Antibodies neutralizing substances having a substitutive activity of the function of coagulation factor VIII (F.VIII)

Abstract

This study aimed to prepare antibodies that neutralize the activity of bispecific antibodies with F.VIII functional substitution activity, and to develop a method for measuring F.VIII reactivity in the presence of bispecific antibodies with F.VIII functional substitution activity. Results showed that F.VIII activity in the plasma of hemophilia A patients could be accurately assessed using the generated antibodies via an APTT-based one-stage coagulation assay against a wide range of bispecific antibodies with F.VIII functional substitution activity. It was also found that the titer of F.VIII inhibitors in the plasma of hemophilia A patients carrying F.VIII inhibitors could be accurately assessed using an APTT-based Bethesda assay.

Description

Technical Field

[0001] This invention relates to antibodies that neutralize substances having activity that substitutes for the function of coagulation factor VIII (F.VIII). The invention also relates to antibodies for a method of measuring the reactivity of F.VIII in the presence of substances having F.VIII functional substitution activity. Background Technology

[0002] Hemophilia is a bleeding disorder caused by a congenital defect or dysfunction of factor VIII or clotting factor IX (F.IX). The former is called hemophilia A, and the latter is called hemophilia B. Both genes are located on the X chromosome; because they are X-linked recessive genetic abnormalities, 99% or more of those affected are males. The known incidence is approximately 1 in 10,000 male births, with a ratio of approximately 5:1 between hemophilia A and hemophilia B.

[0003] The main bleeding sites in hemophilia patients include intra-articular, intramuscular, subcutaneous, oral, intracranial, gastrointestinal, and nasal sites. Among these, recurrent intra-articular bleeding can develop into hemophilic arthropathy, accompanied by joint dysfunction and difficulty walking, ultimately requiring joint replacement. Therefore, it is a major factor reducing the quality of life for hemophilia patients.

[0004] The severity of hemophilia is closely related to the activity of F.VIII or F.IX in the blood. Patients with clotting factor activity below 1% are classified as severe, those with activity between 1% and 5% are classified as moderate, and those with activity between 5% and 40% are classified as mild. Patients with severe symptoms, accounting for about half of all hemophilia patients, experience bleeding symptoms several times a month if they do not receive the prophylactic replacement therapy described later; this frequency is significantly higher compared to patients with moderate and mild symptoms.

[0005] Besides hemophilia and acquired hemophilia, von Willebrand disease (VWF), caused by functional abnormalities or a deficiency of VWF, is also known as a related bleeding disorder. VWF is not only essential for the normal adhesion of platelets to the subendothelial tissue at sites of vascular wall injury, but also for forming a complex with F.VIII and maintaining normal levels of F.VIII in the blood. In patients with von Willebrand disease, these functions are reduced, leading to impaired hemostasis.

[0006] To prevent and / or treat bleeding in patients with hemophilia, clotting factors purified from plasma or produced through genetic engineering are primarily used. In patients with severe hemophilia, maintaining F.VIII or F.IX activity in the blood at 1% or higher through F.VIII or F.IX replacement therapy is considered an effective method for preventing the onset of bleeding symptoms (NPL 1,2). On the other hand, in patients with hemophilia, especially those with severe hemophilia, antibodies against F.VIII or F.IX, known as inhibitors, may be produced. When these inhibitors are produced, the effect of clotting factor preparations is blocked by the inhibitors. As a result, neutralization is achieved using large doses of clotting factor preparations, or bypass treatment is performed using compound concentrates or activated clotting factor VII preparations (F.VIIa preparations).

[0007] The measurement of F.VIII activity in hemophilia A is mainly performed by a one-stage coagulation assay based on activated partial prothrombin time (APTT) (NPL 3) and a colorimetric assay using a system reconstituted with purified coagulation factors (NPL 4).

[0008] The titer of F.VIII inhibitors in hemophilia A was mainly measured by Bethesda assay or Nijmegen Bethesda assay (NPL 5, 6).

[0009] Recently, a bispecific antibody, emmicizumab, was discovered that binds to both F.IX and / or activated coagulation factor IX (F.IXa) and coagulation factor X (FX) and / or activated coagulation factor X (F.Xa), and substitutes for the cofactor function of F.VIII, or more specifically, promotes the function of activated FX through F.IXa (NPL 7,8; ​​PTL 1,2,3). The bispecific antibody functionally substitutes for F.VIII to improve the reduction in coagulation responses due to F.VIII deficiency or dysfunction. For example, regarding thrombin production and APTT (an indicator of coagulation response), regardless of the presence of F.VIII inhibitors, the bispecific antibody shortened the APTT derived from plasma from hemophilia A patients and increased thrombin production. The APTT-shortening effect of the bispecific antibody was significantly greater than that of F.VIII. This is because F.VIII in plasma only exhibits cofactor activity after being activated by activating factor X (F.Xa) or thrombin, while the aforementioned bispecific antibody does not require this activation process and therefore exhibits cofactor function more quickly.

[0010] In addition, antibodies against the bispecific antibodies F.IXa Fab and FX Fab were obtained, and the concentration of the bispecific antibodies in plasma samples from animal experiments (NPL 9) was determined.

[0011] The bispecific antibody of this invention replaces the cofactor function of F.VIII, thereby affecting the assay system for measuring F.VIII autoreactivity. For example, when measuring plasma F.VIII activity via an APTT-based one-stage coagulation assay to diagnose the severity of hemophilia A or to monitor the pharmacological activity of F.VIII formulations in patients receiving them, the presence of the bispecific antibody strongly interferes with its clotting time-promoting effect, significantly reducing measurement accuracy. Furthermore, when measuring plasma F.VIII inhibitor titers via the APTT-based Bethesda assay, the presence of the bispecific antibody strongly interferes with its clotting time-promoting effect, significantly reducing measurement accuracy. In other words, F.VIII activity and F.VIII inhibitor titers cannot be accurately measured in patients using bispecific antibodies. Therefore, a method is needed that can measure F.VIII activity and F.VIII inhibitor titers even in the presence of bispecific antibodies.

[0012] Antibodies against emecizumab (an alternative bispecific antibody that promotes FX activation via F.IXa) and methods (PTL 4 and 5) for measuring F.VIII activity and F.VIII inhibitor titers using these antibodies were also developed.

[0013] Bispecific antibodies that can replace the function of promoting FX activation via F.IXa are not limited to emecizumab; novel bispecific antibodies with further improved function are also known (PTL 6).

[0014] Reference List

[0015] Patent documents

[0016] [PTL 1]WO2005 / 035756

[0017] [PTL 2]WO2006 / 109592

[0018] [PTL 3]WO2012 / 067176

[0019] [PTL 4]WO2016 / 047656

[0020] [PTL 5]WO2016 / 047652

[0021] [PTL 6]WO2019 / 065795

[0022] Non-patent literature

[0023] [NPL 1]N Engl J Med.2007;357(6):535-44

[0024] [NPL 2]Thromb Res.2011;127(suppl1):S14-7

[0025] [NPL 3]Thromb Diath Haemorrh.1962May 15;7:215-28

[0026] [NPL 4]Haemostasis.1989 19:196-204.

[0027] [NPL 5]Thromb Diath Haemorrh.1975;34(3):869-72

[0028] [NPL 6] Thromb Haemost.1995Feb;73(2):247-51.

[0029] [NPL 7]Nat Med.2012;18(10):1570-74

[0030] [NPL 8]PLoS One.2013;8(2):e57479.

[0031] [NPL 9]J Thromb Haemost.2014;12(2):206-13Supporting Information Summary of the Invention

[0032] Technical issues

[0033] As mentioned above, in patients with bleeding disorders (such as hemophilia) who receive bispecific antibodies, there is a problem that makes it difficult to accurately measure F.VIII activity and F.VIII inhibitor titers due to the presence of bispecific antibodies in plasma samples. The invention of this application solves these problems. The object of this invention is to provide an antibody that neutralizes substances having functional substitution activity for coagulation factor VIII (F.VIII), which can be used in methods for accurately measuring the reactivity of F.VIII in the presence of substances having functional substitution activity for F.VIII, such as methods for accurately measuring F.VIII activity and F.VIII inhibitor titers. Furthermore, the object of this invention is to provide methods, kits, etc., for measuring the reactivity of F.VIII (e.g., F.VIII activity and F.VIII inhibitor titers) in the presence of substances having functional substitution activity for F.VIII.

[0034] Solution to the problem

[0035] To address the aforementioned problems, the inventors focused on assays for measuring F.VIII reactivity and prepared substances that neutralize the activity of bispecific antibodies with F.VIII functional substitution activity. They also examined whether the accuracy of F.VIII reactivity assessment was maintained even in the presence of bispecific antibodies. As a result, the inventors found that by using neutralizing antibodies against bispecific antibodies with F.VIII functional substitution activity at concentrations that allow for sufficient neutralization, F.VIII activity in the plasma of hemophilia A patients can be accurately assessed by a one-stage APTT-based coagulation assay. The inventors also successfully discovered a kit containing neutralizing antibodies against bispecific antibodies with F.VIII functional substitution activity, which can be used for this assay. Furthermore, the inventors found that the antibodies of this invention neutralize a wide range of bispecific antibodies. Based on these findings, the present invention provides the following.

[0036] [1] An antibody that neutralizes bispecific antibodies binding to coagulation factor IX and / or activated coagulation factor IX and coagulation factor X and / or activated coagulation factor X, wherein the bispecificity is selected from the group consisting of (a) to (t):

[0037] (a) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:83, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:88, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:100, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:111.

[0038] (b) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:84, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:89, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:100, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:111.

[0039] (c) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:85, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:90, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:101, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:112.

[0040] (d) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:85, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:91, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:101, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:112.

[0041] (e) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:84, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:89, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:102, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:113.

[0042] (f) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:84, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:89, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:103, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:114.

[0043] (g) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:84, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:89, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:101, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:112.

[0044] (h) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:86, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:92, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:101, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:112.

[0045] (i) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:86, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:93, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:101, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:112.

[0046] (j) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:86, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:93, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:104, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:115.

[0047] (k) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:86, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:94, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:104, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:115.

[0048] (l) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:86, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:94, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:105, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:116.

[0049] (m) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:86, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:95, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:104, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:115.

[0050] (n) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:86, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:95, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:105, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:116.

[0051] (o) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:87, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:96, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:106, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:117.

[0052] (p) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:86, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:97, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:107, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:118.

[0053] (q) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:87, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:98, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:106, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:117.

[0054] (r) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:87, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:98, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:108, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:119.

[0055] (s) a bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:87, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:96, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:109, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:120; and

[0056] (t) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:122, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:99, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:110, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:121.

[0057] The neutralizing antibody of [2][1], wherein the bispecific antibody further comprises:

[0058] (1) A first antibody heavy chain constant region containing the amino acid sequence of SEQ ID NO:139 and a first antibody light chain constant region containing the amino acid sequence of SEQ ID NO:140, and

[0059] (2) A second antibody heavy chain constant region containing the amino acid sequence of SEQ ID NO:141 and a second antibody light chain constant region containing the amino acid sequence of SEQ ID NO:142.

[0060] [3] An antibody that neutralizes bispecific antibodies binding to coagulation factor IX and / or activated coagulation factor IX and coagulation factor X and / or activated coagulation factor X, wherein the bispecificity is selected from the group consisting of (a) to (t):

[0061] (a) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:143, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:149, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:161, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:172.

[0062] (b) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:144, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:150, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:161, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:172.

[0063] (c) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:145, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:151, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:162, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:173.

[0064] (d) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:145, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:152, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:162, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:173.

[0065] (e) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:144, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:150, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:163, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:174.

[0066] (f) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:144, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:150, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:164, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:175.

[0067] (g) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:144, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:150, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:162, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:173.

[0068] (h) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:146, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:153, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:162, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:173.

[0069] (i) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:146, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:154, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:162, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:173.

[0070] (j) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:146, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:154, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:165, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:176.

[0071] (k) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:146, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:155, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:165, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:176.

[0072] (l) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:146, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:155, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:166, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:177.

[0073] (m) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:146, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:156, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:165, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:176.

[0074] (n) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:146, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:156, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:166, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:177.

[0075] (o) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:147, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:157, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:167, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:178.

[0076] (p) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:146, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:158, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:168, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:179.

[0077] (q) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:147, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:159, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:167, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:178.

[0078] (r) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:147, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:159, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:169, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:180.

[0079] (s) a bispecific antibody comprising a first antibody heavy chain containing the amino acid sequence of SEQ ID NO:147, a first antibody light chain containing the amino acid sequence of SEQ ID NO:157, a second antibody heavy chain containing the amino acid sequence of SEQ ID NO:170, and a second antibody light chain containing the amino acid sequence of SEQ ID NO:181; and

[0080] (t) A bispecific antibody comprising a first antibody heavy chain containing the amino acid sequence of SEQ ID NO:148, a first antibody light chain containing the amino acid sequence of SEQ ID NO:160, a second antibody heavy chain containing the amino acid sequence of SEQ ID NO:171, and a second antibody light chain containing the amino acid sequence of SEQ ID NO:182.

[0081] [4] An antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:2, or an antibody that binds to an epitope that overlaps with or is the same as the epitope bound to the antibody.

[0082] [5] An antibody comprising an antibody heavy chain comprising the amino acid sequence of SEQ ID NO:131 and an antibody light chain comprising the amino acid sequence of SEQ ID NO:132, or an antibody that binds to an epitope that overlaps with or is the same as the epitope that binds to the antibody.

[0083] [6] An antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:4, or an antibody that binds to an epitope that overlaps with or is the same as the epitope that binds to the antibody.

[0084] [7] An antibody comprising an antibody heavy chain comprising the amino acid sequence of SEQ ID NO:135 and a light chain comprising the amino acid sequence of SEQ ID NO:136, or an antibody binding to an epitope that overlaps with or is the same as the epitope bound to the antibody.

[0085] [8] Nucleic acid, which encodes any one of [1] to [7] antibodies.

[0086] [9] A vector in which the nucleic acid described in [8] is inserted.

[0087]

[10] Cells containing the nucleic acid described in [8] or the vector described in [9].

[0088]

[11] A method for producing antibodies, which includes the step of culturing the cells described in

[10] .

[0089]

[12] A composition comprising the antibody described in [4] and / or the antibody described in [6].

[0090]

[13] A composition comprising the antibody described in [5] and / or the antibody described in [7].

[0091]

[14] A method for measuring the responsiveness of coagulation factor VIII, comprising the step of contacting the following (1) with the following (2):

[0092] (1) A blood-derived sample containing a bispecific antibody binding to coagulation factor IX and / or activated coagulation factor IX and coagulation factor X and / or activated coagulation factor X; and

[0093] (2) The antibodies described in [4] or [5] and / or the antibodies described in [6] or [7].

[0094]

[15] A method for measuring the responsiveness of coagulation factor VIII, comprising the step of contacting the following (1) with the following (2):

[0095] (1) A blood-derived sample containing a bispecific antibody binding to coagulation factor IX and / or activated coagulation factor IX and coagulation factor X and / or activated coagulation factor X; and

[0096] (2) The composition described in

[12] or

[13] .

[0097]

[16] A kit for use in the method described in

[15] , comprising the composition described in

[12] or

[13] .

[0098] Furthermore, the present invention provides the following

[101] to

[106] .

[0099]

[101] An antibody binding to Fab, wherein Fab contains an antigen-binding site that binds to coagulation factor IX and / or activated coagulation factor IX, wherein

[0100] a) The heavy chain variable region comprising CDR1 composed of the amino acid sequence of SEQ ID NO:12, CDR2 composed of the amino acid sequence of SEQ ID NO:13, and CDR3 composed of the amino acid sequence of SEQ ID NO:14; and

[0101] b) Light chain variable region comprising CDR1 consisting of the amino acid sequence of SEQ ID NO:18, CDR2 consisting of the amino acid sequence of SEQ ID NO:19, and CDR3 consisting of the amino acid sequence of SEQ ID NO:20.

[0102]

[102] An antibody binding to Fab, wherein Fab contains an antigen-binding site that binds to coagulation factor X and / or activated coagulation factor X, wherein

[0103] a) The heavy chain variable region comprising CDR1 composed of the amino acid sequence of SEQ ID NO:24, CDR2 composed of the amino acid sequence of SEQ ID NO:25, and CDR3 composed of the amino acid sequence of SEQ ID NO:26; and

[0104] b) Light chain variable region comprising CDR1 consisting of the amino acid sequence of SEQ ID NO:30, CDR2 consisting of the amino acid sequence of SEQ ID NO:31, and CDR3 consisting of the amino acid sequence of SEQ ID NO:32.

[0105]

[103] Nucleic acid, which encodes any one of

[101] to

[102] antibodies.

[0106]

[104] A vector in which the nucleic acid described in

[103] is inserted.

[0107]

[105] Cells containing the nucleic acid described in

[103] or the vector described in

[104] .

[0108]

[106] A method for producing antibodies, comprising the step of culturing the cells described in

[105] .

[0109] The effects of the invention

[0110] This invention provides antibodies that can be used to measure F.VIII activity and F.VIII inhibitor titers without being affected by the activity of substances with F.VIII functional substitution activity. Examples of substances with F.VIII functional substitution activity include bispecific antibodies binding to F.IX and / or F.IXa and FX and / or FXa. By using the antibodies provided by this invention, F.VIII activity and F.VIII inhibitor titers can be accurately measured even when substances with F.VIII functional substitution activity are present in the sample. Attached Figure Description

[0111] Figure 1 The results of a one-stage coagulation assay performed using IDA0288 and IDA0339 or rAQ8 and rAJ540 to neutralize the anti-F.IXa / FX bispecific antibody are shown. Detailed Implementation

[0112] The invention of this application relates to antibodies that neutralize substances having F.VIII functional substitution activity and nucleic acids encoding said antibodies. The antibodies of the present invention can be used to measure F.VIII activity and F.VIII inhibitor titers in a sample when measuring F.VIII reactivity in the presence of a substance having F.VIII functional substitution activity, without being affected by the activity of the substance having F.VIII functional substitution activity.

[0113] The nucleic acids in this invention include nucleic acids in the form of DNA and nucleic acids in the form of mRNA.

[0114] F.VIII Functional Replacement Activity

[0115] F.VIII is one of a series of molecules involved in blood clotting. When activated by thrombin or F.Xa, it exhibits cofactor activity and promotes the FX activation response via F.IXa.

[0116] In this invention, substances exhibiting F.VIII functional substitution activity can be renamed substances exhibiting F.VIII-like activity. In this invention, the phrase "functional substitution F.VIII" means promoting the activation of FX via F.IXa (promoting the generation of F.Xa via F.IXb). More specifically, in this invention, the phrase "functional substitution F.VIII" means recognizing F.IX and / or F.IXa, FX and / or F.Xa, and promoting the activation of FX via F.IXa (promoting the generation of F.IXa via F.IX). For example, the activity promoting F.Xa production can be assessed using a measurement system consisting of F.IXa, FX, synthetic substrate S-2222 (a synthetic substrate of F.Xa), and phospholipids. Such a measurement system demonstrates the correlation between disease severity and clinical symptoms in hemophilia A cases (Rosen S, Andersson M, Blomba). ·· ck M et al. Clinical applications of achromogenic substrate method for determination of F.VIII activity. ThrombHaemost 1985;54:811-23).

[0117] In this invention, a preferred embodiment of a substance having activity that substitutes for the function of F.VIII includes, for example, a bispecific antibody that binds to F.IX and / or F.IXa and FX and / or F.Xa. Such an antibody can be obtained according to the methods described, for example, in WO2005 / 035756, WO2006 / 109592, WO2012 / 067176, and WO2019 / 065795. The bispecific antibodies of this invention include those described in these documents.

[0118] Preferred bispecific antibodies include emecizumab (Q499-z121 / J327-z119 / L404-k), which is the bispecific antibody described in patent document (WO 2012 / 067176) (a bispecific antibody wherein the heavy chain consisting of the amino acid sequence of SEQ ID NO:9 is associated with the light chain of SEQ ID NO:10, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:11 is associated with the light chain of SEQ ID NO:10), hBS23 (Q153-G4k / J142-G4h / L180-k) (a bispecific antibody wherein the heavy chain consisting of the amino acid sequence of SEQ ID NO:36 is associated with the light chain of SEQ ID NO:38, and the heavy chain consisting of the amino acid sequence of SEQ ID NO:37 is associated with the light chain of SEQ ID NO:38), and any one of the following antibodies (a) to (t), which is described in patent document (WO 2012 / 067176). The bispecific antibody described in (2019 / 065795):

[0119] (a) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:83, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:88, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:100, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:111.

[0120] (b) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:84, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:89, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:100, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:111.

[0121] (c) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:85, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:90, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:101, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:112.

[0122] (d) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:85, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:91, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:101, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:112.

[0123] (e) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:84, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:89, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:102, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:113.

[0124] (f) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:84, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:89, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:103, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:114.

[0125] (g) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:84, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:89, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:101, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:112.

[0126] (h) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:86, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:92, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:101, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:112.

[0127] (i) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:86, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:93, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:101, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:112.

[0128] (j) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:86, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:93, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:104, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:115.

[0129] (k) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:86, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:94, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:104, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:115.

[0130] (l) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:86, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:94, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:105, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:116.

[0131] (m) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:86, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:95, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:104, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:115.

[0132] (n) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:86, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:95, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:105, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:116.

[0133] (o) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:87, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:96, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:106, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:117.

[0134] (p) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:86, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:97, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:107, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:118.

[0135] (q) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:87, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:98, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:106, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:117.

[0136] (r) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:87, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:98, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:108, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:119.

[0137] (s) a bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:87, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:96, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:109, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:120; and

[0138] (t) A bispecific antibody comprising a first antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:122, a first antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:99, a second antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO:110, and a second antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:121.

[0139] The bispecific antibodies (a) to (t) may further include:

[0140] (1) A first antibody heavy chain constant region containing the amino acid sequence of SEQ ID NO:139 and / or a second antibody light chain constant region containing the amino acid sequence of SEQ ID NO:140, and / or

[0141] (2) A second antibody heavy chain constant region containing the amino acid sequence of SEQ ID NO:141 and / or a second antibody light chain constant region containing the amino acid sequence of SEQ ID NO:142.

[0142] The preferred bispecific antibody of the present invention is, for example, any one of the antibodies (a1) to (t1) described below, which is the bispecific antibody described in patent document (WO 2019 / 065795). In the following antibodies, the heavy chain of the first antibody is associated with the light chain of the first antibody, and the heavy chain of the second antibody is associated with the light chain of the second antibody:

[0143] (a1) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:143, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:149, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:161, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:172.

[0144] (b1) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:144, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:150, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:161, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:172.

[0145] (c1) A bispecific antibody comprising a first antibody heavy chain containing the amino acid sequence of SEQ ID NO:145, a first antibody light chain containing the amino acid sequence of SEQ ID NO:151, a second antibody heavy chain containing the amino acid sequence of SEQ ID NO:162, and a second antibody light chain containing the amino acid sequence of SEQ ID NO:173.

[0146] (d1) A bispecific antibody comprising a first antibody heavy chain containing the amino acid sequence of SEQ ID NO:145, a first antibody light chain containing the amino acid sequence of SEQ ID NO:152, a second antibody heavy chain containing the amino acid sequence of SEQ ID NO:162, and a second antibody light chain containing the amino acid sequence of SEQ ID NO:173.

[0147] (e1) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:144, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:150, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:163, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:174.

[0148] (f1) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:144, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:150, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:164, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:175.

[0149] (g1) A bispecific antibody comprising a first antibody heavy chain containing the amino acid sequence of SEQ ID NO:144, a first antibody light chain containing the amino acid sequence of SEQ ID NO:150, a second antibody heavy chain containing the amino acid sequence of SEQ ID NO:162, and a second antibody light chain containing the amino acid sequence of SEQ ID NO:173.

[0150] (h1) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:146, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:153, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:162, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:173.

[0151] (i1) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:146, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:154, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:162, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:173.

[0152] (j1) A bispecific antibody comprising a first antibody heavy chain containing the amino acid sequence of SEQ ID NO:146, a first antibody light chain containing the amino acid sequence of SEQ ID NO:154, a second antibody heavy chain containing the amino acid sequence of SEQ ID NO:165, and a second antibody light chain containing the amino acid sequence of SEQ ID NO:176.

[0153] (k1) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:146, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:155, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:165, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:176.

[0154] (l1) A bispecific antibody comprising a first antibody heavy chain containing the amino acid sequence of SEQ ID NO:146, a first antibody light chain containing the amino acid sequence of SEQ ID NO:155, a second antibody heavy chain containing the amino acid sequence of SEQ ID NO:166, and a second antibody light chain containing the amino acid sequence of SEQ ID NO:177.

[0155] (m1) A bispecific antibody comprising a first antibody heavy chain containing the amino acid sequence of SEQ ID NO:146, a first antibody light chain containing the amino acid sequence of SEQ ID NO:156, a second antibody heavy chain containing the amino acid sequence of SEQ ID NO:165, and a second antibody light chain containing the amino acid sequence of SEQ ID NO:176.

[0156] (n1) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:146, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:156, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:166, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:177.

[0157] (o1) A bispecific antibody comprising a first antibody heavy chain containing the amino acid sequence of SEQ ID NO:147, a first antibody light chain containing the amino acid sequence of SEQ ID NO:157, a second antibody heavy chain containing the amino acid sequence of SEQ ID NO:167, and a second antibody light chain containing the amino acid sequence of SEQ ID NO:178.

[0158] (p1) A bispecific antibody comprising a first antibody heavy chain containing the amino acid sequence of SEQ ID NO:146, a first antibody light chain containing the amino acid sequence of SEQ ID NO:158, a second antibody heavy chain containing the amino acid sequence of SEQ ID NO:168, and a second antibody light chain containing the amino acid sequence of SEQ ID NO:179.

[0159] (q1) A bispecific antibody comprising a first antibody heavy chain comprising the amino acid sequence of SEQ ID NO:147, a first antibody light chain comprising the amino acid sequence of SEQ ID NO:159, a second antibody heavy chain comprising the amino acid sequence of SEQ ID NO:167, and a second antibody light chain comprising the amino acid sequence of SEQ ID NO:178.

[0160] (r1) A bispecific antibody comprising a first antibody heavy chain containing the amino acid sequence of SEQ ID NO:147, a first antibody light chain containing the amino acid sequence of SEQ ID NO:159, a second antibody heavy chain containing the amino acid sequence of SEQ ID NO:169, and a second antibody light chain containing the amino acid sequence of SEQ ID NO:180.

[0161] (s1) A bispecific antibody comprising a first antibody heavy chain containing the amino acid sequence of SEQ ID NO:147, a first antibody light chain containing the amino acid sequence of SEQ ID NO:157, a second antibody heavy chain containing the amino acid sequence of SEQ ID NO:170, and a second antibody light chain containing the amino acid sequence of SEQ ID NO:181; and

[0162] (t1) A bispecific antibody comprising a first antibody heavy chain containing the amino acid sequence of SEQ ID NO:148, a first antibody light chain containing the amino acid sequence of SEQ ID NO:160, a second antibody heavy chain containing the amino acid sequence of SEQ ID NO:171, and a second antibody light chain containing the amino acid sequence of SEQ ID NO:182.

[0163] neutralization

[0164] In this invention, "neutralization" in the context of a substance that neutralizes a substance with F.VIII functional substitution activity means, for example, completely or partially inhibiting the F.VIII functional substitution activity in the substance. For example, when the substance with F.VIII functional substitution activity is an antibody, complete or partial inhibition of the F.VIII functional substitution activity can be achieved by completely or partially inhibiting the binding of the antibody to the antigen, but this is not the only possibility.

[0165] Antibody

[0166] When the substance having F.VIII functional substitution activity is a bispecific antibody binding to F.IX and / or F.IXa and FX and / or F.Xa, examples of antibodies binding to the substance having F.VIII functional substitution activity include antibodies selected from the group consisting of: antibodies binding to a Fab containing an antigen-binding site for F.IX; antibodies binding to a Fab containing an antigen-binding site for F.IXa; antibodies binding to a Fab containing an antigen-binding site for FX; antibodies binding to a Fab containing an antigen-binding site for F.Xa; and bispecific antibodies binding to a Fab containing an antigen-binding site for F.IX and / or F.IXa and a Fab containing an antigen-binding site for FX and / or FXa. The above antibodies can be used alone or in various combinations, and they can be used as compositions or kits. For example, multiple antibodies binding to a Fab containing an antigen-binding site for one antigen can be used, such as multiple types of antibodies binding to a Fab containing an antigen-binding site for F.IX. For example, when the substance with F.VIII functional substitution activity is a bispecific antibody that binds to F.IX and / or F.IXa and FX and / or F.Xa, the antibody can be used in the following combinations:

[0167] (a) Antibodies that bind to Fab containing an antigen-binding site that binds to F.IX, and antibodies that bind to Fab containing an antigen-binding site that binds to FX.

[0168] (b) Antibodies that bind to Fab containing an antigen-binding site for binding F.IXa, and antibodies that bind to Fab containing an antigen-binding site for binding FX.

[0169] (c) Antibodies that bind to Fab containing an antigen-binding site for F.IX, and antibodies that bind to Fab containing an antigen-binding site for F.IXa; and

[0170] (d) Antibodies that bind to Fab containing an antigen-binding site for binding F.IX, antibodies that bind to Fab containing an antigen-binding site for binding FX, and antibodies that bind to Fab containing an antigen-binding site for binding F.IXa.

[0171] In other words, the present invention relates to compositions or kits comprising the neutralizing antibody combination described herein.

[0172] Examples of antibodies that bind to Fab containing antigen-binding sites for F.IX and / or F.IXa include the IDA0288 antibody. Nucleotide sequences of the variable regions and amino acid sequences predicted from them were analyzed using GENTYX Ver.9 (GENETYX CORPORATION).

[0173] The amino acid sequence and nucleic acid sequence of the heavy chain variable region of IDA0288 are represented by the following SEQ ID NO:

[0174] Amino acid sequence: SEQ ID NO:1; and

[0175] Nucleic acid sequence: SEQ ID NO:5.

[0176] The amino acid sequence and nucleic acid sequence of the light chain variable region of IDA0288 are represented by the following SEQ ID NO:

[0177] Amino acid sequence: SEQ ID NO:2; and

[0178] Nucleic acid sequence: SEQ ID NO:6.

[0179] The amino acid and nucleic acid sequences of the heavy chain CDR1 to 3 of IDA0288 are represented by the following SEQ ID NO:

[0180] CDR1 amino acid sequence: SEQ ID NO:12;

[0181] CDR2 amino acid sequence: SEQ ID NO:13;

[0182] CDR3 amino acid sequence: SEQ ID NO:14;

[0183] CDR1 nucleic acid sequence: SEQ ID NO:15;

[0184] CDR2 nucleic acid sequence: SEQ ID NO:16; and

[0185] CDR3 nucleic acid sequence: SEQ ID NO:17.

[0186] The amino acid and nucleic acid sequences of the light chain CDR1 to 3 of IDA0288 are represented by the following SEQ ID NO:

[0187] CDR1 amino acid sequence: SEQ ID NO:18;

[0188] CDR2 amino acid sequence: SEQ ID NO:19;

[0189] CDR3 amino acid sequence: SEQ ID NO:20;

[0190] CDR1 nucleic acid sequence: SEQ ID NO:21;

[0191] CDR2 nucleic acid sequence: SEQ ID NO:22; and

[0192] CDR3 nucleic acid sequence: SEQ ID NO:23.

[0193] The amino acid and nucleic acid sequences of the antibody heavy chain constant region of IDA0288 are represented by the following SEQ ID NO:

[0194] Amino acid sequence: SEQ ID NO:123; and

[0195] Nucleic acid sequence: SEQ ID NO:125.

[0196] The amino acid and nucleic acid sequences of the constant region of the antibody light chain of IDA0288 are represented by the following SEQ ID NO:

[0197] Amino acid sequence: SEQ ID NO:124; and

[0198] Nucleic acid sequence: SEQ ID NO:126.

[0199] The amino acid and nucleic acid sequences of the antibody heavy chain of IDA0288 are represented by the following SEQ ID NO:

[0200] Amino acid sequence: SEQ ID NO:131; and

[0201] Nucleic acid sequence: SEQ ID NO:133.

[0202] The amino acid and nucleic acid sequences of the antibody light chain of IDA0288 are represented by the following SEQ ID NO:

[0203] Amino acid sequence: SEQ ID NO:132; and

[0204] Nucleic acid sequence: SEQ ID NO:134.

[0205] Examples of antibodies that bind to Fab containing antigen-binding sites for FX and / or F.Xa include the IDA0339 antibody. Nucleotide sequences of the variable regions and amino acid sequences predicted from them were analyzed using GENTYX Ver.9 (GENETYX CORPORATION).

[0206] The amino acid sequence and nucleic acid sequence of the heavy chain variable region of IDA0339 are represented by the following SEQ ID NO:

[0207] Amino acid sequence: SEQ ID NO:3; and

[0208] Nucleic acid sequence: SEQ ID NO:7.

[0209] The amino acid sequence and nucleic acid sequence of the light chain variable region of IDA0339 are represented by the following SEQ ID NO:

[0210] Amino acid sequence: SEQ ID NO:4; and

[0211] Nucleic acid sequence: SEQ ID NO:8.

[0212] The amino acid and nucleic acid sequences of the heavy chain CDR1 to 3 of IDA0339 are represented by the following SEQ ID NO:

[0213] CDR1 amino acid sequence: SEQ ID NO:24;

[0214] CDR2 amino acid sequence: SEQ ID NO:25;

[0215] CDR3 amino acid sequence: SEQ ID NO:26;

[0216] CDR1 nucleic acid sequence: SEQ ID NO:27;

[0217] CDR2 nucleic acid sequence: SEQ ID NO:28; and

[0218] CDR3 nucleic acid sequence: SEQ ID NO:29.

[0219] The amino acid and nucleic acid sequences of the light chain CDR1 to 3 of IDA0339 are represented by the following SEQ ID NO:

[0220] CDR1 amino acid sequence: SEQ ID NO:30;

[0221] CDR2 amino acid sequence: SEQ ID NO:31;

[0222] CDR3 amino acid sequence: SEQ ID NO:32;

[0223] CDR1 nucleic acid sequence: SEQ ID NO:33;

[0224] CDR2 nucleic acid sequence: SEQ ID NO:34; and

[0225] CDR3 nucleic acid sequence: SEQ ID NO:35.

[0226] The amino acid and nucleic acid sequences of the antibody heavy chain constant region of IDA0339 are represented by the following SEQ ID NO:

[0227] Amino acid sequence: SEQ ID NO:127; and

[0228] Nucleic acid sequence: SEQ ID NO:129.

[0229] The amino acid and nucleic acid sequences of the constant region of the antibody light chain of IDA0339 are represented by the following SEQ ID NO:

[0230] Amino acid sequence: SEQ ID NO:128; and

[0231] Nucleic acid sequence: SEQ ID NO:130.

[0232] The amino acid and nucleic acid sequences of the antibody heavy chain of IDA0339 are represented by the following SEQ ID NO:

[0233] Amino acid sequence: SEQ ID NO:135; and

[0234] Nucleic acid sequence: SEQ ID NO:137.

[0235] The amino acid and nucleic acid sequences of the antibody light chain of IDA0288 are represented by the following SEQ ID NO:

[0236] Amino acid sequence: SEQ ID NO:136; and

[0237] Nucleic acid sequence: SEQ ID NO:138.

[0238] The term “antibody” is used in the broadest sense and can refer to monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies), antibody derivatives, and modified antibody products (Miller K et al. J Immunol. 2003, 170(9), 4854-61), provided they exhibit the desired biological activity. Antibodies can be mouse antibodies, human antibodies, humanized antibodies, chimeric antibodies, or antibodies derived from other species, or they can be synthetically produced antibodies. The antibodies disclosed herein 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 molecules. Immunoglobulins can be derived from any species (e.g., human, mouse, or rabbit). The terms “antibody,” “immunoglobulin,” and “immunoglobulin” are used interchangeably in a broad sense.

[0239] The term "antibody derivative" includes a portion of an antibody, preferably the variable region of the antibody, or at least the antigen-binding region of the antibody. Antibody derivatives include, for example, Fab, Fab', F(ab')2, Fv fragments, linear antibodies and single-chain antibodies (scFv), sc(Fv)2, Fab3, domain antibodies (dAb) (WO2004 / 058821, WO2003 / 002609), biantibodies, triplexes, tetraantibodies, small antibodies, and multispecific antibodies formed from antibody derivatives, but are not limited thereto. Here, "Fab" consists of a CH1 domain and a variable region of a single light chain and a single heavy chain. Furthermore, "Fv" is the smallest antibody derivative, including both the complete antigen recognition region and the antigen-binding region. Antibody derivatives can be, for example, fusions between IgG antibodies and Fc. For example, see Example 2 in the specification of U.S. Patent No. 5641870; 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; and Wu et al. Nat Biotechnol. 2007, 25(11), 1290-7.

[0240] Examples of modified antibody products may include antibodies linked to various molecules such as polyethylene glycol (PEG). The antibodies of the present invention include such modified antibody products. The substances to be linked are not limited to the modified antibody products of the present invention. To produce such modified antibody products, the obtained antibodies may be chemically modified. Such methods have been established in the art.

[0241] A "bispecific" antibody is an antibody that has variable regions that recognize different epitopes, and these regions are located within the same antibody molecule. A bispecific antibody can be an antibody that recognizes two or more different antigens or an antibody that recognizes two or more different epitopes on the same antigen. Bispecific antibodies include not only whole antibodies but also antibody derivatives. The antibodies of this invention also include bispecific antibodies. Here, anti-F.IXa / FX bispecific antibody and bispecific antibody binding to F.IXa and FX are used synonymously.

[0242] Methods for producing genetically engineered antibodies

[0243] Recombinant antibodies, produced using genetic engineering techniques, can be used as antibodies. Recombinant antibodies are obtained by cloning the DNA encoding the antibody from a hybridoma or antibody-producing cell, such as antibody-sensitized lymphocytes; inserting it into a vector; and then introducing the vector into a host (host cell) to produce antibodies.

[0244] Antibodies include human antibodies, mouse antibodies, and rat antibodies, and their sources are unrestricted. They can also be genetically modified antibodies, such as chimeric antibodies and humanized antibodies.

[0245] Methods for obtaining human antibodies are known. For example, transgenic animals carrying all human antibody genes can be immunized with target antigens to obtain target human antibodies (see international publications WO 93 / 12227, WO 92 / 03918, WO 94 / 02602, WO96 / 25585, WO 96 / 34096 and WO 96 / 33735).

[0246] Genetically modified antibodies can be produced using known methods. Specifically, for example, chimeric antibodies comprise the heavy and light chain variable regions of an immunized animal antibody and the heavy and light chain constant regions of a human antibody. Chimeric antibodies can be obtained by linking DNA encoding the variable region of an antibody from an immunized animal with DNA encoding the constant region of a human antibody, inserting this into an expression vector, and then introducing the expression vector into a host to produce antibodies.

[0247] Humanized antibodies are modified antibodies, also known as reconstructed human antibodies. Humanized antibodies are constructed by transferring the CDR of an antibody derived from an immunized animal to the complementarity-determining region of a human antibody. Conventional gene recombination techniques used for this purpose are known (see European Patent Application Publication No. EP 239400; International Publication No. WO 96 / 02576; Sato K et al., Cancer Research 1993, 53:851-856; International Publication No. WO 99 / 51743).

[0248] Bispecific antibodies are antibodies that are specific to two different antigens.

[0249] Although bispecific antibodies are not limited to IgG type antibodies, for example, IgG type bispecific antibodies can be secreted from heterozygous hybridomas (tetravalent hybridomas) produced by fusing two hybridomas that produce IgG antibodies (Milstein C. et al., Nature 1983, 305:537-540). They can also be secreted by introducing the light chain and heavy chain genes (a total of four types of genes) that constitute the two types of target IgG into the cell to co-express these genes.

[0250] In this context, by introducing appropriate amino acid substitutions into the CH3 region of the heavy chain, IgG with a heterogeneous combination of heavy chains can be preferentially secreted (Ridgway JB et al. Protein Engineering 1996, 9: 617-621; Merchant AM et al. Nature Biotechnology 1998, 16: 677-681; WO 2006 / 106905; Davis JH et al. Protein Eng Des Sel. 2010, 4: 195-202).

[0251] Regarding the light chain, since the diversity of variable regions in the light chain is lower than that in the heavy chain, it is desirable to obtain a common light chain capable of conferring binding ability to both heavy chains. The bispecific antibody of this invention can be an antibody containing a common light chain. By introducing the genes for the common light chain and both heavy chains into cells, bispecific IgG can be effectively expressed.

[0252] Epitope

[0253] The antibody used as an embodiment of the present invention to neutralize substances having F.VIII functional substitution activity includes an antibody that binds to an epitope overlapping with the epitope to which the antibody binds, preferably an antibody that binds to the same epitope.

[0254] Whether an antibody recognizes an epitope that overlaps with or is the same as an epitope recognized by another antibody can be confirmed by competition between the two antibodies for that epitope. Competition between antibodies can be assessed using competitive binding assays employing techniques such as enzyme-linked immunosorbent assay (ELISA), fluorescence energy transfer assay (FRET), and fluorescence microvolume assay (FMAT). The amount of antibody binding to the antigen is indirectly related to the binding ability of candidate competing antibodies (test antibodies) that competitively bind to the same or overlapping epitopes. In other words, as the amount or affinity of test antibodies targeting the same or overlapping epitopes increases, the amount of antibody binding to the antigen decreases, and the amount of test antibody binding to the antigen increases. Specifically, an appropriately labeled antibody and a test antibody are simultaneously added to the antigen, and then the binding antibody is detected using the label. The amount of antibody binding to the antigen can be easily determined by pre-labeling the antibody. There are no particular limitations on the labeling, and the labeling method is chosen based on the assay technique used. Specific examples of labeling methods include fluorescent labeling, radioactive labeling, and enzyme labeling.

[0255] In this article, "antibody that binds to overlapping epitopes" or "antibody that binds to the same / identical epitope" refers to antibody that reduces the amount of labeled antibody bound by 50% (IC50) compared to unlabeled antibody binding. 50The test antibody, typically at a concentration 100 times higher, preferably 80 times higher, more preferably 50 times higher, even more preferably 30 times higher, and still more preferably 10 times higher, can reduce the binding amount of the labeled antibody by at least 50%. The epitopes recognized by the antibody can be analyzed by methods known to those skilled in the art, such as Western blotting.

[0256] In the case of neutralizing antibodies against antibodies having antigen-binding sites that bind to F.IX and / or F.IXa, the antibodies that bind to epitopes that overlap or are identical to the epitopes bound to the neutralizing antibodies can be determined by measuring their binding activity to the anti-F.IX side of the antibody emecizumab (Q499-z121 / L404-k) and the QT15 antibody which is an anti-F.IX antibody.

[0257] In the case of neutralizing antibodies against antibodies having antigen-binding sites that bind to FX and / or F.Xa, the antibodies that bind to epitopes that overlap or are identical to the epitopes bound to the neutralizing antibodies can be determined by measuring their binding activity to the anti-F.IX side of the antibody emecizumab (J327-z119 / L404-k) and the JT13 antibody which is an anti-FX antibody.

[0258] In the compositions of the present invention containing antibodies, antibodies that bind to epitopes that overlap or are identical to the epitopes bound to the neutralizing antibodies of the present invention can be determined by measuring their binding to a mixed composition of emecizumab, QT15 antibody, and JT13 antibody.

[0259] Antibody production methods

[0260] The antibodies of this invention can be produced by methods known to those skilled in the art. Specifically, DNA encoding the target antibody is inserted into an expression vector. Insertion into the expression vector is performed such that expression is controlled by expression regulatory regions such as enhancers and promoters. Next, host cells are transformed using the expression vector to express the antibody. In this step, a suitable combination of host and expression vector can be used. The method for producing antibodies in this invention may include the step of culturing the aforementioned host cells. The host cells can be cultured by methods known to those skilled in the art.

[0261] Examples of vectors include the M13 series, pUC series, pBR322, pBluescript, and pCR-Script. In addition to these vectors, pGEM-T, pDIRECT, or pT7 can also be used for cDNA subcloning and excision.

[0262] In particular, expression vectors can be used for the purpose of preparing antibodies. For example, when the host is *E. coli*, such as JM109, DH5α, HB101, or XL1-Blue, it is essential that the expression vector has a promoter that allows for efficient expression in *E. coli*, such as the lacZ promoter (Ward et al., *Nature* (1989) 341, 544-546; and FASEB J (1992) 6, 2422-2427), the araB promoter (Better et al., *Science* (1988) 240, 1041-1043), or the T7 promoter. Examples of such vectors include the vectors described above, as well as pGEX-5X-1 (manufactured by Pharmacia), the “QIAexpress system” (manufactured by QIAGEN), pEGFP, and pET (in this case, the host is preferably BL21 expressing T7 RNA polymerase).

[0263] The vector may contain a signal sequence for peptide secretion. Signal sequences for peptide secretion known to those skilled in the art can be used, and in cases where produced in the periplasm of *E. coli*, for example, the pelB signal sequence can be used (Lei, SP et al., J. Bacteriol. (1987) 169, 4397). The vector can be transferred to host cells using, for example, calcium chloride methods or electroporation methods.

[0264] Besides *E. coli* expression vectors, examples of vectors used to generate the antibodies of the present invention include mammalian-derived expression vectors (e.g., pcDNA3 (manufactured by Invitrogen Corp.), pEGF-BOS (Nucleic Acids. Res. 1990, 18(17), p. 5322), pEF, and pCDM8), insect cell-derived expression vectors (e.g., the "Bac-to-BAC Baculovirus Expression System" (manufactured by GIBCO BRL) and 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., the "Pichia pastoris Expression Kit" (manufactured by Invitrogen Corp.), pNV11, and SP-Q01), and *Bacillus subtilis*. Expression vectors derived from subtilis (e.g., pPL608 and pKTH50).

[0265] For expression in animal cells such as CHO cells, COS cells, or NIH3T3 cells, the vector must essentially possess the promoter required 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 more preferably, it must possess a gene for screening transformed cells (e.g., a drug resistance gene that can serve as a marker against a drug) (neomycin, G418, etc.). Examples of vectors with this property include pMAM, pDR2, pBK-RSV, pBK-CMV, pOPRSV, and pOP13.

[0266] Exemplary methods for stably expressing genes and increasing intracellular gene copy number include transfecting CHO cells with a defective nucleic acid synthesis pathway using a vector (e.g., pCHOI) with the DHFR gene as its complement and using methotrexate (MTX) for gene amplification. Exemplary methods for transiently expressing genes include transforming COS cells expressing a gene for the SV40 T antigen on their chromosomes with cells containing a vector (pcD, etc.) with an SV40 origin of replication. Additionally, origins of replication derived from polyomaviruses, adenoviruses, bovine papillomaviruses (BPV), etc., can also be used. Expression vectors used to increase the number of gene copies in a host cell system may additionally contain selective markers such as aminoglycoside transferase (APH) genes, thymidine kinase (TK) genes, *E. coli* xanthine-guanine phosphoribosyltransferase (Ecogpt) genes, or dihydrofolate reductase (dhfr) genes.

[0267] This invention also provides vectors in which nucleic acids encoding the antibodies described herein have been inserted. As used herein, the term "vector" refers to a nucleic acid molecule capable of propagating another nucleic acid linked thereto. This term includes vectors as self-replicating nucleic acid structures, as well as vectors incorporated into the genome of a host cell into which they have been introduced. Certain vectors are capable of directing the expression of nucleic acids operatively linked to them. Such vectors are referred to herein as "expression vectors."

[0268] Furthermore, the present invention provides isolated nucleic acids encoding the antibodies of the present invention. Such nucleic acids may encode amino acid sequences comprising variable regions of the antibody light chain and / or variable regions of the antibody heavy chain (e.g., antibody light chain and / or heavy chain). The isolated nucleic acid encoding the antibody may be inserted into one or more vectors for further cloning and / or expression in host cells. Such nucleic acids can be readily isolated and sequenced using conventional procedures, e.g., by using oligonucleotide probes that specifically bind to genes encoding antibody heavy chains and / or light chains.

[0269] This invention also relates to cells comprising nucleic acids encoding antibodies of this specification or vectors containing such nucleic acids. In this document, “cell” means a cell into which a foreign nucleic acid has been introduced (including progeny of such cells). The cells of this invention include “transformers” and “transformed cells,” which include primary transformed cells and progeny derived therefrom, regardless of passage number. The nucleic acid content of progeny cells may not be exactly the same as that of parent cells, and may contain mutations. It also includes mutant progeny that have the same function or biological activity as those used in screening or selecting the original transformed cells. Here, cells include (e.g., cells that have been transformed with):

[0270] (1) A vector comprising an amino acid sequence encoding an amino acid sequence comprising a light chain variable region containing an antibody and / or an amino acid sequence comprising a heavy chain variable region containing an antibody, or

[0271] (2) A first vector containing a nucleic acid encoding an amino acid sequence of a light chain variable region containing an antibody, and a second vector containing a nucleic acid encoding an amino acid sequence of a heavy chain variable region containing an antibody.

[0272] In this invention, the host may be a eukaryotic cell (e.g., CHO cells or lymphocytes (e.g., Y0, NSO or SP20 cells)).

[0273] The antibodies of the present invention obtained by the methods described herein can be isolated from or outside host cells (culture medium, etc.) and purified into practically pure and homogeneous antibodies. Antibodies can be isolated and purified using methods conventionally used for antibody isolation and purification, and the type of method is not limited. For example, antibodies can be isolated and purified by appropriately selecting and combining column chromatography, filtration, ultrafiltration, salting out, solvent precipitation, solvent extraction, distillation, immunoprecipitation, SDS-polyacrylamide gel electrophoresis, isoelectric focusing, dialysis, recrystallization, etc.

[0274] Chromatographic methods include, for example, 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 chromatographic methods can be performed using liquid chromatography methods such as HPLC and FPLC. Columns used for affinity chromatography include protein A columns and protein G columns. Columns using protein A include, for example, HyperD, POROS, and Sepharose FF (GE Amersham Biosciences). This invention includes antibodies highly purified using these purification methods.

[0275] The obtained antibodies can be purified to homogenization. Antibody separation and purification can be performed using methods commonly used for protein separation and purification. For example, antibodies can be separated and purified by appropriate selection and combination of column chromatography techniques, such as affinity chromatography, filtration, ultrafiltration, salting out, dialysis, SDS-polyacrylamide gel electrophoresis, isoelectric focusing, etc., but are not limited to these (Antibodies: A Laboratory Manual. Ed Harlow and David Lane, Cold Spring Harbor Laboratory, 1988). Chromatographic columns used for affinity chromatography include, for example, protein A columns and protein G columns.

[0276] As described above, the neutralizing antibody of the present invention can be used in methods for measuring the reactivity of F.VIII in the presence of a substance having F.VIII functional substitution activity, such as methods for measuring F.VIII activity and F.VIII inhibitor titers. The method of the present invention for measuring F.VIII activity includes the step of contacting (1) below with (2) below. Otherwise, the method can be performed according to conventional methods for measuring F.VIII activity.

[0277] (1) Blood-derived samples containing substances with F.VIII functional replacement activity.

[0278] (2) Substances that neutralize substances with F.VIII functional substitution activity.

[0279] In this invention, examples of substances that neutralize substances with F.VIII functional substitution activity are preferably antibodies that neutralize substances with F.VIIII functional substitution activity, or more preferably neutralizing antibodies IDA0288, IDA0339, or the neutralizing antibodies described in this specification. In the method for measuring F.VIII activity according to this invention, the substance can be used alone or in combination of two or more types. Furthermore, in this invention, the aforementioned substance that neutralizes substances with F.VIII functional substitution activity can be in the form of a composition. This composition may contain a buffer, a substance commonly used to measure F.VIII reactivity, etc.

[0280] Methods for measuring F.VIII activity

[0281] As commonly used methods for measuring F.VIII activity, methods known to those skilled in the art can be used, and for example, a one-stage coagulation assay using factor VIII-deficient plasma (Sysmex, Kobe, Japan) (Casillas et al., (1971) Coagulation 4:107-11) based on coagulation time (aPTT measurement) can be used. For example, a one-stage coagulation assay is performed by mixing three solutions: 50 μL of 10-fold diluted test plasma, 50 μL of F.VIII-deficient plasma, and 50 μL of APTT reagent; incubating at 37°C for 5 minutes; and then measuring the coagulation time when the coagulation reaction is initiated by adding 50 μL of calcium solution. Alternatively, instead of test plasma, serially diluted samples of normal plasma (F.VIII activity in 10-fold diluted normal plasma is defined as 100%) are measured, and a calibration curve is generated by plotting F.VIII activity on the horizontal axis and coagulation time on the vertical axis. The clotting time of the test plasma is converted to F.VIII activity using a calibration curve, and the F.VIII activity in the test plasma is calculated. Here, unless otherwise stated, the phrase “measurement of F.VIII activity” is used as a phrase that may include “measurement of activated coagulation factor VIII (F.VIIIa) activity”.

[0282] In addition to methods such as one-stage coagulation assay, thrombin generation assay (TGA), rotational thromboelastography, F.VIII colorimetric assay, coagulation waveform analysis, and thrombin and activating factor X generation assay, which can be used to measure F.VIII activity, the method of the present invention for measuring F.VIII inhibitor titers includes the step of bringing (1) below into contact with (2) below. Otherwise, the method can be performed according to commonly used methods for measuring F.VIII inhibitor titers.

[0283] (1) Blood-derived samples containing substances with F.VIII functional alternative activity.

[0284] (2) Substances that neutralize substances with F.VIII functional substitution activity.

[0285] In this invention, the neutralizing antibody can be used at a concentration capable of neutralizing substances with F.VIII functional substitution activity. This concentration can be appropriately adjusted by those skilled in the art. Specific examples include, but are not limited to, 1 to 100 μg / mL, preferably 5 to 80 μg / mL, more preferably 10 to 60 μg / mL, and particularly preferably 20 to 40 μg / mL.

[0286] Methods for measuring F.VIII inhibitor titers

[0287] As a commonly used method for measuring F.VIII inhibitor titers, methods known to those skilled in the art can be used, for example, the Bethesda assay (Kasper et al., (1975) Thrombos Diath Haemorrh 34:869-872), ELISA, and the Nijmegen Bethesda assay (a Nijmegen-modified assay) (Verbruggen et al., (1995) Thromb Haemost 73:247-251). The Bethesda assay is performed, for example, by mixing equal volumes of normal plasma and test plasma to prepare a solution, incubating it at 37°C for two hours, and then measuring the residual factor VIII activity in normal plasma using a one-stage coagulation assay based on activated partial prothrombin time (APTT). The effect of inhibiting 50% of factor VIII activity in normal plasma is designated as 1 Bethesda (1 BU), therefore, F.VIII inhibitor titers are calculated in Bethesda units. When the titer of F.VIII inhibitor in the test plasma is high and the residual F.VIII activity is not in the range of 25% to 75%, the Bethesda units are recalculated using test plasma appropriately diluted with buffer, and then the value is multiplied by the dilution ratio to calculate the titer of F.VIII inhibitor in the test plasma.

[0288] F.VIII inhibitors

[0289] F.VIII inhibitors are alloantibodies against exogenous F.VIII, present in 20% to 30% of hemophilia A patients. A normal individual may later develop autoantibodies against F.VIII. Generally, the alloantibodies and autoantibodies of most F.VIII inhibitors act as anti-F.VIII neutralizing antibodies, reducing or eliminating F.VIII activity.

[0290] Sample acquisition methods

[0291] In this invention, the blood-derived sample is preferably a blood-derived sample collected from the test subject. Such blood-derived samples can be obtained from subjects receiving a substance with F.VIII alternative activity. For example, test subjects include patients with bleeding symptoms in any part of the body (patients with hemorrhagic disorders). Common bleeding sites include, but are not limited to, intra-articular, intramuscular, subcutaneous, intraoral, intracranial, digestive tract, and intranasal sites. Patients with hemorrhagic disorders are preferably those with hemorrhagic disorders caused by decreased or absent F.VIII activity and / or F.VIIIa activity. Patients with hemorrhagic disorders caused by decreased or absent F.VIII activity and / or F.VIIIa activity are patients with bleeding symptoms, examples of which include patients with a priori or a posteriori decrease or insufficiency of either or both of F.VIII activity and F.VIIIa activity. The reduced activity of F.VIII and F.VIIIa means that, compared with the activity of healthy individuals, these activities are preferably less than 40% (e.g., less than 40%, less than 30%, less than 20%, or less than 10%), more preferably less than 10% (e.g., less than 10%, less than 9%, less than 8%, less than 7%, or less than 6%), even more preferably less than 5% (e.g., less than 5%, less than 4%, less than 3%, or less than 2%), particularly preferably less than 1%, but not limited thereto.

[0292] More specifically, examples of such diseases include, but are not limited to, diseases selected from hemophilia (hemophilia A and hemophilia B), acquired hemophilia, and von Willebrand disease caused by a functional abnormality or deficiency of von Willebrand factor (vWF). Blood-derived samples include serum, plasma, or whole blood. In this invention, plasma samples are preferred. Methods for obtaining blood-derived samples from test subjects are well known to those skilled in the art.

[0293] Compositions and kits

[0294] The neutralizing antibodies of the present invention can be used to form compositions comprising buffers required for methods of measuring F.VIII reactivity, substances commonly used for measuring F.VIII reactivity, etc. Furthermore, the neutralizing antibodies of the present invention can be pre-packaged with various types of reagents, such as buffers required for methods of measuring F.VIII reactivity and substances commonly used for measuring F.VIII reactivity, and provided as kits. Examples of neutralizing antibodies constituting the compositions or kits of the present invention are preferably neutralizing antibodies IDA0288, IDA0339, and the neutralizing antibodies described herein. The compositions or kits of the present invention may include one or preferably two of these neutralizing antibodies. In addition to buffers, the compositions and kits of the present invention may include substances commonly used for measuring F.VIII reactivity, plasma samples isolated from individuals with normal F.VIII and F.IX activity in their blood, substances with F.VIII substitution activity, and any substances that can be used for measuring F.VIII activity, or any substances that can be used for measuring F.VIII inhibitor titers. Furthermore, depending on the mode of use of the kit, the various types of reagents included in the kit may be in powder or liquid form. Furthermore, they may be stored in suitable containers and used as appropriate.

[0295] For example, by using the method utilizing the antibody of the present invention, the severity of disease in a patient receiving a substance with F.VIII functional replacement activity can be diagnosed. The responsiveness to F.VIII can be measured using the method utilizing the antibody of the present invention, and the severity of the patient and / or inhibitor titer can be diagnosed / assessed based on the measurement results. The diagnostic and assessment methods can be performed using methods known to those skilled in the art. Those skilled in the art can determine a treatment strategy for the patient based on the diagnosis and assessment. The present invention may include the steps of determining the dosage of the substance with F.VIII functional replacement activity according to the determined treatment strategy, and the steps of administering the substance with F.VIII functional replacement activity.

[0296] By using the method employing the antibodies of the present invention, for example, the pharmacological activity of substances and / or formulations having F.VIII functional replacement activity can be monitored in patients receiving such substances and / or formulations. Monitoring can be performed using methods known to those skilled in the art.

[0297] Kits containing the antibodies of this invention can, for example, be used to diagnose the severity of illness in patients receiving substances with F.VIII functional replacement activity. Reactivity to F.VIII can be measured using kits containing the antibodies of this invention, and the severity of the patient and / or inhibitor titers can be diagnosed / assessed based on the measurement results. Diagnostic and assessment methods can be performed using methods known to those skilled in the art.

[0298] The kit containing the antibody of this invention can be used, for example, as a kit for monitoring the pharmacological activity of F.VIII formulations in patients receiving substances with F.VIII functional replacement activity and F.VIII formulations. Monitoring can be performed using methods known to those skilled in the art.

[0299] Patients who are subjects using the antibodies of the present invention or the kits containing the antibodies of the present invention are, for example, patients with hemophilia A, patients with acquired hemophilia A, patients with von Willebrand disease, and patients with hemophilia A who have inhibitors against F.VIII and / or F.VIIIa.

[0300] When used herein, an implementation scheme indicated by the expression "comprising..." includes an implementation scheme indicated by the expression "consistently composed of..." and an implementation scheme indicated by the expression "composed of...".

[0301] All patents and references explicitly cited in this article are incorporated herein by reference in their entirety.

[0302] The present invention will be further illustrated by the following embodiments, but should not be construed as being limited thereto.

[0303] Example

[0304] [Example 1] Generation of bispecific antibodies against emecizumab and anti-F.IXa / FX, variable region sequencing, and expression vector.

[0305] QT15 F(ab')2 or JT13 F(ab'2) was prepared by methods known to those skilled in the art and three New Zealand white rabbits (Kitayama Labes Co., Ltd.) were immunized four times. Details of the anti-F.IX antibody QT15 and the anti-FX antibody JT13 are shown in Table 1.

[0306] [Table 1]

[0307]

[0308] One week after final immunization, peripheral blood mononuclear cells and spleen cells were recovered. Cells bound to either the QT15 whole antibody or the JT13 whole antibody were concentrated using MACS. Next, cells possessing either the QT15 whole antibody or the JT13 whole antibody were selected using a cell sorter (FACS aria III, BD) with PE-labeled anti-rabbit IgG antibody (Southern Biotech). Using antibodies secreted from the culture supernatant of these B cells, B cells secreting antibodies that bind only to the variable region of either the QT15 whole antibody or the JT13 whole antibody and the variable region of emecizumab, but not the constant region, were selected. The variable region sequence obtained from the selected B cells by RT-PCR was inserted into an expression vector containing a known rabbit IgG constant region sequence (heavy chain: IgG / SEQ ID NO:123; light chain: Igκ / SEQ ID NO:124). Using the obtained plasmids, antibodies (named IDA0288) binding to the variable regions of QT15 Whole and emecizumab but not to the constant regions and JT13 Whole were prepared using methods known to those skilled in the art, and 2) antibodies binding to the variable regions of JT13 Whole and emecizumab but not to the constant regions and QT15 Whole. The nucleotide sequences encoding the regions of IDA0288 and IDA0339 were identified by DNA sequencing.

[0309] Heavy chain variable region of IDA0288;

[0310] Amino acid sequence: SEQ ID NO:1

[0311] Nucleic acid sequence: SEQ ID NO:5

[0312] CDR1 amino acid sequence: SEQ ID NO:12

[0313] CDR2 amino acid sequence: SEQ ID NO:13

[0314] CDR3 amino acid sequence: SEQ ID NO:14

[0315] CDR1 nucleic acid sequence: SEQ ID NO:15

[0316] CDR2 nucleic acid sequence: SEQ ID NO:16

[0317] CDR3 nucleic acid sequence: SEQ ID NO:17

[0318] The light chain variable region of IDA0288;

[0319] Amino acid sequence: SEQ ID NO:2

[0320] Nucleic acid sequence: SEQ ID NO:6

[0321] CDR1 amino acid sequence: SEQ ID NO:18

[0322] CDR2 amino acid sequence: SEQ ID NO:19

[0323] CDR3 amino acid sequence: SEQ ID NO:20

[0324] CDR1 nucleic acid sequence: SEQ ID NO:21

[0325] CDR2 nucleic acid sequence: SEQ ID NO:22

[0326] CDR3 nucleic acid sequence: SEQ ID NO:23

[0327] Heavy chain variable region of IDA0339;

[0328] Amino acid sequence: SEQ ID NO:3

[0329] Nucleic acid sequence: SEQ ID NO:7

[0330] CDR1 amino acid sequence: SEQ ID NO:24

[0331] CDR2 amino acid sequence: SEQ ID NO:25

[0332] CDR3 amino acid sequence: SEQ ID NO:26

[0333] CDR1 nucleic acid sequence: SEQ ID NO:27

[0334] CDR2 nucleic acid sequence: SEQ ID NO:28

[0335] CDR3 nucleic acid sequence: SEQ ID NO:29

[0336] The light chain variable region of IDA0339;

[0337] Amino acid sequence: SEQ ID NO:4

[0338] Nucleic acid sequence: SEQ ID NO:8

[0339] CDR1 amino acid sequence: SEQ ID NO:30

[0340] CDR2 amino acid sequence: SEQ ID NO:31

[0341] CDR3 amino acid sequence: SEQ ID NO:32

[0342] CDR1 nucleic acid sequence: SEQ ID NO:33

[0343] CDR2 nucleic acid sequence: SEQ ID NO:34

[0344] CDR3 nucleic acid sequence: SEQ ID NO:35

[0345] [Example 2] A one-stage coagulation assay was performed using IDA0288 and IDA0339 or rAQ8 and rAJ540 to neutralize the anti-F.IXa / FX bispecific antibody.

[0346] The expression clone plasmids prepared and obtained in Example 1 were introduced into Expi293 cells, cultured on a large scale, and purified with ProA to produce IDA0288 and IDA0339 antibodies.

[0347] The IDA0288, IDA0339, rAQ8 (heavy chain variable region: SEQ ID NO: 79; light chain variable region: SEQ ID NO: 80) and rAJ540 (heavy chain variable region: SEQ ID NO: 81; light chain variable region: SEQ ID NO: 82) described in the examples of WO2016 / 047656 were diluted with TBS to 300 μg / mL, and then equal volumes of IDA0288 and IDA0339 or rAQ8 and rAJ540 were mixed to generate an anti-antibody solution.

[0348] Anti-F.IXa / FX bispecific antibodies (emecizumab, #1 to #6) were prepared using standard methods. The amino acid sequences of these antibodies are summarized in Tables 2-1 and 2-2. Each anti-F.IXa / FX bispecific antibody (emecizumab, #1 to #6) was stepwise diluted to 12.5 μg / mL with F.VIII-deficient plasma (Siemens) to generate antibody solutions. 120 μL of anti-antibody solution and 30 μL of antibody solution were mixed according to the combinations shown in Table 3 to prepare the measurement sample solutions, and the mixtures were allowed to stand at room temperature for 5 minutes.

[0349] Mix 50 μL of the measurement sample solution with 50 μL of Thrombocheck APTT-SLA (Sysmex) and incubate at 37 °C for 190 seconds. After incubation, add 50 μL of 0.02 M calcium chloride solution (Sysmex) to initiate clotting, and measure the clotting time using a CS-2000i (Sysmx). Details of the combination of anti-F.IXa / FX bispecific antibody and measurement sample are shown in Table 3 below.

[0350] [Table 2-1]

[0351]

[0352] [Table 2-2]

[0353]

[0354] [Table 2-3]

[0355]

[0356] [Table 3]

[0357]

[0358] result

[0359] The results of two measurements and calculation of the mean clotting time are as follows: Figure 1 As shown. In the group without added anti-antibody solutions, each anti-F.IXa / FX bispecific antibody shortened the clotting time. In the group with added anti-antibodies IDA0288 / IDA0339, the clotting time was partially shortened by #1 and #2, but the clotting time with the addition of emecizumab and other anti-F.IXa / FX bispecific antibodies was the same as in the group without added anti-F.IXa / FX bispecific antibodies. The activities of emecizumab and anti-F.IXa / FX bispecific antibodies, rather than the activities of #1 and #2, were completely neutralized. On the other hand, in the group with added anti-antibody rAQ8 / rAJ540, the clotting time due to the addition of emecizumab was similar to that in the group without added anti-F.IXa / FX bispecific antibodies. The clotting time was partially shortened by the addition of other anti-F.IXa / FX bispecific antibodies, and the activities of these other anti-F.IXa / FX bispecific antibodies were not completely neutralized.

[0360] Industrial applicability

[0361] This invention provides antibodies for measuring F.VIII reactivity in the presence of bispecific antibodies with F.VIII functional substitution activity, such as methods for measuring F.VIII activity or F.VIII inhibitor titers. Methods using the antibodies of this invention enable accurate measurement of F.VIII reactivity in patients during treatment with bispecific antibodies for bleeding disorders such as hemophilia. sequence list <110> Chugai Pharmaceutical Co., Ltd. <120> Antibodies that neutralize substances with factor VIII (F.VIII) functional replacement activity <130> C1-A2009P <150> JP 2020-089570 <151> 2020-05-22 <160> 182 <170> PatentIn version 3.5 <210> 1 <211> 118 <212> PRT <213> European rabbit (Oryctolagus cuniculus) <400> 1 Arg Glu Gln Leu Glu Glu Ser Gly Gly Asp Leu Val Lys Pro Glu Gly 1 5 10 15 Ser Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Ser 20 25 30 Tyr Trp Val Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Cys Ile Asp Thr Gly Ser Gly Asn Thr Ala Tyr Ala Ser Trp 50 55 60 Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr 65 70 75 80 Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Gly Tyr Val Val Ala His Phe Asn Leu Trp Gly Pro Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 2 <211> 111 <212> PRT <213> European rabbit (Oryctolagus cuniculus) <400> 2 Ala Asp Val Val Met Thr Gln Thr Pro Ala Ser Val Ser Glu Pro Val 1 5 10 15 Gly Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Asp Ile Glu Arg 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu 35 40 45 Ile Asp Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Lys 50 55 60 Gly Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Ala Leu Glu 65 70 75 80 Cys Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Tyr Tyr Ala Ile Ser 85 90 95 Thr Tyr Gly Val Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110 <210> 3 <211> 118 <212> PRT <213> European rabbit (Oryctolagus cuniculus) <400> 3 Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Asp 20 25 30 Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly 35 40 45 Tyr Ile Thr Val Asn Gly Val Thr Tyr Tyr Ala Asn Trp Ala Lys Gly 50 55 60 Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Ser 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Asp Gln 85 90 95 Tyr Ile Asn Asn Gly Gly Ala Glu Phe Asn Ile Trp Gly Pro Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 4 <211> 110 <212> PRT <213> Oryctolagus cuniculus <400> 4 Ala Tyr Asp Met Thr Gln Thr Pro Ser Phe Val Glu Ala Ala Val Gly 1 5 10 15 Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45 Tyr Gln Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly 50 55 60 Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys 65 70 75 80 Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ser Tyr Gly Asp 85 90 95 Val Asp Asn Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110 <210> 5 <211> 354 <212> DNA <213> Oryctolagus cuniculus <400> 5 cgggagcaac tggaggagtc cgggggagac ctggtcaagc ctgagggatc cctgacactc 60 acctgcacag cctctggatt ctccttcagt agcagctact gggtgtgctg ggtccgccag 120 gctccaggga aggggctgga gtggatcgga tgcattgata ctggtagtgg taacactgcc 180 tacgcgagct gggcgaaagg ccgattcacc atctccaaga cctcgtcgac cacggtgact 240 ctgcaaatga ccagtctgac agccgcggac acggccacct atttctgtgc gagaggttat 300 gttgttgctc actttaactt gtggggccca ggcaccctgg tcaccgtctc ctcc 354 <210> 6 <211> 333 <212> DNA <213> Oryctolagus cuniculus <400> 6 gccgatgttg tgatgaccca gactccagcc tccgtgtctg aacctgtggg aggcacagtc 60 accatcaagt gccaggccag tgaggacatt gaaaggtatt tagcctggta tcagcagaaa 120 ccagggcagc ctcccaagct cctgatcgat gatgcatccg atctggcatc tggggtccca 180 tcgcggttca aaggcagtgg atctgggaca gaatacactc tcaccatcag cgccctggag 240 tgtgccgatg ctgccactta ctactgtcaa agctattatg ctattagtac ttatggtgtt 300 gctttcggcg gagggaccga ggtggtggtc aaa 333 <210> 7 <211> 354 <212> DNA <213> Oryctolagus cuniculus <400> 7 cagtcggtgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60 tgcacagtct ctggattctc cctcagcagc tacgacatga gctgggtccg ccaggctcca 120 ggaaaggggc tggagtacat cggatacatt actgttaatg gtgtcacata ctacgcgaac 180 tgggcgaaag gccgattcac catctccaaa acctcgacca cggtggatct gaaaatctcc 240 agtccgacaa ccgaggacac ggccacctat ttctgtgcca gagatcaata tattaataat 300 ggtggtgctg aatttaacat ctggggccca ggcaccctgg tcaccgtctc ctcc 354 <210> 8 <211> 330 <212> DNA <213> Oryctolagus cuniculus <400> 8 gcctatgata tgacccagac tccatccttc gtggaggcag ctgtgggagg cacagtcacc 60 atcaagtgcc aggccagtga gagcattagc agttggttat cctggtatca gcagaaacca 120 gggcagcctc ccaagctcct gatctaccag gcatccactt tggcatctgg ggtctcatcg 180 cggttcaaag gcagtggatc tgggacacag ttcactctca ccatcagcga cctggagtgt 240 gccgatgctg ccacttacta ttgtcaacag ggttatagtt atggtgatgt tgataatgct 300 ttcggcggag ggaccgaggt ggtggtcaaa 330 <210> 9 <211> 448 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 9 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr 20 25 30 Asp Ile Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Thr Gly Arg Glu Tyr Gly Gly Gly Trp Tyr Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 130 135 140 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 145 150 155 160 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190 Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val 195 200 205 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 210 215 220 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 260 265 270 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Gln Lys Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 <210> 10 <211> 214 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 10 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Arg Asn Ile Glu Arg Gln 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Gln Ala Ser Arg Lys Glu Ser Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Arg Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Asp Pro Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 11 <211> 444 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 11 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Asn 20 25 30 Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Ser Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asp Arg Val Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Glu Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Glu Ser Leu Ser Leu Ser Pro 435 440 <210> 12 <211> 6 <212> PRT <213> Oryctolagus cuniculus <400> 12 Ser Ser Tyr Trp Val Cys 1 5 <210> 13 <211> 17 <212> PRT <213> Oryctolagus cuniculus <400> 13 Cys Ile Asp Thr Gly Ser Gly Asn Thr Ala Tyr Ala Ser Trp Ala Lys 1 5 10 15 Gly <210> 14 <211> 9 <212> PRT <213> European rabbit (Oryctolagus cuniculus) <400> 14 Gly Tyr Val Val Ala His Phe Asn Leu 1 5 <210> 15 <211> 18 <212> DNA <213> European rabbit (Oryctolagus cuniculus) <400> 15 agcagctact gggtgtgc 18 <210> 16 <211> 51 <212> DNA <213> European rabbit (Oryctolagus cuniculus) <400> 16 tgcattgata ctggtagtgg taacactgcc tacgcgagct gggcgaaagg c 51 <210> 17 <211> 27 <212> DNA <213> European rabbit (Oryctolagus cuniculus) <400> 17 ggttatgttg ttgctcactt taacttg 27 <210> 18 <211> 11 <212> PRT <213> European rabbit (Oryctolagus cuniculus) <400> 18 Gln Ala Ser Glu Asp Ile Glu Arg Tyr Leu Ala 1 5 10 <210> 19 <211> 7 <212> PRT <213> European rabbit (Oryctolagus cuniculus) <400> 19 Asp Ala Ser Asp Leu Ala Ser 1 5 <210> 20 <211> 12 <212> PRT <213> European rabbit (Oryctolagus cuniculus) <400> 20 Gln Ser Tyr Tyr Ala Ile Ser Thr Tyr Gly Val Ala 1 5 10 <210> 21 <211> 33 <212> DNA <213> European rabbit (Oryctolagus cuniculus) <400> 21 caggccagtg aggacattga aaggtattta gcc 33 <210> 22 <211> 21 <212> DNA <213> European rabbit (Oryctolagus cuniculus) <400> 22 gatgcatccg atctggcatc t 21 <210> 23 <211> 36 <212> DNA <213> European rabbit (Oryctolagus cuniculus) <400> 23 caaagctatt atgctattag tacttatggt gttgct 36 <210> 24 <211> 5 <212> PRT <213> European rabbit (Oryctolagus cuniculus) <400> 24 Ser Tyr Asp Met Ser 1 5 <210> 25 <211> 16 <212> PRT <213> European rabbit (Oryctolagus cuniculus) <400> 25 Tyr Ile Thr Val Asn Gly Val Thr Tyr Tyr Ala Asn Trp Ala Lys Gly 1 5 10 15 <210> 26 <211> 13 <212> PRT <213> European rabbit (Oryctolagus cuniculus) <400> 26 Asp Gln Tyr Ile Asn Asn Gly Gly Ala Glu Phe Asn Ile 1 5 10 <210> 27 <211> 15 <212> DNA <213> European rabbit (Oryctolagus cuniculus) <400> 27 agctacgaca tgagc 15 <210> 28 <211> 48 <212> DNA <213> European rabbit (Oryctolagus cuniculus) <400> 28 tacattactg ttaatggtgt cacatactac gcgaactggg cgaaaggc 48 <210> 29 <211> 39 <212> DNA <213> European rabbit (Oryctolagus cuniculus) <400> 29 gatcaatata ttaataatgg tggtgctgaa tttaacatc 39 <210> 30 <211> 11 <212> PRT <213> Oryctolagus cuniculus <400> 30 Gln Ala Ser Glu Ser Ile Ser Ser Trp Leu Ser 1 5 10 <210> 31 <211> 7 <212> PRT <213> Oryctolagus cuniculus <400> 31 Gln Ala Ser Thr Leu Ala Ser 1 5 <210> 32 <211> 12 <212> PRT <213> Oryctolagus cuniculus <400> 32 Gln Gln Gly Tyr Ser Tyr Gly Asp Val Asp Asn Ala 1 5 10 <210> 33 <211> 33 <212> DNA <213> Oryctolagus cuniculus <400> 33 caggccagtg agagcattag cagttggtta tcc 33 <210> 34 <211> 21 <212> DNA <213> Oryctolagus cuniculus <400> 34 caggcatcca ctttggcatc t 21 <210> 35 <211> 36 <212> DNA <213> Oryctolagus cuniculus <400> 35 caacagggtt atagttatgg tgatgttgat aatgct 36 <210> 36 <211> 448 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 36 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr 20 25 30 Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ser Ile Ser Pro Ser Gly Gly Ser Thr Tyr Tyr Arg Arg Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Arg Ala Gly His Asn Tyr Gly Ala Gly Trp Tyr Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 130 135 140 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 145 150 155 160 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 195 200 205 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 210 215 220 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 260 265 270 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 340 345 350 Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 435 440 445 <210> 37 <211> 444 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 37 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Asn 20 25 30 Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Ser Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asp Arg Val Thr Met Thr Ile Asp Lys Ser Thr Gly Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ser Tyr Gly Tyr Tyr His Asp Glu Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Cys Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Val Ser Arg Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 435 440 <210> 38 <211> 214 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 38 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Arg Asn Ile Glu Arg Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Arg Lys Glu Ser Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Arg Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Leu Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Pro Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 39 <211> 122 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 39 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr 20 25 30 Asp Ile Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Thr Gly Arg Glu Glu Gly Gly Trp Ile Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 40 <211> 325 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 40 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Lys Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro 100 105 110 Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 145 150 155 160 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 165 170 175 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 180 185 190 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 210 215 220 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Lys Glu Met Thr Lys 225 230 235 240 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 260 265 270 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 290 295 300 Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr Arg Lys Glu 305 310 315 320 Leu Ser Leu Ser Pro 325 <210> 41 <211> 107 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 41 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Ser Val Arg Arg Glu 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala 65 70 75 80 Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Pro Gly 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 42 <211> 107 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 42 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Glu Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Glu Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> 43 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Artificially Synthesized Sequence <400> 43 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gln Asn 20 25 30 Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Val Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asp Arg Leu Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Val Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 44 <211> 325 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 44 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Glu Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Glu Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro 100 105 110 Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 145 150 155 160 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 165 170 175 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 180 185 190 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 210 215 220 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys 225 230 235 240 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 260 265 270 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 290 295 300 Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr Arg Glu Glu 305 310 315 320 Leu Ser Leu Ser Pro 325 <210> 45 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Artificially synthesized sequence <400> 45 Ser Tyr Val Leu Thr Gln Pro Val Ser Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Glu Gln Ile Gly Ser Lys Glu Val 20 25 30 His Trp Tyr His Gln Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Glu Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Tyr Thr 85 90 95 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val 100 105 <210> 46 <211> 106 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 46 Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser 1 5 10 15 Glu Glu Leu Gln Ala Asn Lys Ala Lys Leu Val Cys Leu Ile Ser Asp 20 25 30 Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro 35 40 45 Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn 50 55 60 Lys Tyr Ala Ala Ser Ser Tyr Leu Lys Leu Thr Pro Glu Gln Trp Lys 65 70 75 80 Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val 85 90 95 Glu Lys Thr Val Ala Pro Thr Glu Cys Ser 100 105 <210> 47 <211> 123 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 47 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr 20 25 30 Asp Ile Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Thr Gly Arg Glu Tyr Gly Gly Gly Trp Tyr Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 48 <211> 325 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized sequence <400> 48 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro 100 105 110 Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 145 150 155 160 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 165 170 175 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 180 185 190 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 210 215 220 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Lys Glu Met Thr Lys 225 230 235 240 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 260 265 270 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 290 295 300 Cys Ser Val Met His Glu Ala Leu His Asn Arg Tyr Thr Gln Lys Ser 305 310 315 320 Leu Ser Leu Ser Pro 325 <210> 49 <211> 107 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 49 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Arg Asn Ile Glu Arg Gln 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Gln Ala Ser Arg Lys Glu Ser Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Arg Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Asp Pro Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 50 <211> 107 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 50 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> 51 <211> 325 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 51 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro 100 105 110 Glu Phe Arg Arg Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 145 150 155 160 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 165 170 175 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 180 185 190 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 210 215 220 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Lys Glu Met Thr Lys 225 230 235 240 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 260 265 270 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 290 295 300 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 305 310 315 320 Leu Ser Leu Ser Pro 325 <210> 52 <211> 106 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 52 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Lys Arg Pro Leu Thr 85 90 95 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 53 <211> 107 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 53 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> 54 <211> 106 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 54 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Arg Arg Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Lys Ser Pro Leu Thr 85 90 95 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 55 <211> 122 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 55 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr 20 25 30 Asp Ile Gln Trp Val Arg Glu Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Thr Gly Arg Glu Glu Gly Gly Trp Ile Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 56 <211> 325 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 56 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Lys Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro 100 105 110 Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 145 150 155 160 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 165 170 175 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 180 185 190 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 210 215 220 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Lys Glu Met Thr Lys 225 230 235 240 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 260 265 270 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 290 295 300 Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr Arg Lys Glu 305 310 315 320 Leu Ser Leu Ser Pro 325 <210> 57 <211> 107 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 57 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Ser Val Arg Arg Glu 20 25 30 Leu Ala Trp Tyr Gln Lys Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Met Ala Val Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Pro Gly 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 58 <211> 107 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 58 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Glu Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Glu Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> 59 <211> 122 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 59 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr 20 25 30 Asp Ile Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Thr Gly Arg Glu Glu Gly Gly Trp Ile Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 60 <211> 107 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 60 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Ser Val Arg Arg Glu 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Met Ala Val Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Pro Gly 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 61 <211> 107 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 61 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Ser Val Arg Arg Glu 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala 65 70 75 80 Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Pro Gly 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 62 <211> 107 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 62 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Ser Val Arg Arg Glu 20 25 30 Leu Ala Trp Tyr Gln Lys Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala 65 70 75 80 Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Pro Gly 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 63 <211> 119 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 63 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Asn 20 25 30 Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Ser Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asp Arg Val Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Glu Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 64 <211> 325 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 64 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro 100 105 110 Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 145 150 155 160 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 165 170 175 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 180 185 190 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 210 215 220 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys 225 230 235 240 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 260 265 270 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 290 295 300 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Glu Ser 305 310 315 320 Leu Ser Leu Ser Pro 325 <210> 65 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Artificially synthesized sequences <400> 65 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Arg Asn Ile Glu Arg Gln 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Gln Ala Ser Arg Lys Glu Ser Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Arg Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Asp Pro Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 66 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Artificially synthesized sequences <400> 66 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> 67 <211> 325 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 67 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro 100 105 110 Glu Phe Arg Arg Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 145 150 155 160 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 165 170 175 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 180 185 190 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 210 215 220 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys 225 230 235 240 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 260 265 270 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 290 295 300 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Glu Ser 305 310 315 320 Leu Ser Leu Ser Pro 325 <210> 68 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Artificially synthesized sequences <400> 68 Ser Tyr Val Leu Thr Gln Pro Val Ser Val Ser Val Ala Arg Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Asn His Ile Gly Asp Lys His Val 20 25 30 His Trp Tyr His Gln Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Gln Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Ala Val 85 90 95 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val 100 105 <210> 69 <211> 106 <212> PRT <213> Artificial sequence <220> <223> Artificially synthesized sequences <400> 69 Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser 1 5 10 15 Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp 20 25 30 Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro 35 40 45 Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn 50 55 60 Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys 65 70 75 80 Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val 85 90 95 Glu Lys Thr Val Ala Pro Thr Glu Cys Ser 100 105 <210> 70 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 70 Ser Tyr Val Leu Thr Gln Pro Val Ser Val Ser Val Ala Arg Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Asn His Ile Gly Asp Lys His Val 20 25 30 His Trp Tyr His Gln Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Gln Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Tyr Thr 85 90 95 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val 100 105 <210> 71 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 71 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gln Asn 20 25 30 Asn Met Asp Trp Val Arg Lys Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Val Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asp Arg Leu Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Val Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 72 <211> 325 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 72 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Glu Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Glu Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro 100 105 110 Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 145 150 155 160 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 165 170 175 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 180 185 190 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 210 215 220 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys 225 230 235 240 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 260 265 270 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 290 295 300 Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr Arg Glu Glu 305 310 315 320 Leu Ser Leu Ser Pro 325 <210> 73 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 73 Ser Tyr Val Leu Thr Gln Pro Val Ser Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Glu Gln Ile Gly Ser Lys Glu Val 20 25 30 His Trp Tyr His Glu Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Glu Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Tyr Thr 85 90 95 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val 100 105 <210> 74 <211> 106 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 74 Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser 1 5 10 15 Glu Glu Leu Gln Ala Asn Lys Ala Lys Leu Val Cys Leu Ile Ser Asp 20 25 30 Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro 35 40 45 Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn 50 55 60 Lys Tyr Ala Ala Ser Ser Tyr Leu Lys Leu Thr Pro Glu Gln Trp Lys 65 70 75 80 Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val 85 90 95 Glu Lys Thr Val Ala Pro Thr Glu Cys Ser 100 105 <210> 75 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Artificial Synthesized Sequence <400> 75 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gln Asn 20 25 30 Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Val Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asp Arg Leu Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Val Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 76 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Artificial synthesized sequence <400> 76 Ser Tyr Val Leu Thr Gln Pro Val Ser Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Glu Gln Ile Gly Ser Lys Glu Val 20 25 30 His Trp Tyr His Gln Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Glu Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Tyr Thr 85 90 95 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val 100 105 <210> 77 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Artificial synthesis <400> 77 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gln Asn 20 25 30 Asn Met Asp Trp Val Arg Lys Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Val Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asp Arg Leu Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Glu Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 78 <211> 107 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 78 Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Glu Gln Ile Gly Ser Lys Glu Val 20 25 30 His Trp Tyr His Glu Arg Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Glu Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Tyr Thr 85 90 95 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val 100 105 <210> 79 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> AQ8 VH <400> 79 Glu Val Asn Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Met Ser Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Ala Leu Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Ala Leu Arg Ala Glu Asp Ser Ala Thr Tyr 85 90 95 Tyr Cys Ala Arg Asp Ser Tyr Tyr Ser Tyr Asp Gly Tyr Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 80 <211> 107 <212> PRT <213> artificial sequence <220> <223> AQ8 VL <400> 80 Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ala Ala Ser Val Gly 1 5 10 15 Glu Thr Ile Thr Ile Thr Cys Gln Ala Ser Glu Asn Ile Tyr Phe Ser 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Ile 35 40 45 Tyr Asn Thr Asp Ser Leu Lys Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Gln Tyr Ser Met Lys Ile Asn Ser Met Gln Pro 65 70 75 80 Glu Asp Thr Ala Thr Tyr Phe Cys Arg Gln Ser Tyr Asp Phe Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 81 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> AJ540 VH <400> 81 Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ala Met His Trp Val Lys Gln Val Pro Gly Lys Gly Leu Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Lys Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Gly Arg Phe Val Phe Ser Leu Glu Ala Ser Ala Ser Thr Ala Asn 65 70 75 80 Leu Gln Ile Ser Asn Leu Lys Asn Glu Asp Thr Ala Asn Val Phe Cys 85 90 95 Ala Arg Glu Gly Gly Gly Tyr Tyr Trp Tyr Phe Asp Phe Trp Gly Pro 100 105 110 Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 82 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> AJ540 VL <400> 82 Asp Ile Val Met Thr Gln Ser Pro Thr Ser Met Ser Ile Ser Val Gly 1 5 10 15 Asp Arg Val Thr Met Asn Cys Lys Ala Asn Gln Asn Val Asp Phe Asn 20 25 30 Val Asp Trp Tyr Gln Gln Lys Thr Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Lys Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Asn Met Gln Ala 65 70 75 80 Glu Asp Leu Ala Val Tyr Tyr Cys Met Gln Ser Asn Ser Phe Pro Leu 85 90 95 Thr Phe Gly Ser Gly Thr Asn Leu Glu Ile Lys 100 105 <210> 83 <211> 123 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 83 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr 20 25 30 Asp Ile Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Thr Gly Arg Glu Tyr Asp Gly Gly Trp Tyr Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 84 <211> 123 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 84 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr 20 25 30 Asp Ala Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Thr Gly Ser Glu Asp Gly Ala Gly Trp Tyr Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 85 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 85 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr 20 25 30 Asp Ile Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Thr Gly Arg Glu Asp Gly Gly Trp His Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 86 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Artificially synthesized sequences <400> 86 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr 20 25 30 Asp Ile Gln Trp Val Arg Glu Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Tyr Arg Arg Glu Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Thr Gly Arg Glu Glu Gly Gly Trp Ile Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 87 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Artificially synthesized sequences <400> 87 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr 20 25 30 Asp Ile Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Thr Gly Arg Glu Glu Gly Gly Trp Ile Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 88 <211> 106 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 88 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Arg Arg Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Lys Ser Pro Leu Thr 85 90 95 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 89 <211> 106 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 89 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Thr Gln Ser Val Arg Arg Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Arg Ser Pro Leu Thr 85 90 95 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 90 <211> 106 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 90 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Thr Gln Ser Val Arg Arg Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Arg Ser Pro Leu Thr 85 90 95 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 91 <211> 106 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 91 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Ser Val Arg Arg Glu 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Leu Thr 85 90 95 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 92 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Artificially synthesized sequences <400> 92 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Ser Val Arg Arg Glu 20 25 30 Leu Ala Trp Tyr Gln Lys Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Met Ala Val Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Pro Gly 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 93 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Artificially synthesized sequences <400> 93 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Ser Val Arg Arg Glu 20 25 30 Leu Ala Trp Tyr Gln Lys Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Met Ala Val Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Pro Gly 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 94 <211> 107 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 94 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Thr Arg Ser Val Arg Arg Asp 20 25 30 Leu Ala Trp Tyr Gln Lys Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Arg Arg Glu Thr Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Pro Gly 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 95 <211> 107 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 95 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Ser Val Arg Arg Glu 20 25 30 Leu Ala Trp Tyr Gln Lys Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Pro Gly 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 96 <211> 107 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 96 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Ser Val Arg Arg Glu 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Met Ala Val Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Pro Gly 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 97 <211> 107 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 97 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Ser Val Arg Arg Glu 20 25 30 Leu Ala Trp Tyr Gln Lys Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala 65 70 75 80 Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Pro Gly 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 98 <211> 107 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 98 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Ser Val Arg Arg Glu 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala 65 70 75 80 Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Pro Gly 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 99 <211> 107 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 99 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Thr Arg Ser Val Arg Arg Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Arg Arg Glu Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala 65 70 75 80 Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Pro Gly 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 100 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 100 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Asn 20 25 30 Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ser Asn Thr Arg Ser Gly Thr Ser Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asp Arg Val Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Glu Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 101 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 101 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn 20 25 30 Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Val Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asn Arg Val Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Val Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 102 <211> 119 <212> PRT <213> Artificial sequence <220> Artificially synthesized sequence <400> 102 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Asn 20 25 30 Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Arg Val Ile Ser Asn Glu Glu Phe 50 55 60 Gln Asp Arg Val Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Glu Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 103 <211> 119 <212> PRT <213> Artificial Sequence <220> Artificially synthesized sequence <400> 103 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gln Asn 20 25 30 Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Val Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Gln Arg Val Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Val Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 104 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 104 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gln Asn 20 25 30 Asn Met Asp Trp Val Arg Lys Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Val Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asp Arg Leu Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Val Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 105 <211> 119 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 105 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Glu Phe Thr His Asn 20 25 30 Asn Met Asp Trp Val Arg Lys Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Arg Ser Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asp Arg Val Ile Met Thr Val Asp Ile Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Val Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 106 <211> 119 <212> PRT <213> Artificial sequence <220> <223> Artificially synthesized sequences <400> 106 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gln Asn 20 25 30 Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Val Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asp Arg Leu Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Val Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 107 <211> 119 <212> PRT <213> Artificial sequence <220> <223> Artificially synthesized sequences <400> 107 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gln Asn 20 25 30 Asn Met Asp Trp Val Arg Lys Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Val Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asp Arg Leu Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Glu Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 108 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 108 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gln Asn 20 25 30 Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Val Ile Tyr Asn Glu Lys Phe 50 55 60 Gln Asp Arg Val Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Glu Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Val Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 109 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 109 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Glu Phe Thr His Asn 20 25 30 Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Arg Ser Ile Tyr Asn Arg Glu Phe 50 55 60 Gln Asp Arg Val Ile Met Thr Val Asp Ile Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Glu Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 110 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 110 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gln Asn 20 25 30 Asn Met Asp Trp Val Arg Lys Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Val Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asp Arg Leu Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Glu Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Glu Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 111 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Artificial synthesized sequence <400> 111 Ser Tyr Val Leu Thr Gln Pro Val Ser Val Ser Val Ala Arg Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Asn His Ile Gly Asp Lys His Val 20 25 30 His Trp Tyr His Gln Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Gln Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Tyr Thr 85 90 95 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val 100 105 <210> 112 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 112 Ser Tyr Val Leu Thr Gln Pro Val Ser Val Ser Val Ala Arg Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Asn His Ile Gly Asp Lys His Val 20 25 30 His Trp Tyr His Gln Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Gln Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Gln Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Tyr Thr 85 90 95 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val 100 105 <210> 113 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 113 Ser Tyr Val Leu Thr Gln Pro Val Ser Val Ser Val Ala Arg Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Thr Gly Asn His Ile Ser Asp Lys His Val 20 25 30 His Trp Tyr His Gln Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Gln Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Gln Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Asp Tyr Thr 85 90 95 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val 100 105 <210> 114 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> Artificial synthesis <400> 114 Ser Tyr Val Leu Thr Gln Pro Val Ser Val Ser Val Ala Arg Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Asn Gln Ile Ser Gln Lys Gln Val 20 25 30 His Trp Tyr His Gln Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Gln Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ala Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Val Thr Val Val 100 105 <210> 115 <211> 107 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 115 Ser Tyr Val Leu Thr Gln Pro Val Ser Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Glu Gln Ile Gly Ser Lys Glu Val 20 25 30 His Trp Tyr His Glu Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Glu Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Tyr Thr 85 90 95 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val 100 105 <210> 116 <211> 106 <212> PRT <213> Artificial sequence <220> <223> Artificially synthesized sequence <400> 116 Ser Tyr Val Leu Thr Gln Pro Val Ser Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Asn Gln Ile Gly Ser Arg Glu Val 20 25 30 His Trp Tyr His Glu Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Glu Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Ala Ser Asp Ala Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Val Thr Val Val 100 105 <210> 117 <211> 107 <212> PRT <213> Artificial Sequence <220> Artificially synthesized sequence <400> 117 Ser Tyr Val Leu Thr Gln Pro Val Ser Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Glu Gln Ile Gly Ser Lys Glu Val 20 25 30 His Trp Tyr His Gln Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Glu Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Tyr Thr 85 90 95 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val 100 105 <210> 118 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 118 Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Glu Gln Ile Gly Ser Lys Glu Val 20 25 30 His Trp Tyr His Glu Arg Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Glu Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Tyr Thr 85 90 95 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val 100 105 <210> 119 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Artificially synthesized sequences <400> 119 Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Glu Gln Ile Gly Ser Lys Glu Val 20 25 30 His Trp Tyr His Gln Arg Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Glu Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Tyr Thr 85 90 95 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val 100 105 <210> 120 <211> 106 <212> PRT <213> Artificial sequence <220> <223> Artificially synthesized sequences <400> 120 Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Asn Gln Ile Gly Glu Lys Glu Val 20 25 30 His Trp Tyr His Gln Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Glu Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Ala Ser Asp Ala Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Val Thr Val Val 100 105 <210> 121 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 121 Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Glu Gln Ile Gly Ser Lys Glu Val 20 25 30 His Trp Tyr His Glu Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Glu Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Tyr Thr 85 90 95 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val 100 105 <210> 122 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 122 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Ile Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Thr Asp Arg Glu Asp His Gly Trp Ile Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 123 <211> 323 <212> PRT <213> European rabbit (Oryctolagus cuniculus) <400> 123 Gly Gln Pro Lys Ala Pro Ser Val Phe Pro Leu Ala Pro Cys Cys Gly 1 5 10 15 Asp Thr Pro Ser Ser Thr Val Thr Leu Gly Cys Leu Val Lys Gly Tyr 20 25 30 Leu Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Thr Leu Thr Asn 35 40 45 Gly Val Arg Thr Phe Pro Ser Val Arg Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Ser Val Thr Ser Ser Ser Gln Pro Val Thr Cys 65 70 75 80 Asn Val Ala His Pro Ala Thr Asn Thr Lys Val Asp Lys Thr Val Ala 85 90 95 Pro Ser Thr Cys Ser Lys Pro Thr Cys Pro Pro Pro Glu Leu Leu Gly 100 105 110 Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 115 120 125 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln 130 135 140 Asp Asp Pro Glu Val Gln Phe Thr Trp Tyr Ile Asn Asn Glu Gln Val 145 150 155 160 Arg Thr Ala Arg Pro Pro Leu Arg Glu Gln Gln Phe Asn Ser Thr Ile 165 170 175 Arg Val Val Ser Thr Leu Pro Ile Thr His Gln Asp Trp Leu Arg Gly 180 185 190 Lys Glu Phe Lys Cys Lys Val His Asn Lys Ala Leu Pro Ala Pro Ile 195 200 205 Glu Lys Thr Ile Ser Lys Ala Arg Gly Gln Pro Leu Glu Pro Lys Val 210 215 220 Tyr Thr Met Gly Pro Pro Arg Glu Glu Leu Ser Ser Arg Ser Val Ser 225 230 235 240 Leu Thr Cys Met Ile Asn Gly Phe Tyr Pro Ser Asp Ile Ser Val Glu 245 250 255 Trp Glu Lys Asn Gly Lys Ala Glu Asp Asn Tyr Lys Thr Thr Pro Ala 260 265 270 Val Leu Asp Ser Asp Gly Ser Tyr Phe Leu Tyr Asn Lys Leu Ser Val 275 280 285 Pro Thr Ser Glu Trp Gln Arg Gly Asp Val Phe Thr Cys Ser Val Met 290 295 300 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Ile Ser Arg Ser 305 310 315 320 Pro Gly Lys <210> 124 <211> 104 <212> PRT <213> Oryctolagus cuniculus <400> 124 Gly Asp Pro Val Ala Pro Thr Val Leu Ile Phe Pro Pro Ala Ala Asp 1 5 10 15 Gln Val Ala Thr Gly Thr Val Thr Ile Val Cys Val Ala Asn Lys Tyr 20 25 30 Phe Pro Asp Val Thr Val Thr Trp Glu Val Asp Gly Thr Thr Gln Thr 35 40 45 Thr Gly Ile Glu Asn Ser Lys Thr Pro Gln Asn Ser Ala Asp Cys Thr 50 55 60 Tyr Asn Leu Ser Ser Thr Leu Thr Leu Thr Ser Thr Gln Tyr Asn Ser 65 70 75 80 His Lys Glu Tyr Thr Cys Lys Val Thr Gln Gly Thr Thr Ser Val Val 85 90 95 Gln Ser Phe Asn Arg Gly Asp Cys 100 <210> 125 <211> 969 <212> DNA <213> Oryctolagus cuniculus <400> 125 gggcaaccta aggctccatc agtcttccca ctggccccct gctgcgggga cacacccagc 60 tccacggtga ccctgggctg cctggtcaaa ggctacctcc cggagccagt gaccgtgacc 120 tggaactcgg gcaccctcac caatggggta cgcaccttcc cgtccgtccg gcagtcctca 180 ggcctctact cgctgagcag cgtggtgagc gtgacctcaa gcagccagcc cgtcacctgc 240 aacgtggccc acccagccac caacaccaaa gtggacaaga ccgttgcacc ctcgacatgc 300 agcaagccca cgtgcccacc ccctgaactc ctggggggac cgtctgtctt catcttcccc 360 ccaaaaccca aggacaccct catgatctca cgcacccccg aggtcacatg cgtggtggtg 420 gacgtgagcc aggatgaccc cgaggtgcag ttcacatggt acataaacaa cgagcaggtg 480 cgcaccgccc ggccgccgct acgggagcag cagttcaaca gcacgatccg cgtggtcagc 540 accctcccca tcacgcacca ggactggctg aggggcaagg agttcaagtg caaagtccac 600 aacaaggcac tcccggcccc catcgagaaa accatctcca aagccagagg gcagcccctg 660 gagccgaagg tctacaccat gggccctccc cgggaggagc tgagcagcag gtcggtcagc 720 ctgacctgca tgatcaacgg cttctaccct tccgacatct cggtggagtg ggagaagaac 780 gggaaggcag aggacaacta caagaccacg ccggccgtgc tggacagcga cggctcctac 840 ttcctctaca acaagctctc agtgcccacg agtgagtggc agcggggcga cgtcttcacc 900 tgctccgtga tgcacgaggc cttgcacaac cactacacgc agaagtccat ctcccgctct 960 ccgggtaaa 969 <210> 126 <211> 312 <212> DNA <213> *Oryctolagus cuniculus* <400> 126 ggtgatccag ttgcacctac tgtcctcatc ttcccaccag ctgctgatca ggtggcaact 60 ggaacagtca ccatcgtgtg tgtggcgaat aaatactttc ccgatgtcac cgtcacctgg 120 gaggtggatg gcaccaccca aacaactggc atcgagaaca gtaaaacacc gcagaattct 180 gcagattgta cctacaacct cagcagcact ctgacactga ccagcacaca gtacaacagc 240 cacaaagagt acacctgcaa ggtgacccag ggcacgacct cagtcgtcca gagcttcaat 300 aggggtgact gt 312 <210> 127 <211> 323 <212> PRT <213> European rabbit (Oryctolagus cuniculus) <400> 127 Gly Gln Pro Lys Ala Pro Ser Val Phe Pro Leu Ala Pro Cys Cys Gly 1 5 10 15 Asp Thr Pro Ser Ser Thr Val Thr Leu Gly Cys Leu Val Lys Gly Tyr 20 25 30 Leu Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Thr Leu Thr Asn 35 40 45 Gly Val Arg Thr Phe Pro Ser Val Arg Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Ser Val Thr Ser Ser Ser Gln Pro Val Thr Cys 65 70 75 80 Asn Val Ala His Pro Ala Thr Asn Thr Lys Val Asp Lys Thr Val Ala 85 90 95 Pro Ser Thr Cys Ser Lys Pro Thr Cys Pro Pro Pro Glu Leu Leu Gly 100 105 110 Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 115 120 125 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln 130 135 140 Asp Asp Pro Glu Val Gln Phe Thr Trp Tyr Ile Asn Asn Glu Gln Val 145 150 155 160 Arg Thr Ala Arg Pro Pro Leu Arg Glu Gln Gln Phe Asn Ser Thr Ile 165 170 175 Arg Val Val Ser Thr Leu Pro Ile Thr His Gln Asp Trp Leu Arg Gly 180 185 190 Lys Glu Phe Lys Cys Lys Val His Asn Lys Ala Leu Pro Ala Pro Ile 195 200 205 Glu Lys Thr Ile Ser Lys Ala Arg Gly Gln Pro Leu Glu Pro Lys Val 210 215 220 Tyr Thr Met Gly Pro Pro Arg Glu Glu Leu Ser Ser Arg Ser Val Ser 225 230 235 240 Leu Thr Cys Met Ile Asn Gly Phe Tyr Pro Ser Asp Ile Ser Val Glu 245 250 255 Trp Glu Lys Asn Gly Lys Ala Glu Asp Asn Tyr Lys Thr Thr Pro Ala 260 265 270 Val Leu Asp Ser Asp Gly Ser Tyr Phe Leu Tyr Asn Lys Leu Ser Val 275 280 285 Pro Thr Ser Glu Trp Gln Arg Gly Asp Val Phe Thr Cys Ser Val Met 290 295 300 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Ile Ser Arg Ser 305 310 315 320 Pro Gly Lys <210> 128 <211> 104 <212> PRT <213> Oryctolagus cuniculus <400> 128 Gly Asp Pro Val Ala Pro Thr Val Leu Ile Phe Pro Pro Ala Ala Asp 1 5 10 15 Gln Val Ala Thr Gly Thr Val Thr Ile Val Cys Val Ala Asn Lys Tyr 20 25 30 Phe Pro Asp Val Thr Val Thr Trp Glu Val Asp Gly Thr Thr Gln Thr 35 40 45 Thr Gly Ile Glu Asn Ser Lys Thr Pro Gln Asn Ser Ala Asp Cys Thr 50 55 60 Tyr Asn Leu Ser Ser Thr Leu Thr Leu Thr Ser Thr Gln Tyr Asn Ser 65 70 75 80 His Lys Glu Tyr Thr Cys Lys Val Thr Gln Gly Thr Thr Ser Val Val 85 90 95 Gln Ser Phe Asn Arg Gly Asp Cys 100 <210> 129 <211> 969 <212> DNA <213> Oryctolagus cuniculus <400> 129 gggcaaccta aggctccatc agtcttccca ctggccccct gctgcgggga cacacccagc 60 tccacggtga ccctgggctg cctggtcaaa ggctacctcc cggagccagt gaccgtgacc 120 tggaactcgg gcaccctcac caatggggta cgcaccttcc cgtccgtccg gcagtcctca 180 ggcctctact cgctgagcag cgtggtgagc gtgacctcaa gcagccagcc cgtcacctgc 240 aacgtggccc acccagccac caacaccaaa gtggacaaga ccgttgcacc ctcgacatgc 300 agcaagccca cgtgcccacc ccctgaactc ctggggggac cgtctgtctt catcttcccc 360 420. ccaaaaccca aggacaccct catgatctca cgcacccccg aggtcacatg cgtggtggtg gacgtgagcc aggatgaccc cgaggtgcag ttcacatggt acataaacaa cgagcaggtg 480 cgcaccgccc ggccgccgct acgggagcag cagttcaaca gcacgatccg cgtggtcagc 540 accctcccca tcacgcacca ggactggctg aggggcaagg agttcaagtg caaagtccac 660. aacaaggcac tcccggcccc catcgagaa accatctcca aagccagagg gcagcccctg gagccgaagg tctacaccat gggccctccc cgggaggagc tgagcagcag gtcggtcagc 720 ctgacctgca tgatcaacgg cttctaccct tccgacatct cggtggagtg ggagaagaac 780 gggaaggcag aggacaacta caagaccacg ccggccgtgc tggacagcga cggctcctac 840 ttcctctaca acaagctctc agtgcccacg agtcgggcg cgtcttcacc 900 tgctccgtga tgcacgaggc cttgcacaac cactacacgc agaagtccat ctcccgctct ccgggtaaa <210> 130 <211> 312 <212> DNA <213> Oryctolagus cuniculus <400> 130 ggtgatccag ttgcacctac tgtcctcatc ttcccaccag ctgctgatca ggtggcaact 60 ggaacagtca ccatcgtgtg tgtggcgaat aaatactttc ccgatgtcac cgtcacctgg 120 gaggtggatg gcaccaccca aacaactggc atcgagaaca gtaaaacacc gcagaattct 180 gcagattgta cctacaacct cagcagcact ctgacactga ccagcacaca gtacaacagc 240 cacaaagagt acacctgcaa ggtgacccag ggcacgacct cagtcgtcca gagcttcaat 300 aggggtgact gt 312 <210> 131 <211> 441 <212> PRT <213> Oryctolagus cuniculus <400> 131 Arg Glu Gln Leu Glu Glu Ser Gly Gly Asp Leu Val Lys Pro Glu Gly 1 5 10 15 Ser Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Ser 20 25 30 Tyr Trp Val Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Cys Ile Asp Thr Gly Ser Gly Asn Thr Ala Tyr Ala Ser Trp 50 55 60 Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr 65 70 75 80 Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Gly Tyr Val Val Ala His Phe Asn Leu Trp Gly Pro Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gln Pro Lys Ala Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Cys Cys Gly Asp Thr Pro Ser Ser Thr Val Thr Leu Gly 130 135 140 Cys Leu Val Lys Gly Tyr Leu Pro Glu Pro Val Thr Val Thr Trp Asn 145 150 155 160 Ser Gly Thr Leu Thr Asn Gly Val Arg Thr Phe Pro Ser Val Arg Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Ser Val Thr Ser Ser 180 185 190 Ser Gln Pro Val Thr Cys Asn Val Ala His Pro Ala Thr Asn Thr Lys 195 200 205 Val Asp Lys Thr Val Ala Pro Ser Thr Cys Ser Lys Pro Thr Cys Pro 210 215 220 Pro Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys 225 230 235 240 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 245 250 255 Val Val Asp Val Ser Gln Asp Asp Pro Glu Val Gln Phe Thr Trp Tyr 260 265 270 Ile Asn Asn Glu Gln Val Arg Thr Ala Arg Pro Pro Leu Arg Glu Gln 275 280 285 Gln Phe Asn Ser Thr Ile Arg Val Val Ser Thr Leu Pro Ile Thr His 290 295 300 Gln Asp Trp Leu Arg Gly Lys Glu Phe Lys Cys Lys Val His Asn Lys 305 310 315 320 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Arg Gly Gln 325 330 335 Pro Leu Glu Pro Lys Val Tyr Thr Met Gly Pro Pro Arg Glu Glu Leu 340 345 350 Ser Ser Arg Ser Val Ser Leu Thr Cys Met Ile Asn Gly Phe Tyr Pro 355 360 365 Ser Asp Ile Ser Val Glu Trp Glu Lys Asn Gly Lys Ala Glu Asp Asn 370 375 380 Tyr Lys Thr Thr Pro Ala Val Leu Asp Ser Asp Gly Ser Tyr Phe Leu 385 390 395 400 Tyr Asn Lys Leu Ser Val Pro Thr Ser Glu Trp Gln Arg Gly Asp Val 405 410 415 Phe Thr Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 420 425 430 Lys Ser Ile Ser Arg Ser Pro Gly Lys 435 440 <210> 132 <211> 215 <212> PRT <213> Oryctolagus cuniculus <400> 132 Ala Asp Val Val Met Thr Gln Thr Pro Ala Ser Val Ser Glu Pro Val 1 5 10 15 Gly Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Asp Ile Glu Arg 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu 35 40 45 Ile Asp Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Lys 50 55 60 Gly Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Ala Leu Glu 65 70 75 80 Cys Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Tyr Tyr Ala Ile Ser 85 90 95 Thr Tyr Gly Val Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys Gly 100 105 110 Asp Pro Val Ala Pro Thr Val Leu Ile Phe Pro Pro Ala Ala Asp Gln 115 120 125 Val Ala Thr Gly Thr Val Thr Ile Val Cys Val Ala Asn Lys Tyr Phe 130 135 140 Pro Asp Val Thr Val Thr Trp Glu Val Asp Gly Thr Thr Gln Thr Thr 145 150 155 160 Gly Ile Glu Asn Ser Lys Thr Pro Gln Asn Ser Ala Asp Cys Thr Tyr 165 170 175 Asn Leu Ser Ser Thr Leu Thr Leu Thr Ser Thr Gln Tyr Asn Ser His 180 185 190 Lys Glu Tyr Thr Cys Lys Val Thr Gln Gly Thr Thr Ser Val Val Gln 195 200 205 Ser Phe Asn Arg Gly Asp Cys 210 215 <210> 133 <211> 1326 <212> DNA <213> European rabbit (Oryctolagus cuniculus) <400> 133 cgggagcaac tggaggagtc cgggggagac ctggtcaagc ctgagggatc cctgacactc 60 acctgcacag cctctggatt ctccttcagt agcagctact gggtgtgctg ggtccgccag 120 gctccaggga aggggctgga gtggatcgga tgcattgata ctggtagtgg taacactgcc 180 tacgcgagct gggcgaaagg ccgattcacc atctccaaga cctcgtcgac cacggtgact 240 ctgcaaatga ccagtctgac agccgcggac acggccacct atttctgtgc gagaggttat 300 gttgttgctc actttaactt gtggggccca ggcaccctgg tcaccgtctc ctccgggcaa 360 cctaaggctc catcagtctt cccactggcc ccctgctgcg gggacacacc cagctccacg 420 gtgaccctgg gctgcctggt caaaggctac ctcccggagc cagtgaccgt gacctggaac 480 tcgggcaccc tcaccaatgg ggtacgcacc ttcccgtccg tccggcagtc ctcaggcctc 540 tactcgctga gcagcgtggt gagcgtgacc tcaagcagcc agcccgtcac ctgcaacgtg 600 gcccacccag ccaccaacac caaagtggac aagaccgttg caccctcgac atgcagcaag 660 cccacgtgcc caccccctga actcctgggg ggaccgtctg tcttcatctt ccccccaaaaa 720 cccaaggaca ccctcatgat ctcacgcacc cccgaggtca catgcgtggt ggtggacgtg 780 agccaggatg accccgaggt gcagttcaca tggtacataa acaacgagca ggtgcgcacc 840 gcccggccgga cgctacggga gcagcagttc aacagcacga tccgcgtggt cagcaccctc 900 cccatcacgc accaggactg gctgaggggc aaggagttca agtgcaaagt ccacaacaag 960 gcactcccgg cccccatcga gaaaaccatc tccaaagcca gagggcagcc cctggagccg 1020 aaggtctaca ccatgggccc tccccgggag gagctgagca gcaggtcggt cagcctgacc 1080 tgcatgatca acggcttcta cccttccgac atctcggtgg agtgggagaa gaacgggaag 1140 gcagaggaca actacaagac cacgccggcc gtgctggaca gcgacggctc ctacttctc 1200 tacaacaagc tctcagtgcc cacgagtgag tggcagcggg gcgacgtctt cacctgctcc 1260 gtgatgcacg aggccttgca caaccactac acgcagaagt ccatctcccg ctctccgggt 1320 aatga 1326 <210> 134 <211> 648 <212> DNA <213> European rabbit (Oryctolagus cuniculus) <400> 134 gccgatgttg tgatgaccca gactccagcc tccgtgtctg aacctgtggg aggcacagtc 60 accatcaagt gccaggccag tgaggacatt gaaaggtatt tagcctggta tcagcagaaa 120 ccagggcagc ctcccaagct cctgatcgat gatgcatccg atctggcatc tggggtccca 180 tcgcggttca aaggcagtgg atctgggaca gaatacactc tcaccatcag cgccctggag 240 tgtgccgatg ctgccactta ctactgtcaa agctattatg ctattagtac ttatggtgtt 300 gctttcggcg gagggaccga ggtggtggtc aaaggtgatc cagttgcacc tactgtcctc 360 atcttcccac cagctgctga tcaggtggca actggaacag tcaccatcgt gtgtgtggcg 420 aataaatact ttcccgatgt caccgtcacc tgggaggtgg atggcaccac ccaaacaact 480 ggcatcgaga acagtaaaac accgcagaat tctgcagatt gtacctacaa cctcagcagc 540 actctgacac tgaccagcac acagtacaac agccacaaag agtacacctg caaggtgacc 600 cagggcacga cctcagtcgt ccagagcttc aataggggtg actgttag 648 <210> 135 <211> 441 <212> PRT <213> European rabbit (Oryctolagus cuniculus) <400> 135 Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Asp 20 25 30 Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly 35 40 45 Tyr Ile Thr Val Asn Gly Val Thr Tyr Tyr Ala Asn Trp Ala Lys Gly 50 55 60 Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Ser 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Asp Gln 85 90 95 Tyr Ile Asn Asn Gly Gly Ala Glu Phe Asn Ile Trp Gly Pro Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gln Pro Lys Ala Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Cys Cys Gly Asp Thr Pro Ser Ser Thr Val Thr Leu Gly 130 135 140 Cys Leu Val Lys Gly Tyr Leu Pro Glu Pro Val Thr Val Thr Trp Asn 145 150 155 160 Ser Gly Thr Leu Thr Asn Gly Val Arg Thr Phe Pro Ser Val Arg Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Ser Val Thr Ser Ser 180 185 190 Ser Gln Pro Val Thr Cys Asn Val Ala His Pro Ala Thr Asn Thr Lys 195 200 205 Val Asp Lys Thr Val Ala Pro Ser Thr Cys Ser Lys Pro Thr Cys Pro 210 215 220 Pro Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys 225 230 235 240 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 245 250 255 Val Val Asp Val Ser Gln Asp Asp Pro Glu Val Gln Phe Thr Trp Tyr 260 265 270 Ile Asn Asn Glu Gln Val Arg Thr Ala Arg Pro Pro Leu Arg Glu Gln 275 280 285 Gln Phe Asn Ser Thr Ile Arg Val Val Ser Thr Leu Pro Ile Thr His 290 295 300 Gln Asp Trp Leu Arg Gly Lys Glu Phe Lys Cys Lys Val His Asn Lys 305 310 315 320 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Arg Gly Gln 325 330 335 Pro Leu Glu Pro Lys Val Tyr Thr Met Gly Pro Pro Arg Glu Glu Leu 340 345 350 Ser Ser Arg Ser Val Ser Leu Thr Cys Met Ile Asn Gly Phe Tyr Pro 355 360 365 Ser Asp Ile Ser Val Glu Trp Glu Lys Asn Gly Lys Ala Glu Asp Asn 370 375 380 Tyr Lys Thr Thr Pro Ala Val Leu Asp Ser Asp Gly Ser Tyr Phe Leu 385 390 395 400 Tyr Asn Lys Leu Ser Val Pro Thr Ser Glu Trp Gln Arg Gly Asp Val 405 410 415 Phe Thr Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 420 425 430 Lys Ser Ile Ser Arg Ser Pro Gly Lys 435 440 <210> 136 <211> 214 <212> PRT <213> European rabbit (Oryctolagus cuniculus) <400> 136 Ala Tyr Asp Met Thr Gln Thr Pro Ser Phe Val Glu Ala Ala Val Gly 1 5 10 15 Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45 Tyr Gln Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly 50 55 60 Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys 65 70 75 80 Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ser Tyr Gly Asp 85 90 95 Val Asp Asn Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys Gly Asp 100 105 110 Pro Val Ala Pro Thr Val Leu Ile Phe Pro Pro Ala Ala Asp Gln Val 115 120 125 Ala Thr Gly Thr Val Thr Ile Val Cys Val Ala Asn Lys Tyr Phe Pro 130 135 140 Asp Val Thr Val Thr Trp Glu Val Asp Gly Thr Thr Gln Thr Thr Gly 145 150 155 160 Ile Glu Asn Ser Lys Thr Pro Gln Asn Ser Ala Asp Cys Thr Tyr Asn 165 170 175 Leu Ser Ser Thr Leu Thr Leu Thr Ser Thr Gln Tyr Asn Ser His Lys 180 185 190 Glu Tyr Thr Cys Lys Val Thr Gln Gly Thr Thr Ser Val Val Gln Ser 195 200 205 Phe Asn Arg Gly Asp Cys 210 <210> 137 <211> 1326 <212> DNA <213> European rabbit (Oryctolagus cuniculus) <400> 137 cagtcggtgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60 tgcacagtct ctggattctc cctcagcagc tacgacatga gctgggtccg ccaggctcca 120 ggaaaggggc tggagtacat cggatacatt actgttaatg gtgtcacata ctacgcgaac 180 tgggcgaaag gccgattcac catctccaaa acctcgacca cggtggatct gaaaatctcc 240 agtccgacaa ccgaggacac ggccacctat ttctgtgcca gagatcaata tattaataat 300 ggtggtgctg aatttaacat ctggggccca ggcaccctgg tcaccgtctc ctccgggcaa 360 cctaaggctc catcagtctt cccactggcc ccctgctgcg gggacacacc cagctccacg 420 gtgaccctgg gctgcctggt caaaggctac ctcccggagc cagtgaccgt gacctggaac 480 tcgggcaccc tcaccaatgg ggtacgcacc ttcccgtccg tccggcagtc ctcaggcctc 540 tactcgctga gcagcgtggt gagcgtgacc tcaagcagcc agcccgtcac ctgcaacgtg 600 gcccacccag ccaccaacac caaagtggac aagaccgttg caccctcgac atgcagcaag 660 cccacgtgcc caccccctga actcctgggg ggaccgtctg tcttcatctt ccccccaaaaa 720 cccaaggaca ccctcatgat ctcacgcacc cccgaggtca catgcgtggt ggtggacgtg 780 agccaggatg accccgaggt gcagttcaca tggtacataa acaacgagca ggtgcgcacc 840 gcccggccgga cgctacggga gcagcagttc aacagcacga tccgcgtggt cagcaccctc 900 cccatcacgc accaggactg gctgaggggc aaggagttca agtgcaaagt ccacaacaag 960 gcactcccgg cccccatcga gaaaaccatc tccaaagcca gagggcagcc cctggagccg 1020 aaggtctaca ccatgggccc tccccgggag gagctgagca gcaggtcggt cagcctgacc 1080 tgcatgatca acggcttcta cccttccgac atctcggtgg agtgggagaa gaacgggaag 1140 gcagaggaca actacaagac cacgccggcc gtgctggaca gcgacggctc ctacttcctc 1200 tacaacaagc tctcagtgcc cacgagtgag tggcagcggg gcgacgtctt cacctgctcc 1260 gtgatgcacg aggccttgca caaccactac acgcagaagt ccatctcccg ctctccgggt 1320 aaatga 1326 <210> 138 <211> 645 <212> DNA <213> European rabbit (Oryctolagus cuniculus) <400> 138 gcctatgata tgacccagac tccatccttc gtggaggcag ctgtgggagg cacagtcacc 60 atcaagtgcc aggccagtga gagcattagc agttggttat cctggtatca gcagaaacca 120 gggcagcctc ccaagctcct gatctaccag gcatccactt tggcatctgg ggtctcatcg 180 cggttcaaag gcagtggatc tgggacacag ttcactctca ccatcagcga cctggagtgt 240 gccgatgctg ccacttacta ttgtcaacag ggttatagtt atggtgatgt tgataatgct 300 ttcggcggag ggaccgaggt ggtggtcaaa ggtgatccag ttgcacctac tgtcctcatc 360 ttcccaccag ctgctgatca ggtggcaact ggaacagtca ccatcgtgtg tgtggcgaat 420 aaatactttc ccgatgtcac cgtcacctgg gaggtggatg gcaccaccca aacaactggc 480 atcgagaaca gtaaaacacc gcagaattct gcagattgta cctacaacct cagcagcact 540 ctgacactga ccagcacaca gtacaacagc cacaaagagt acacctgcaa ggtgacccag 600 ggcacgacct cagtcgtcca gagcttcaat aggggtgact gttag 645 <210> 139 <211> 325 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 139 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Lys Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro 100 105 110 Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 145 150 155 160 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 165 170 175 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 180 185 190 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 210 215 220 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Lys Glu Met Thr Lys 225 230 235 240 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 260 265 270 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 290 295 300 Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr Arg Lys Glu 305 310 315 320 Leu Ser Leu Ser Pro 325 <210> 140 <211> 107 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 140 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Glu Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Glu Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> 141 <211> 325 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 141 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Glu Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Glu Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro 100 105 110 Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 145 150 155 160 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 165 170 175 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 180 185 190 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 210 215 220 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys 225 230 235 240 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 260 265 270 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 290 295 300 Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr Arg Glu Glu 305 310 315 320 Leu Ser Leu Ser Pro 325 <210> 142 <211> 106 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 142 Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser 1 5 10 15 Glu Glu Leu Gln Ala Asn Lys Ala Lys Leu Val Cys Leu Ile Ser Asp 20 25 30 Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro 35 40 45 Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn 50 55 60 Lys Tyr Ala Ala Ser Ser Tyr Leu Lys Leu Thr Pro Glu Gln Trp Lys 65 70 75 80 Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val 85 90 95 Glu Lys Thr Val Ala Pro Thr Glu Cys Ser 100 105 <210> 143 <211> 448 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 143 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr 20 25 30 Asp Ile Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Thr Gly Arg Glu Tyr Asp Gly Gly Trp Tyr Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 130 135 140 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 145 150 155 160 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175 Pro Ala Val Leu Lys Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190 Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val 195 200 205 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 210 215 220 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 260 265 270 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Gln Lys Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His 420 425 430 Glu Ala Leu His Ala His Tyr Thr Arg Lys Glu Leu Ser Leu Ser Pro 435 440 445 <210> 144 <211> 448 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 144 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr 20 25 30 Asp Ala Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Thr Gly Ser Glu Asp Gly Ala Gly Trp Tyr Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 130 135 140 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 145 150 155 160 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175 Pro Ala Val Leu Lys Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190 Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val 195 200 205 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 210 215 220 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 260 265 270 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Gln Lys Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His 420 425 430 Glu Ala Leu His Ala His Tyr Thr Arg Lys Glu Leu Ser Leu Ser Pro 435 440 445 <210> 145 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 145 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr 20 25 30 Asp Ile Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Thr Gly Arg Glu Asp Gly Gly Trp His Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Lys Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Lys Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu 420 425 430 Ala Leu His Ala His Tyr Thr Arg Lys Glu Leu Ser Leu Ser Pro 435 440 445 <210> 146 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 146 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr 20 25 30 Asp Ile Gln Trp Val Arg Glu Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Thr Gly Arg Glu Glu Gly Gly Trp Ile Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Lys Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Lys Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu 420 425 430 Ala Leu His Ala His Tyr Thr Arg Lys Glu Leu Ser Leu Ser Pro 435 440 445 <210> 147 <211> 447 <212> PRT <213> Artificial sequence <220> <223> Artificial synthesized sequence <400> 147 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr 20 25 30 Asp Ile Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Thr Gly Arg Glu Glu Gly Gly Trp Ile Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Lys Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Lys Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu 420 425 430 Ala Leu His Ala His Tyr Thr Arg Lys Glu Leu Ser Leu Ser Pro 435 440 445 <210> 148 <211> 447 <212> PRT <213> Artificial sequence <220> <223> Artificially synthesized sequence <400> 148 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Ile Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Thr Asp Arg Glu Asp His Gly Trp Ile Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Lys Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Lys Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu 420 425 430 Ala Leu His Ala His Tyr Thr Arg Lys Glu Leu Ser Leu Ser Pro 435 440 445 <210> 149 <211> 213 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 149 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Arg Arg Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Lys Ser Pro Leu Thr 85 90 95 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Glu Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Glu Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> 150 <211> 213 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 150 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Thr Gln Ser Val Arg Arg Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Arg Ser Pro Leu Thr 85 90 95 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Glu Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Glu Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> 151 <211> 213 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 151 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Thr Gln Ser Val Arg Arg Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Arg Ser Pro Leu Thr 85 90 95 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Glu Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Glu Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> 152 <211> 213 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 152 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Ser Val Arg Arg Glu 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Leu Thr 85 90 95 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Glu Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Glu Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> 153 <211> 214 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 153 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Ser Val Arg Arg Glu 20 25 30 Leu Ala Trp Tyr Gln Lys Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Met Ala Val Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Pro Gly 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Glu Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Glu Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 154 <211> 214 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 154 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Ser Val Arg Arg Glu 20 25 30 Leu Ala Trp Tyr Gln Lys Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Met Ala Val Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Pro Gly 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Glu Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Glu Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 155 <211> 214 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 155 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Thr Arg Ser Val Arg Arg Asp 20 25 30 Leu Ala Trp Tyr Gln Lys Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Arg Arg Glu Thr Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Pro Gly 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Glu Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Glu Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 156 <211> 214 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 156 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Ser Val Arg Arg Glu 20 25 30 Leu Ala Trp Tyr Gln Lys Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Pro Gly 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Glu Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Glu Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 157 <211> 214 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 157 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Ser Val Arg Arg Glu 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Met Ala Val Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Pro Gly 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Glu Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Glu Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 158 <211> 214 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 158 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Ser Val Arg Arg Glu 20 25 30 Leu Ala Trp Tyr Gln Lys Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala 65 70 75 80 Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Pro Gly 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Glu Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Glu Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 159 <211> 214 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 159 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Ser Val Arg Arg Glu 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala 65 70 75 80 Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Pro Gly 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Glu Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Glu Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 160 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 160 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Thr Arg Ser Val Arg Arg Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Arg Arg Glu Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala 65 70 75 80 Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Arg Asp Pro Pro Gly 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Glu Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Glu Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 161 <211> 444 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 161 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Asn 20 25 30 Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ser Asn Thr Arg Ser Gly Thr Ser Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asp Arg Val Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Glu Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Glu Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His 420 425 430 Ala His Tyr Thr Arg Glu Glu Leu Ser Leu Ser Pro 435 440 <210> 162 <211> 444 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 162 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn 20 25 30 Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Val Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asn Arg Val Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Val Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Glu Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His 420 425 430 Ala His Tyr Thr Arg Glu Glu Leu Ser Leu Ser Pro 435 440 <210> 163 <211> 444 <212> PRT <213> Artificial Sequence <220> Artificially Synthesized Sequence <400> 163 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Asn 20 25 30 Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Arg Val Ile Ser Asn Glu Glu Phe 50 55 60 Gln Asp Arg Val Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Glu Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Glu Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His 420 425 430 Ala His Tyr Thr Arg Glu Glu Leu Ser Leu Ser Pro 435 440 <210> 164 <211> 444 <212> PRT <213> Artificial sequence <220> Artificially synthesized sequence <400> 164 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gln Asn 20 25 30 Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Val Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Gln Arg Val Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Val Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Glu Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His 420 425 430 Ala His Tyr Thr Arg Glu Glu Leu Ser Leu Ser Pro 435 440 <210> 165 <211> 444 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 165 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gln Asn 20 25 30 Asn Met Asp Trp Val Arg Lys Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Val Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asp Arg Leu Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Val Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Glu Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His 420 425 430 Ala His Tyr Thr Arg Glu Glu Leu Ser Leu Ser Pro 435 440 <210> 166 <211> 444 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 166 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Glu Phe Thr His Asn 20 25 30 Asn Met Asp Trp Val Arg Lys Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Arg Ser Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asp Arg Val Ile Met Thr Val Asp Ile Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Val Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Glu Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His 420 425 430 Ala His Tyr Thr Arg Glu Glu Leu Ser Leu Ser Pro 435 440 <210> 167 <211> 444 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 167 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gln Asn 20 25 30 Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Val Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asp Arg Leu Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Val Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Glu Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His 420 425 430 Ala His Tyr Thr Arg Glu Glu Leu Ser Leu Ser Pro 435 440 <210> 168 <211> 444 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 168 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gln Asn 20 25 30 Asn Met Asp Trp Val Arg Lys Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Val Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asp Arg Leu Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Glu Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Glu Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His 420 425 430 Ala His Tyr Thr Arg Glu Glu Leu Ser Leu Ser Pro 435 440 <210> 169 <211> 444 <212> PRT <213> Artificial Sequence <220> Artificially synthesized sequence <400> 169 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gln Asn 20 25 30 Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Val Ile Tyr Asn Glu Lys Phe 50 55 60 Gln Asp Arg Val Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Glu Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Val Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Glu Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His 420 425 430 Ala His Tyr Thr Arg Glu Glu Leu Ser Leu Ser Pro 435 440 <210> 170 <211> 444 <212> PRT <213> Artificial sequence <220> <223> Artificially synthesized sequence <400> 170 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Glu Phe Thr His Asn 20 25 30 Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Arg Ser Ile Tyr Asn Arg Glu Phe 50 55 60 Gln Asp Arg Val Ile Met Thr Val Asp Ile Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Glu Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Glu Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His 420 425 430 Ala His Tyr Thr Arg Glu Glu Leu Ser Leu Ser Pro 435 440 <210> 171 <211> 444 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 171 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gln Asn 20 25 30 Asn Met Asp Trp Val Arg Lys Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Val Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asp Arg Leu Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Glu Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Glu Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Glu Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His 420 425 430 Ala His Tyr Thr Arg Glu Glu Leu Ser Leu Ser Pro 435 440 <210> 172 <211> 213 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized sequence <400> 172 Ser Tyr Val Leu Thr Gln Pro Val Ser Val Ser Val Ala Arg Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Asn His Ile Gly Asp Lys His Val 20 25 30 His Trp Tyr His Gln Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Gln Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Tyr Thr 85 90 95 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val Gly Gln Pro Lys Ala 100 105 110 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala 115 120 125 Asn Lys Ala Lys Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala 130 135 140 Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val 145 150 155 160 Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser 165 170 175 Ser Tyr Leu Lys Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr 180 185 190 Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala 195 200 205 Pro Thr Glu Cys Ser 210 <210> 173 <211> 213 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 173 Ser Tyr Val Leu Thr Gln Pro Val Ser Val Ser Val Ala Arg Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Asn His Ile Gly Asp Lys His Val 20 25 30 His Trp Tyr His Gln Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Gln Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Gln Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Tyr Thr 85 90 95 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val Gly Gln Pro Lys Ala 100 105 110 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala 115 120 125 Asn Lys Ala Lys Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala 130 135 140 Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val 145 150 155 160 Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser 165 170 175 Ser Tyr Leu Lys Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr 180 185 190 Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala 195 200 205 Pro Thr Glu Cys Ser 210 <210> 174 <211> 213 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 174 Ser Tyr Val Leu Thr Gln Pro Val Ser Val Ser Val Ala Arg Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Thr Gly Asn His Ile Ser Asp Lys His Val 20 25 30 His Trp Tyr His Gln Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Gln Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Gln Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Asp Tyr Thr 85 90 95 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val Gly Gln Pro Lys Ala 100 105 110 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala 115 120 125 Asn Lys Ala Lys Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala 130 135 140 Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val 145 150 155 160 Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser 165 170 175 Ser Tyr Leu Lys Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr 180 185 190 Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala 195 200 205 Pro Thr Glu Cys Ser 210 <210> 175 <211> 212 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 175 Ser Tyr Val Leu Thr Gln Pro Val Ser Val Ser Val Ala Arg Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Asn Gln Ile Ser Gln Lys Gln Val 20 25 30 His Trp Tyr His Gln Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Gln Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ala Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Val Thr Val Val Gly Gln Pro Lys Ala Ala 100 105 110 Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn 115 120 125 Lys Ala Lys Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala Val 130 135 140 Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val Glu 145 150 155 160 Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser Ser 165 170 175 Tyr Leu Lys Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr Ser 180 185 190 Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala Pro 195 200 205 Thr Glu Cys Ser 210 <210> 176 <211> 213 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 176 Ser Tyr Val Leu Thr Gln Pro Val Ser Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Glu Gln Ile Gly Ser Lys Glu Val 20 25 30 His Trp Tyr His Glu Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Glu Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Tyr Thr 85 90 95 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val Gly Gln Pro Lys Ala 100 105 110 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala 115 120 125 Asn Lys Ala Lys Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala 130 135 140 Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val 145 150 155 160 Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser 165 170 175 Ser Tyr Leu Lys Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr 180 185 190 Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala 195 200 205 Pro Thr Glu Cys Ser 210 <210> 177 <211> 212 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 177 Ser Tyr Val Leu Thr Gln Pro Val Ser Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Asn Gln Ile Gly Ser Arg Glu Val 20 25 30 His Trp Tyr His Glu Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Glu Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Ala Ser Asp Ala Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Val Thr Val Val Gly Gln Pro Lys Ala Ala 100 105 110 Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn 115 120 125 Lys Ala Lys Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala Val 130 135 140 Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val Glu 145 150 155 160 Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser Ser 165 170 175 Tyr Leu Lys Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr Ser 180 185 190 Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala Pro 195 200 205 Thr Glu Cys Ser 210 <210> 178 <211> 213 <212> PRT <213> artificial sequence <220> <223> Artificial synthesis <400> 178 Ser Tyr Val Leu Thr Gln Pro Val Ser Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Glu Gln Ile Gly Ser Lys Glu Val 20 25 30 His Trp Tyr His Gln Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Glu Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Tyr Thr 85 90 95 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val Gly Gln Pro Lys Ala 100 105 110 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala 115 120 125 Asn Lys Ala Lys Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala 130 135 140 Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val 145 150 155 160 Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser 165 170 175 Ser Tyr Leu Lys Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr 180 185 190 Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala 195 200 205 Pro Thr Glu Cys Ser 210 <210> 179 <211> 213 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 179 Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Glu Gln Ile Gly Ser Lys Glu Val 20 25 30 His Trp Tyr His Glu Arg Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Glu Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Tyr Thr 85 90 95 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val Gly Gln Pro Lys Ala 100 105 110 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala 115 120 125 Asn Lys Ala Lys Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala 130 135 140 Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val 145 150 155 160 Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser 165 170 175 Ser Tyr Leu Lys Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr 180 185 190 Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala 195 200 205 Pro Thr Glu Cys Ser 210 <210> 180 <211> 213 <212> PRT <213> Artificial sequence <220> <223> Artificially synthesized sequence <400> 180 Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Glu Gln Ile Gly Ser Lys Glu Val 20 25 30 His Trp Tyr His Gln Arg Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Glu Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Tyr Thr 85 90 95 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val Gly Gln Pro Lys Ala 100 105 110 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala 115 120 125 Asn Lys Ala Lys Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala 130 135 140 Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val 145 150 155 160 Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser 165 170 175 Ser Tyr Leu Lys Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr 180 185 190 Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala 195 200 205 Pro Thr Glu Cys Ser 210 <210> 181 <211> 212 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 181 Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Asn Gln Ile Gly Glu Lys Glu Val 20 25 30 His Trp Tyr His Gln Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Glu Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Ala Ser Asp Ala Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Val Thr Val Val Gly Gln Pro Lys Ala Ala 100 105 110 Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn 115 120 125 Lys Ala Lys Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala Val 130 135 140 Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val Glu 145 150 155 160 Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser Ser 165 170 175 Tyr Leu Lys Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr Ser 180 185 190 Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala Pro 195 200 205 Thr Glu Cys Ser 210 <210> 182 <211> 213 <212> PRT <213> Artificial Sequence <220> <223> Artificially Synthesized Sequence <400> 182 Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Ala Thr Ile Thr Cys Glu Gly Glu Gln Ile Gly Ser Lys Glu Val 20 25 30 His Trp Tyr His Glu Arg Pro Gly Gln Ala Pro Ile Leu Val Met Phe 35 40 45 Arg Asp Ala Arg Arg Pro Ser Gly Ile Pro Glu Arg Leu Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Ala Glu Ala Gly 65 70 75 80 Asp Glu Gly Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Tyr Thr 85 90 95 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val Gly Gln Pro Lys Ala 100 105 110 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala 115 120 125 Asn Lys Ala Lys Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala 130 135 140 Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val 145 150 155 160 Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser 165 170 175 Ser Tyr Leu Lys Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr 180 185 190 Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala 195 200 205 Pro Thr Glu Cys Ser 210

Claims

1. An antibody that neutralizes bispecific antibodies binding to coagulation factor IX and / or activated coagulation factor IX and coagulation factor X and / or activated coagulation factor X, comprising a heavy chain variable region containing the amino acid sequence of SEQ ID NO:1 and a light chain variable region containing the amino acid sequence of SEQ ID NO:

2.

2. An antibody that neutralizes bispecific antibodies binding to coagulation factor IX and / or activated coagulation factor IX and coagulation factor X and / or activated coagulation factor X, comprising an antibody heavy chain containing the amino acid sequence of SEQ ID NO:131 and an antibody light chain containing the amino acid sequence of SEQ ID NO:

132.

3. An antibody that neutralizes bispecific antibodies binding to coagulation factor IX and / or activated coagulation factor IX and coagulation factor X and / or activated coagulation factor X, comprising a heavy chain variable region containing the amino acid sequence of SEQ ID NO:3 and a light chain variable region containing the amino acid sequence of SEQ ID NO:

4.

4. An antibody that neutralizes bispecific antibodies binding to coagulation factor IX and / or activated coagulation factor IX and coagulation factor X and / or activated coagulation factor X, comprising an antibody heavy chain containing the amino acid sequence of SEQ ID NO:135 and an antibody light chain containing the amino acid sequence of SEQ ID NO:

136.

5. A nucleic acid encoding an antibody as described in any one of claims 1 to 4.

6. A vector wherein the nucleic acid of claim 5 has been inserted.

7. A cell comprising the nucleic acid of claim 5 or the vector of claim 6.

8. A method for producing antibodies, comprising the step of culturing the cells of claim 7.

9. A composition comprising the antibody of claim 1 and the antibody of claim 3.

10. A composition comprising the antibody of claim 2 and the antibody of claim 4.

11. Use of the antibody of claim 1 or 2 and the antibody of claim 3 or 4 in the preparation of a product for measuring the reactivity of coagulation factor VIII in a blood-derived sample, wherein the blood-derived sample comprises a bispecific antibody that binds to coagulation factor IX and / or activated coagulation factor IX and coagulation factor X and / or activated coagulation factor X.

12. Use of the composition of claim 9 or 10 in the preparation of a product for measuring the reactivity of coagulation factor VIII in a blood-derived sample, wherein the blood-derived sample comprises a bispecific antibody binding coagulation factor IX and / or activated coagulation factor IX and coagulation factor X and / or activated coagulation factor X.

13. A kit for measuring the reactivity of coagulation factor VIII in a blood-derived sample containing a bispecific antibody that binds to and / or activates coagulation factor IX and coagulation factor X and / or activates coagulation factor X, comprising the composition of claim 9 or 10.

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