 5 patients (16.7%) had 7 serious adverse events, none of which were causally related to emicizumab. No TMA (thrombotic microangiopathy) or TE (thromboembolism) were reported. [Table 2] Number of soft tissue changes in the AOZORA study (A total of 116 knee and ankle joints across 29 subjects were evaluated during Week 1, and a total of 104 knee and ankle joints across 26 subjects were evaluated during Week 145. * Synovial thickening and hemosiderin scores were performed simultaneously. The mean annual bleeding rate (95% confidence interval [CI]) for treated bleeds was 3.7 (0.94-9.80) before emicizumab treatment and 0.7 (0.01-5.10) after emicizumab treatment. The mean annual bleeding rate (95% CI) for treated joint bleeds was 0.4 (0.00-4.55) before emicizumab treatment and 0.2 (0.00-4.04) after emicizumab treatment. The three-year interim analysis of the AOZORA study revealed for the first time that emicizumab not only has an effect of suppressing bleeding, but also has the effect of inhibiting and improving synovial thickening and hemosiderin deposition in the joints of hemophilia patients. Inhibiting and improving synovial thickening and hemosiderin deposition will prevent the progression to irreversible joint destruction such as cartilage degradation, suggesting an improvement in the long-term quality of life of patients. In addition, the good safety of emicizumab was confirmed. The present invention provides a drug for use in improving and / or suppressing hemosiderin deposition in joints and / or synovial thickening, which comprises as active ingredients a bispecific antigen-binding molecule that binds to (a) blood coagulation factor IX and / or activated blood coagulation factor IX and (b) blood coagulation factor X and / or activated blood coagulation factor X; use of the bispecific antigen-binding molecule for the improvement and / or suppression and in the manufacture of the drug; and a method for the improvement and / or suppression, which comprises the step of administering the bispecific antigen-binding molecule. The inhibition and improvement of synovial thickening and hemosiderin deposition by the present invention is believed to be particularly useful for inhibiting the progression to irreversible joint destruction such as cartilage degradation, and for improving the long-term QOL of patients.

Claims

1. A drug for use in improving and / or inhibiting hemosiderin deposition in joints and / or synovial thickening, comprising as active ingredients (a) blood coagulation factor IX and / or activated blood coagulation factor IX and (b) a bispecific antigen-binding molecule that binds to blood coagulation factor X and / or activated blood coagulation factor X.

2. The drug according to claim 1 for use in improving and / or inhibiting hemosiderin deposition and / or synovial thickening in the joints of a patient suffering from a disease whose onset and / or progression is due to a decrease or deficiency in the activity of blood coagulation factor VIII and / or activated blood coagulation factor VIII (FVIIIa).

3. The drug according to claim 2, wherein the disease is hemophilia.

4. The drug according to claim 2, wherein the patient also suffers from hemophilic arthropathy.

5. The drug according to claim 2, wherein the patient is confirmed to have hemophilic arthropathy.

6. The drug according to claim 2, wherein the patient is a patient confirmed by MRI to have hemophilic arthropathy.

7. The drug according to claim 2, wherein the patient is a patient in whom MRI has confirmed hemosiderin deposition in joints and / or synovial thickening.

8. The method of claim 1, wherein the antigen-binding molecule is emicizumab.

9. The agent according to claim 1, wherein the antigen-binding molecule is a bispecific antibody in which a first polypeptide is associated with a third polypeptide and a second polypeptide is associated with a fourth polypeptide, and the bispecific antibody is any one of the following (a) to (c): (a) a bispecific antibody comprising a first polypeptide which is an H chain comprising an H chain variable region comprising the amino acid sequences of CDRs 1, 2, and 3 of SEQ ID NOs: 1, 2, and 3, respectively; a second polypeptide which is an H chain comprising an H chain variable region comprising the amino acid sequences of CDRs 1, 2, and 3 of SEQ ID NOs: 6, 7, and 8, respectively; and third and fourth polypeptides which are shared L chains comprising an L chain variable region comprising the amino acid sequences of CDRs 1, 2, and 3 of SEQ ID NOs: 11, 12, and 13, respectively; (b) a bispecific antibody comprising a first polypeptide, which is a heavy chain comprising the heavy chain variable region amino acid sequence of SEQ ID NO:4; a second polypeptide, which is a heavy chain comprising the heavy chain variable region amino acid sequence of SEQ ID NO:9; and third and fourth polypeptides, which are a shared light chain comprising the light chain variable region amino acid sequence of SEQ ID NO:14; or (c) a bispecific antibody comprising a first polypeptide, which is a heavy chain comprising the amino acid sequence of SEQ ID NO:5; a second polypeptide, which is a heavy chain comprising the amino acid sequence of SEQ ID NO:10; and third and fourth polypeptides, which are a shared light chain comprising the amino acid sequence of SEQ ID NO:

15.

10. The drug described in claim 2, wherein the disease is selected from the group consisting of hemophilia A, acquired hemophilia A, von Willebrand's disease, and hemophilia A accompanied by the appearance of inhibitors to blood coagulation factor VIII and / or activated blood coagulation factor VIII.

11. The method of claim 2, wherein the disease is congenital hemophilia A.

12. The method of claim 3, wherein the hemophilia patient does not have an inhibitor to FVIII.

13. The method of claim 3, wherein the hemophilia patient is a pediatric patient with congenital hemophilia A under the age of 12.

14. The drug described in claim 1, which is administered to a subject who has developed hemosiderin deposition in joints and / or synovial thickening and / or a subject who is at risk of developing the same.

15. The drug described in claim 1, wherein the improvement and / or suppression is exerted upon long-term administration.

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