CN116897165A

CN116897165A - Antibody fusion proteins targeting IL-6 receptor and angiogenic factor

Info

Publication number: CN116897165A
Application number: CN202280017398.2A
Authority: CN
Inventors: 张金忠; 申维勇; 查尔斯·仙波; J·Z·胡; 夏振勤
Original assignee: Dianjing Biomedical Technology Suzhou Co ltd
Current assignee: Dianjing Biomedical Technology Suzhou Co ltd
Priority date: 2021-02-27
Filing date: 2022-02-17
Publication date: 2023-10-17
Also published as: EP4298127A1; JP2024507397A; AU2022227047A1; WO2022179432A1; TW202246359A; MX2023009956A; KR20230150858A; CA3211803A1

Abstract

An antibody fusion protein comprising an antibody or antigen-binding fragment thereof directed against an IL-6 receptor linked to a VEGF binding unit comprising a plurality of Ig-like domains of a first, second, and/or third human VEGF receptor. The antibody fusion proteins are useful for treating or controlling an ocular disease, condition, or disorder whose etiology is aberrant angiogenesis or inflammation.

Description

Antibody fusion proteins targeting IL-6 receptor and angiogenic factor

Background

The present invention relates to antibody fusion proteins that target interleukin-6 receptor ("IL-6R") and angiogenic factors. In particular, the invention relates to antibody fusion proteins targeting IL-6R and vascular endothelial growth factor family members ("VEGF family members"). More specifically, the invention relates to such fusion proteins, uses thereof and methods of production.

The major cellular components of the mammalian vascular system are endothelial, smooth muscle and pericytes. Endothelial cells line the inner surface of all blood vessels of mammals and constitute a non-thrombogenic interface between blood and tissue. Thus, proliferation of endothelial cells is an important component of new capillaries and vascular development, which in turn is an essential process for mammalian tissue growth and/or regeneration.

A family of secreted polypeptides has been shown to play an extremely important role in promoting endothelial cell proliferation and angiogenesis. The pathological feature of uncontrolled angiogenesis caused by VEGF overexpression is increased vascular permeability, which results in leakage of fluid into and swelling of surrounding tissues. In mammals, this family consists of five related growth factors with highly conserved receptor binding structures: vascular endothelial growth factor A-D ("VEGF-A", "VEGF-B", "VEGF-C" and "VEGF-D") and placental growth factor ("PlGF"). In the present disclosure, this family of growth factors is also referred to as the VEGF family.

The cytokine interleukin 6 ("IL-6") plays an important role in host defense against environmental stresses such as infection and injury. Under physiological conditions, IL-6 is barely detectable, but its levels can increase by more than 100,000-fold during the early stages of inflammation. However, not all IL-6 stimulation occurrences are beneficial. Deregulation, sustained production of IL-6 has been associated with the development of various autoimmune, chronic inflammatory diseases. There is evidence that the unconstrained production of IL-6 in inflamed tissues induces the overproduction of VEGF-A and VEGF-C.

VEGF family growth factors act to stimulate angiogenesis through a family of cognate receptor tyrosine kinases that are present only on the surface of vascular endothelial cells: VEGF receptor-1 ("VEGFR-1", also known as "flt-1"), VEGF receptor-2 ("VEGFR-2", also known as "KDR" in humans, and also known as "flk-1" in mice), VEGF receptor-3 ("VEGFR-3", also known as "flt-4").

VEGF-A (sometimes also abbreviated as VEGF) has become the most important member of this family of growth factors. Human VEGF-A is expressed in Sub>A variety of tissues in Sub>A variety of homodimeric forms (121, 145, 165, 183, 189 and 206 amino acids per monomer), each of which results from alternative splicing of Sub>A single RNA transcript.

Since VEGF promotes vascular endothelial cell proliferation and angiogenesis, it can be used to therapeutically treat a number of conditions in which growth promoting activity on vascular endothelial cells is of beneficial importance; for example, for the treatment of ulcers, vascular lesions and myocardial infarction.

However, conversely, while vascular endothelial proliferation is desirable in some instances, vascular endothelial proliferation and angiogenesis are also undesirable components of a variety of diseases and disorders including tumor growth and metastasis, rheumatoid arthritis, psoriasis, atherosclerosis, diabetic retinopathy, post-lens fibroplasia, neovascular glaucoma, neovascular age-related macular degeneration, hemangiomas, immune rejection of transplanted corneal tissue and other tissues, and chronic inflammation. In individuals suffering from any of these disorders, it is desirable to inhibit or at least significantly reduce the endothelial proliferation activity of VEGF.

Each of the flt-1, KDR and flt-4 tyrosine kinase receptors has seven extracellular immunoglobulin-like ("Ig-like") domains available for ligand binding, which are transmembrane domains for anchoring the receptor on the surface of the receptor-expressing cell, and an intracellular catalytic tyrosine kinase domain. Flt-1 binds to VEGF-A, VEGF-B and PlGF. KDR binds to VEGF-A, VEGF-C and VEGF-D. Flt-4 binds VEGF-C and VEGF-D.

Given the role of the growth factors of the VEGF family in vascular endothelial proliferation and angiogenesis and the role of these processes in many different diseases and conditions, therapies have been designed to target the control of these growth factors. However, anti-VEGF therapy alone does not completely block the progression of angiogenic diseases.

It is therefore desirable to have a pharmacological means for more completely reducing or inhibiting one or more biological activities of these growth factors in patients whose pathological conditions stem from abnormal angiogenesis. It is also desirable to have a pharmacological means for improved treatment or control of pathological conditions arising from abnormal angiogenesis.

Disclosure of Invention

As used herein, the term "control" also includes reducing, alleviating, ameliorating or preventing.

In general, the invention provides antibody fusion or chimeric proteins, methods of producing the same, and compositions comprising the same, as well as methods of treating or controlling at least one pathological condition in a subject, the cause of which is abnormal angiogenesis. In the present disclosure, the terms "fusion protein" and "chimeric protein" are used interchangeably.

In one aspect, the invention provides antibody fusion proteins or chimeric proteins or antigen-binding fragments or antigen-binding domains thereof that are capable of substantially binding to the membrane-bound or soluble forms of IL-6R, including IL-6R, and one or more VEGF family members; thereby reducing or inhibiting both IL-6 and VEGF family member signaling.

In another aspect, the antibody fusion proteins or chimeric proteins of the invention comprise an antibody or antigen binding fragment or domain thereof directed against IL-6R linked to a VEGF binding unit comprising an Ig-like domain selected from the group consisting of: a first VEGF receptor, a second VEGF receptor, a third VEGF receptor, and combinations thereof. As used herein, a VEGF binding unit comprises a polypeptide that binds to or substantially binds to a VEGF family member. Thus, in one aspect, the antibody fusion proteins of the invention may be regarded as at least bispecific constructs that can bind to two different ligands. In some embodiments, the VEGF binding unit comprises multiple Ig-like domains of one or more VEGF receptors.

In still another aspect, the IL-6R is human IL-6R.

In still another aspect, the antibody fusion proteins or chimeric proteins of the invention comprise an antibody or antigen-binding fragment or domain thereof directed against IL-6R; wherein at least one of the following is linked to a VEGF binding unit: (1) a light chain or antigen binding fragment or domain thereof; and (2) a heavy chain or antigen binding fragment or domain thereof, said VEGF binding unit comprising a plurality of Ig-like domains selected from the group consisting of: an Ig-like domain of a first VEGF receptor, an Ig-like domain of a second VEGF receptor, an Ig-like domain of a third VEGF receptor, and combinations thereof.

In still another aspect, the VEGF binding unit comprises: (1) (a) Ig-like domain 2 or substantially Ig-like domain 2 of human VEGFR-1 (or flt-1); and (b) Ig-like domain 3 or substantially Ig-like domain 3 of human VEGFR-2 (or KDR); or (2) at least one Ig-like domain selected from the group consisting of: ig-like domains 1, 2 and 3 or substantially Ig-like domains 1, 2 and 3 of human VEGFR-3 (or flt-4).

In yet another aspect, each of the light chain or antigen-binding fragment or domain thereof and the heavy chain or antigen-binding fragment or domain thereof of the antibody to IL-6R is linked to a VEGF binding unit comprising: (a) Ig-like domain 2 or substantially Ig-like domain 2 of human VEGFR-1 (or flt-1); and (b) Ig-like domain 3 or substantially Ig-like domain 3 of human VEGFR-2 (or KDR).

In yet another aspect, each of the light chain of the antibody or antigen-binding fragment thereof to IL-6R or antigen-binding fragment or domain thereof is linked to a first VEGF binding unit comprising: (a) Ig-like domain 2 or substantially Ig-like domain 2 of human VEGFR-1 (or flt-1); and (b) Ig-like domain 3 or substantially Ig-like domain 3 of human VEGFR-2 (or KDR); and each of the heavy chains of the antibody or antigen-binding fragment thereof to IL-6R or antigen-binding fragment or domain thereof is linked to a second VEGF binding unit comprising: (a) Ig-like domains 1 and 2 or substantially Ig-like domains 1 and 2 of human VEGFR-3; or (b) Ig-like domains 2 and 3 or substantially Ig-like domains 2 and 3 of human VEGFR-3; or Ig-like domains 1, 2 and 3 or substantially Ig-like domains 1, 2 and 3 of human VEGFR-3.

In yet another aspect, each of the heavy chains of the antibody to IL-6R or antigen binding fragment or domain thereof is linked to a VEGF binding unit selected from the group consisting of: (1) A first VEGF binding unit, the first VEGF binding unit comprising: (a) Ig-like domain 2 or substantially Ig-like domain 2 of human VEGFR-1 (or flt-1); and (b) Ig-like domain 3 or substantially Ig-like domain 3 of human VEGFR-2 (or KDR); (2) A second VEGF binding unit comprising Ig-like domains 1 and 2 or substantially Ig-like domains 1 and 2 of human VEGFR-3 (or flt-4); and (3) a combination of the first VEGF-binding unit and the second VEGF-binding unit.

In yet another aspect, the invention provides an isolated nucleic acid molecule encoding any of the antibody fusion proteins or chimeric proteins.

In yet another aspect, the invention provides a vector comprising the nucleic acid molecule, the vector comprising an expression vector comprising the nucleic acid molecule operably linked to an expression control sequence. As used herein, the phrase "operably linked" refers to the placement of the components of a construct into a functional relationship with each other and each component retains its function. A nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence. For example, if the DNA of a pre-sequence or secretory leader is expressed as a pre-protein that is involved in the secretion of a polypeptide, it is "operably linked" to the DNA of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or if the ribosome binding site is positioned so as to facilitate translation, the ribosome binding site is operatively linked to a coding sequence.

In yet another aspect, the invention provides a host-vector system for producing the antibody fusion protein or chimeric protein, the host-vector system comprising an expression vector in a suitable host cell.

In another aspect, the invention provides a method of producing an antibody fusion protein or chimeric protein, the method comprising: (a) Culturing cells of a host-vector system under conditions that allow production of the antibody fusion protein or chimeric protein; and (b) recovering the antibody fusion protein or chimeric protein so produced.

In yet another aspect, the invention provides a method of treating or controlling at least one disease, condition, or disorder in a subject, the disease, condition, or disorder having a etiology selected from the group consisting of: abnormal angiogenesis, inflammation, and combinations thereof.

In yet another aspect, the invention provides a method of treating or controlling at least one disease, condition, or disorder in a subject, the disease, condition, or disorder having abnormal angiogenesis and/or inflammation of its etiology. In certain embodiments, such a disease, condition, or disorder is an ocular disease, condition, or disorder. In certain other embodiments, such diseases, conditions, or disorders involve tumor growth and metastasis. In other embodiments, such a disease, condition, or disorder is rheumatoid arthritis, psoriasis, or atherosclerosis.

Other features and advantages of the invention will become apparent from the following detailed description, and from the claims.

Drawings

FIG. 1 shows a schematic representation of a first and a second embodiment of an antibody fusion protein of the invention comprising an antibody directed against human IL-6R, each of the light and heavy chains of the antibody fusion protein being linked by a flexible linker to a VEGF binding unit comprising Ig-like domain 2 of VEGFR-1 and Ig-like domain 3 of VEGFR-2.

FIG. 2 shows a schematic representation of a third and fourth embodiment of an antibody fusion protein of the invention comprising an antibody directed against human IL-6R, the light chain of the antibody fusion protein being linked by a flexible linker to a first VEGF binding unit comprising Ig-like domain 2 of VEGFR-1 and Ig-like domain 3 of VEGFR-2, and the heavy chain of the antibody fusion protein being linked by a flexible linker to a second VEGF binding unit comprising Ig-like domains 2 and 3 of VEGFR-3.

FIG. 3 shows a schematic representation of a fifth embodiment of an antibody fusion protein of the invention comprising an scFv of an antibody directed against human IL-6R, each of the variable domains of the heavy chain of the antibody fusion protein being linked to an Fc domain, which in turn is linked via a flexible linker to a VEGF binding unit comprising Ig-like domain 2 of VEGFR-1 and Ig-like domain 3 of VEGFR-2.

FIG. 4 shows a schematic representation of a sixth embodiment of an antibody fusion protein of the invention comprising an scFv of an antibody directed against human IL-6R, each of the variable domains of the heavy chain of the antibody fusion protein being linked by a flexible linker to a VEGF binding unit comprising Ig-like domain 2 of VEGFR-1 and Ig-like domain 3 of VEGFR-2, which in turn is linked by a flexible linker to an Fc domain.

FIG. 5 shows a schematic representation of a seventh embodiment of an antibody fusion protein of the invention comprising an scFv of an antibody directed against human IL-6R, each of the variable domains of the heavy chain of the antibody fusion protein being linked by a flexible linker to a first VEGF binding unit comprising Ig-like domain 2 of VEGFR-1 and Ig-like domain 3 of VEGFR-2, the first VEGF binding unit in turn being linked by a flexible linker to an Fc domain in turn being linked by a flexible linker to a second VEGF binding unit comprising Ig-like domains 1 and 2 of VEGFR-3.

FIG. 6 shows a schematic representation of an eighth embodiment of an antibody fusion protein of the invention comprising an scFv of an antibody directed against human IL-6R, each of the variable domains of the heavy chain of the antibody fusion protein being linked by a flexible linker to a first VEGF binding unit comprising Ig-like domain 2 of VEGFR-1 and Ig-like domain 3 of VEGFR-2 and a second VEGF binding unit comprising Ig-like domains 1 and 2 of VEGFR-3, the latter in turn being linked by a flexible linker to an Fc domain.

FIGS. 7A-D show the molecular design of six antibody fusion proteins (B78401-78406) of the invention.

FIG. 8 shows the molecular design of the fusion proteins EB-DJ1, EB-vvA, EB-vvB and EB-vvC of the invention.

Fig. 9 shows an example of SEC-HPLC chromatogram for purification of B781401 expressed in HEK293 cells.

FIG. 10 shows an example of a SEC-HPLC chromatogram for purification of B781401 expressed in CHO cells.

FIG. 11 shows the use of an enzyme-linked immunosorbent assay (ELISA) pair against recombinant human VEGF-A ₁₆₅ The binding affinity of B78401-78406 was compared with that of Abelmoschus (aflibercept).

FIG. 12 shows the expression of recombinant human VEGF-B ₁₆₇ Comparison of ELISA binding affinity of B78401-78406 with ELISA binding affinity of Abelmoschus.

FIG. 13 shows a comparison of ELISA binding affinity for B78401-78406 to recombinant human PlGF with that of Abelmoschus.

FIG. 14 shows a comparison of ELISA binding affinity for B78401-78406 of recombinant human IL-6R with that of tobalizumab.

FIG. 15 shows that B78401-78406 pair inhibits VEGF-A in VEGFR-2-NFAT-RE luciferase reporter cells ₁₆₅ Comparison of the effects of mediated VEGFR-2 signalling with the effects of Abelmoschus.

FIGS. 16A-B show a comparison of the effect of B78401-78406 on inhibiting IL-6R signaling with the effect of tobrazumab.

FIG. 17 shows a comparison of the effect of B78401-78406 on inhibiting IL-6R signaling with the effect of cetuximab (siltuximab) and tolizumab.

FIG. 18 shows the expression of recombinant human VEGF-A ₁₆₅ ELISA binding affinity of EB-DJ1, EB-vA, EB-vvB and EB-vvC with ELISA binding affinity of Abelmoschus, B781403 and B781405.

FIG. 19 shows the expression of recombinant human VEGF-B ₁₆₇ ELISA binding affinities of EB-DJ1, EB-vA, EB-vvB and EB-vvC compared to ELISA binding affinities of Abelmoschus, B781402, B781403 and B781405.

FIG. 20 shows a comparison of ELISA binding affinities for EB-DJ1, EB-vvA, EB-vvB and EB-vvC for recombinant human PlGF with ELISA binding affinities for Abelmosil, B781403 and B781405.

FIG. 21 shows a comparison of ELISA binding affinities for EB-DJ1, EB-vvA, EB-vvB and EB-vvC for recombinant human IL-6R with ELISA binding affinities for tobrazumab, B781402, B781403 and B781405.

Detailed Description

In general, the present invention provides an antibody fusion protein or chimeric protein or antigen binding fragment or domain thereof that is capable of substantially binding to IL-6R and one or more VEGF family members; thereby reducing or inhibiting both IL-6 and VEGF family member signaling. In the present disclosure, the term "antibody fusion protein" is sometimes used in place of "antibody fusion protein or chimeric protein". In one aspect, the antibody fusion protein or antigen binding fragment thereof is capable of substantially binding to IL-6R and one or more VEGF family members; thereby reducing or inhibiting both IL-6 and VEGF family member signaling.

In another aspect, the antibody fusion proteins or chimeric proteins of the invention comprise an antibody or antigen binding fragment or domain thereof directed against IL-6R linked to a VEGF binding unit comprising a plurality of Ig-like domains selected from the group consisting of: an Ig-like domain of a first VEGF receptor, an Ig-like domain of a second VEGF receptor, and an Ig-like domain of a third VEGF receptor.

An advantage of the antibody fusion proteins of the invention is that they can substantially bind to and thereby inhibit the effects of both membrane-bound IL-6R and soluble IL-6R. It can inhibit all three signaling pathways, including classical, trans-signaling and trans-presentation pathways, whereas antibody fusion proteins, including IL-6 antibodies, can only inhibit free forms of IL-6.

In still another aspect, the IL-6R is human IL-6R.

In yet another aspect, the VEGF receptor is a human VEGF receptor.

In still another aspect, the antibody fusion proteins or chimeric proteins of the invention comprise an antibody or antigen-binding fragment or domain thereof directed against IL-6R; wherein one of the following is linked to a VEGF binding unit: (1) at least a light chain or antigen binding fragment or domain thereof; and (2) a heavy chain or antigen binding fragment or domain thereof, said VEGF binding unit comprising an Ig-like domain selected from the group consisting of: an Ig-like domain of a first VEGF receptor, an Ig-like domain of a second VEGF receptor, and an Ig-like domain of a third VEGF receptor. In certain embodiments, such VEGF binding units comprise a plurality of Ig-like domains selected from the group consisting of: an Ig-like domain of a first VEGF receptor, an Ig-like domain of a second VEGF receptor, and an Ig-like domain of a third VEGF receptor. In one embodiment, the antibody fusion proteins or chimeric proteins of the invention comprise an antibody or antigen-binding fragment or domain thereof directed against IL-6R; wherein the light chain or antigen binding fragment or domain thereof and the heavy chain or antigen binding fragment or domain thereof are linked to a VEGF binding unit comprising a plurality of Ig-like domains selected from the group consisting of: an Ig-like domain of a first VEGF receptor, an Ig-like domain of a second VEGF receptor, and an Ig-like domain of a third VEGF receptor.

In still another aspect, the VEGF binding unit comprises: (1) (a) Ig-like domain 2 or substantially Ig-like domain 2 of human VEGFR-1 (or flt-1); and (b) Ig-like domain 3 or substantially Ig-like domain 3 of human VEGFR-2 (or KDR); or (2) at least one Ig-like domain selected from the group consisting of: ig-like domains 1, 2, 3 of VEGFR-3 (or flt 4), and combinations thereof, or selected from the group consisting of: a domain substantially identical to the Ig-like domain of VEGFR-3. In one embodiment, the VEGF binding unit comprises: human VEGFR-3 (a) Ig like domains 1 and 2 or substantially Ig like domains 1 and 2; or (b) Ig-like domains 2 and 3 or substantially Ig-like domains 2 and 3; or (c) Ig-like domains 1, 2 and 3 or substantially Ig-like domains 1, 2 and 3.

In still another aspect, the light chain of the antibody or antigen-binding fragment thereof directed against IL-6R or the antigen-binding fragment or domain thereof is linked to a first VEGF-binding unit comprising: (a) Ig-like domain 2 or substantially Ig-like domain 2 of human VEGFR-1 (or flt-1); and (b) Ig-like domain 3 or substantially Ig-like domain 3 of human VEGFR-2 (or KDR); and the heavy chain of the antibody or antigen binding fragment thereof directed against IL-6R or the antigen binding fragment or domain thereof is linked to a second VEGF binding unit comprising Ig-like domains 1 and 2 or substantially Ig-like domains 1 and 2 of human VEGFR-3 (or flt-4). In one embodiment, the heavy chain of the antibody or antigen-binding fragment thereof directed against IL-6R or the antigen-binding fragment or domain thereof is linked to a second VEGF binding unit comprising Ig-like domains 2 and 3 or substantially Ig-like domains 2 and 3 of human VEGFR-3 (or flt-4).

As disclosed herein, an "antigen-binding fragment or domain" of a light or heavy chain of an antibody refers to a fragment or portion of such an antibody that comprises complementarity determining regions ("CDRs") of the variable domains of such an antibody. In one embodiment, the antigen binding fragment or domain of such an antibody comprises a variable domain of a light chain or heavy chain of such an antibody. The antigen binding fragment or domain of the heavy chain may further comprise an Fc domain. Other non-limiting examples of antibody fragments or domains include single domain antibodies (sdabs, also known as nanobodies), minibodies, diabodies, trifunctional antibodies, scFv-Fc antibodies, (Fab') ₂ And other antibodies known in the art. Non-limiting examples of sdabs are nanobodies against human IL-6R disclosed in us patent 10,618,964; more specifically, fu Bali bead mab (vobarilizumab), the amino acid sequence of which is set forth below as SEQ ID NO:73.

In one aspect, the antibody fusion proteins of the invention comprise: (1) A heavy chain having an amino acid sequence selected from the group consisting of: 34, 38, 42, 46, 78, 82, 86, 90, 94 and 98; (1) A light chain having an amino acid sequence selected from the group consisting of: 36, 40, 44, 48, 80, 84, 88, 92, 96 and 100.

In example 5, an antibody fusion protein of the invention comprises a pair of IL-6R single chain variable fragments ("IL-6R scFv") or dimers of IL-6R single chain variable fragments, each of which is linked in turn to an Fc domain of IgG1 and a VEGF binding unit comprising: (a) Ig-like domain 2 or substantially Ig-like domain 2 of human VEGFR-1 (or flt-1); and (b) Ig-like domain 3 or substantially Ig-like domain 3 of human VEGFR-2 (or KDR). The amino acid sequence of this example is set forth in SEQ ID NO. 60. The nucleic acid sequence of this example is set forth in SEQ ID NO. 59. In one aspect, the IgG1 is human IgG1.

In example 6, an antibody fusion protein of the invention comprises a pair of IL-6R scFv or dimer of IL-6R scFv; wherein the carboxy terminus (C-terminus) of each IL-6R scFv is linked to a VEGF binding unit comprising: (a) Ig-like domain 2 or substantially Ig-like domain 2 of human VEGFR-1 (or flt-1); and (b) Ig-like domain 3 or substantially Ig-like domain 3 of human VEGFR-2 (or KDR); and the carboxy terminus of each VEGF binding unit is linked to the Fc domain of IgG1. The amino acid sequence of this example is set forth in SEQ ID NO. 62. The nucleic acid sequence of this example is set forth in SEQ ID NO. 61. In one aspect, the IgG1 is human IgG1.

In example 7, an antibody fusion protein of the invention comprises a pair of IL-6R scFv or dimer of IL-6R scFv; wherein the carboxy terminus of each IL-6R scFv is linked to a first VEGF binding unit comprising: (a) Ig-like domain 2 or substantially Ig-like domain 2 of human VEGFR-1 (or flt-1); and (b) Ig-like domain 3 or substantially Ig-like domain 3 of human VEGFR-2 (or KDR); the carboxy terminus of each first VEGF binding unit is linked to the Fc domain of IgG 1; and the carboxy terminus of the Fc domain is linked to a second VEGF binding unit comprising Ig-like domains 1 and 2 or substantially Ig-like domains 1 and 2 of human VEGFR-3 (or flt-4). The amino acid sequence of this example is set forth in SEQ ID NO. 64. The nucleic acid sequence of this example is set forth in SEQ ID NO. 63.

In example 8, an antibody fusion protein of the invention comprises a pair of IL-6R scFv or dimer of IL-6R scFv; wherein the carboxy terminus of each IL-6R scFv is linked to a first VEGF binding unit comprising: (a) Ig-like domain 2 or substantially Ig-like domain 2 of human VEGFR-1 (or flt-1); and (b) Ig-like domain 3 or substantially Ig-like domain 3 of human VEGFR-2 (or KDR); the carboxy terminus of each first VEGF binding unit is linked to a second VEGF binding unit comprising Ig-like domains 1 and 2 or substantially Ig-like domains 1 and 2 of human VEGFR-3 (or flt-4); and the carboxy terminus of the second VEGF binding unit is linked to the Fc domain of IgG 1. The amino acid sequence of this example is set forth in SEQ ID NO. 66. The nucleic acid sequence of this example is set forth in SEQ ID NO. 65.

Example 9 is similar to example 5 except that the Fc domain is linked to the VEGF binding unit by a linker having a different length. The amino acid sequence of this example is set forth in SEQ ID NO. 74. The nucleic acid sequence of this example is set forth in SEQ ID NO. 75.

In example 10, an antibody fusion protein of the invention comprises a pair of IL-6R scFv or dimer of IL-6R scFv; wherein the amino terminus (N-terminus) of each IL-6R scFv is linked to the carboxy terminus (C-terminus) of the Fc domain of IgG1, which amino terminus is linked to a VEGF binding unit comprising: (a) Ig-like domain 2 or substantially Ig-like domain 2 of human VEGFR-1 (or flt-1); and (b) Ig-like domain 3 or substantially Ig-like domain 3 of human VEGFR-2 (or KDR). The amino acid sequence of this example is set forth in SEQ ID NO. 76. The nucleic acid sequence of this example is set forth in SEQ ID NO. 77.

In any of the foregoing embodiments, the VEGF binding unit can be directly linked to the scFv, fc domain, or another VEGF binding unit or linked thereto by a linker. Preferably, the VEGF binding unit is linked to the scFv, fc domain or another VEGF binding unit by a linker.

In yet another embodiment, the antibody fusion proteins of the invention comprise an antibody directed against IL-6R (Fab') ₂ A fragment, wherein each of the light chain and the heavy chain is linked to a VEGF binding unit.

In another embodiment, the antibody fusion proteins of the invention comprise minibodies (minibodies) to antibodies to IL-6R, wherein each of the light and heavy chains is linked to a VEGF binding unit. Such heavy chains may include an Fc region.

In one embodiment, the antibody against human IL-6R ("hIL-6R") includes an antibody called tobrazumab, which is described below: such as U.S. patent 10,323,095;7,479,543; and 5,795,965.

In one aspect, the heavy chain of the antibody fusion protein of the invention comprises the heavy chain complementarity determining regions CDR1, CDR2 and CDR3 ("HCCDR 1", "HCCDR2" and "HCCDR 3") set forth in SEQ ID NOS 53, 54 and 55.

In another aspect, the light chain of the antibody fusion proteins of the invention comprises the light chain complementarity determining regions CDR1, CDR2 and CDR3 ("LCCDR 1", "LCCDR2" and "LCCDR 3") set forth in SEQ ID NOS 56, 57 and 58.

Other antibodies to hIL-6R may be used in the antibody fusion proteins of the invention; sha Lilu mab (sarilumab) as described in us patent 7,582,298; or cetuximab (sarralizumab) described in us patent 8,562,991. In some embodiments, the antibody fusion proteins of the invention may also be produced by linking the heavy and light chains of Sha Lilu mab (SEQ ID NOS: 49 and 50) or rituximab (SEQ ID NOS: 51 and 52) to VEGF binding units as described herein. For example, the heavy and light chains of Sha Lilu mab or sartuzumab can be linked by flexible linkers to VEGF binding units, each comprising the polypeptides of SEQ ID NOs 6 and 8. In other embodiments, the heavy chain of tobrazumab or sartuzumab is linked by a flexible linker to a VEGF binding unit comprising the polypeptide of SEQ ID NO. 10; and the light chain of Sha Lilu mab or sartuzumab is linked via a flexible linker to a VEGF binding unit comprising the polypeptides of SEQ ID NOs 6 and 8.

The VEGF binding units included in the antibody fusion proteins of the invention are capable of binding to at least one member of the VEGF family ("VEGF family member"); whereby the at least one member of the VEGF family is substantially non-binding to VEGF receptors on endothelial cells. Thus, the antibody fusion protein substantially inhibits the biological activity of the at least one VEGF family member to promote angiogenesis; thereby controlling a pathological condition, the etiology of which has abnormal angiogenesis.

In some embodiments, the invention also provides a binding construct comprising or consisting of a plurality of antibody fusion proteins or chimeric proteins as described herein, linked or associated with each other by covalent bonds or other forms of linkage; wherein the antibody portions of such binding constructs may be the same or different. The binding constructs of the invention are capable of binding IL-6R and at least one VEGF family member or a portion thereof and binding with high affinity.

The VEGF binding unit may be linked to the C-terminus (carboxy-terminus) or N-terminus (amino-terminus) of the light and heavy chains of the antibody portion. Preferably, the VEGF binding unit is linked to the C-terminal ends of the light and heavy chains of the antibody portion. More preferably, the VEGF binding unit is linked to the C-terminal ends of the light and heavy chains of the antibody moiety by a flexible linker.

The light or heavy chain of the antibody portion of the antibody fusion protein is preferably linked to a VEGF binding unit. However, the light or heavy chain of the antibody portion may be linked to more than one VEGF binding unit. In this case, the VEGF binding units may be joined together directly or through a linker. The antibody fusion protein or binding construct may further comprise a heterologous peptide or other chemical moiety. Such additions may alter their properties such as stability, solubility, toxicity, serum half-life, immunogenicity, detectability, or other properties.

The term "high affinity" is used in a physiological context and refers to the relative affinity of an antibody fusion protein to IL-6R and a member of the VEGF family in a mammal (laboratory test animal, domestic farm or pet animal or human). The antibody fusion proteins of the invention that bind IL-6R and various VEGF members have a characteristic affinity for their in vivo ligands, typically with a subnanomolar dissociation constant (K _d ) And (5) measuring. For the purposes of the present invention, the antibody fusion proteins of the present invention may bind to IL-6R or a member of the VEGF family targeted thereto, K _d K less than or equal to native IL-6/IL-6R or growth factor/receptor pair _d About 1, or about 5, or about 10, or about 50, or about 100, or about 500, or about 1000 times.

In one aspect, the Ig-like domains of the VEGF binding units can be linked together directly or through an intermediate linker in any order.

In another aspect, the targeted VEGF family member can bind to one or more VEGF binding units of an antibody fusion protein or chimeric protein.

In yet another aspect, the VEGF binding unit comprises substantially an Ig-like domain of a VEGF receptor.

In another aspect, the VEGF binding unit comprises two Ig-like domains selected from the group consisting of: ig-like domains of human VEGFR-1, VEGFR-2 and VEGFR-3.

In still another aspect, each of the light and heavy chains of the antibody fusion protein or chimeric protein of the invention is linked to a VEGF binding unit comprising: (a) Ig-like domain 2 or substantially Ig-like domain 2 of human VEGFR-1 (or flt-1); and (b) Ig-like domain 3 or substantially Ig-like domain 3 of human VEGFR-2 (or KDR). In one embodiment, such VEGF binding units are linked to the C-terminus of the light and heavy chains of the antibody portion.

In still another aspect, each light chain of the antibody fusion protein or chimeric protein of the invention is linked to a first VEGF binding unit comprising: (a) Ig-like domain 2 or substantially Ig-like domain 2 of human VEGFR-1 (or flt-1); and (b) Ig-like domain 3 or substantially Ig-like domain 3 of human VEGFR-2 (or KDR); and each heavy chain of the antibody fusion protein is linked to a second VEGF binding unit comprising Ig-like domains 1 and 2 or substantially Ig-like domains 1 and 2 of VEGFR-3 (or flt-4). In another embodiment, the second VEGF binding unit comprises Ig like domains 2 and 3 or substantially Ig like domains 2 and 3 of VEGFR-3. In yet another embodiment, the second VEGF binding unit comprises at least one Ig-like domain selected from the group consisting of: ig-like domains 1, 2 and 3 or substantially Ig-like domains 1, 2 and 3 of VEGFR-3. In yet another embodiment, such VEGF binding units are linked to the C-terminus of the light and heavy chains of the antibody portion.

In some embodiments, two or more VEGF binding units act together to bind a single ligand molecule of the VEGF family (wherein the ligand may comprise a monomer or dimer). In some other embodiments, the binding units function independently, i.e., each binding unit binds an individual ligand molecule.

In one embodiment, a polypeptide linker is inserted between the C-terminus of the light or heavy chain of the antibody moiety and the VEGF binding unit. The polypeptide linker may be the same or different for the light and heavy chains.

In one aspect, the amino acid sequences of the various portions or examples of the antibody fusion proteins of the invention are listed in table 1.

TABLE 1

Amino acid sequence

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On the other hand, the nucleic acid sequences encoding the amino acid sequences of the respective portions or examples of the antibody fusion proteins of the present invention are listed in table 2.

TABLE 2

Nucleic acid sequences

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In yet another aspect, the antibody fusion protein or chimeric protein of the invention comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 74 or SEQ ID NO. 76.

In yet another aspect, the antibody fusion protein or chimeric protein of the invention comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30, or SEQ ID NO. 32, SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 74, or SEQ ID NO. 76.

In still another aspect, one or more amino acid substitutions may be made in any of the above amino acid sequences. Preferably, such substitutions are conservative substitutions, wherein an amino acid in one of the following groups is substituted by another in the same group: (1) A, S, T; (2) D, E; (3) N, Q; (4) R, K; (5) I, L, M, V; and (6) F, Y, W; and such substitutions are selected in a manner that substantially retains the binding activity of the fusion polypeptide. In one embodiment, the antibody fusion proteins of the invention with conservative substitutions are K for IL-6R or VEGF ligand _d Values are less than about 120% prior to such substitution. Preferably, the K _d Values are less than about 110% prior to such substitution. More preferably, the K _d The value was less than about 105% prior to such substitution.

Most conservative substitutions are not expected to produce a fundamental change in the identity of the Ig-like domain or the domain of the fusion polypeptide. However, when it is difficult to predict the exact effect of a substitution before doing so, those skilled in the art will understand that the effect will be assessed by conventional screening assays. For example, ig-like domain variants are typically made by site-specific mutagenesis of a nucleic acid encoding the complete fusion polypeptide, expression of the variant nucleic acid in recombinant cell culture, purification of the variant fusion polypeptide from the cell culture, and detection of the ability of the variant fusion polypeptide to specifically bind to IL-6R or VEGF ligand. Exemplary binding assays that can be used to determine whether one or more specific substitutions in one or more Ig-like domains affect the ability of a fusion polypeptide to bind to and inhibit the activity of an IL-6R or VEGF family member are described in Park et al, J.Biol.chem.), 269:25646-25654 (1994).

The VEGFR-1-D2 binding unit of the fusion protein is capable of binding free VEGF-A, VEGF-B and placental growth factor ("PlGF") with high affinity (Davis-Smyth et al, J. European molecular biology (EMBO J.)), 15 (18): 4919 (1996)). The VEGFR-2-D3 binding unit of the fusion protein is capable of binding free VEGF-A, VEGF-C and VEGF-D with high affinity (Stuttgeld et al, life, 61 (9): 915 (2009)). The VEGFR-3-D1D2 binding units of the fusion proteins are capable of binding free VEGF-C and VEGF-D with high affinity. Thus, the fusion proteins of the invention are capable of substantially inhibiting the angiogenic activity of these VEGF family members on endothelial cells at the site of disease.

In yet another aspect, the invention provides isolated nucleic acid molecules encoding the heavy and light chains of the antibody fusion proteins.

In yet another aspect, the invention provides an isolated nucleic acid molecule encoding the antibody fusion protein; wherein the isolated nucleic acid molecule comprises: (a) Nucleic acid sequences encoding the heavy chain of an antibody against human IL-6R ("hIL-6R antibody") or an antigen binding fragment or domain thereof; (b) A nucleic acid sequence encoding the light chain of said hll-6R antibody or an antigen binding fragment or domain thereof; and (c) a nucleic acid sequence encoding an Ig-like domain of a VEGF receptor operably linked to each of the nucleic acid sequence encoding a heavy chain of the hll-6R antibody or an antigen-binding fragment or domain thereof and the nucleic acid sequence encoding a light chain of the hll-6R antibody or an antigen-binding fragment or domain thereof.

In yet another aspect, the invention provides an isolated nucleic acid molecule encoding the antibody fusion protein; wherein the isolated nucleic acid molecule comprises: (a) Nucleic acid sequences encoding the heavy chain or antigen binding fragment or domain of an hll-6R antibody; (b) A nucleic acid sequence encoding the light chain of said hll-6R antibody or an antigen binding fragment or domain thereof; and (c) nucleic acid sequences encoding VEGFR-1-D2 and VEGFR-2-D3, said nucleic acid sequences being operably linked to each of said nucleic acid sequence encoding the heavy chain of said hIL-6R antibody or antigen binding fragment or domain thereof and said nucleic acid sequence encoding the light chain of said hIL-6R antibody or antigen binding fragment or domain thereof.

In yet another aspect, the invention provides an isolated nucleic acid molecule encoding the antibody fusion protein; wherein the isolated nucleic acid molecule comprises: (a) A nucleic acid sequence encoding a heavy chain of an hll-6R antibody or an antigen binding fragment or domain thereof, said nucleic acid sequence having the sequence set forth in SEQ ID No. 1; (b) A nucleic acid sequence encoding the light chain of said hll-6R antibody or an antigen binding fragment or domain thereof, said nucleic acid sequence having the sequence set forth in SEQ ID No. 3; and (c) a nucleic acid sequence encoding VEGFR-1-D2 and VEGFR-2-D3 having the sequences set forth in SEQ ID NOs 5 and 7 operably linked to each of the nucleic acid sequence encoding the heavy chain of the hIL-6R antibody or an antigen binding fragment or domain thereof and the nucleic acid sequence encoding the light chain of the hIL-6R antibody or an antigen binding fragment or domain thereof.

In yet another aspect, the invention provides an isolated nucleic acid molecule encoding the antibody fusion protein; wherein the isolated nucleic acid molecule comprises: (a) Nucleic acid sequences encoding the heavy chain or antigen binding fragment or domain of an hll-6R antibody; (b) A nucleic acid sequence encoding the light chain of said hll-6R antibody or an antigen binding fragment or domain thereof; (c) A nucleic acid sequence encoding VEGFR-3-D1D2 operably linked to the nucleic acid sequence encoding the heavy chain of the hIL-6R antibody or antigen binding fragment or domain thereof; and (D) nucleic acid sequences encoding VEGFR-1-D2 and VEGFR-2-D3 operably linked to said nucleic acid sequence encoding the light chain of said hIL-6R antibody or antigen binding fragment or domain thereof. In some embodiments, the nucleic acid sequence encoding VEGFR-3-D1D2 is replaced with a nucleic acid sequence encoding at least one VEGFR-3 Ig-like domain selected from the group consisting of: VEGFR-3-D1, VEGFR-3-D2, and VEGFR3-D3.

In yet another aspect, the invention provides an isolated nucleic acid molecule encoding the antibody fusion protein; wherein the isolated nucleic acid molecule comprises: (a) A nucleic acid sequence encoding a heavy chain of an hll-6R antibody or an antigen binding fragment or domain thereof, said nucleic acid sequence having the sequence set forth in SEQ ID No. 1; (b) A nucleic acid sequence encoding the light chain of said hll-6R antibody or an antigen binding fragment or domain thereof, said nucleic acid sequence having the sequence set forth in SEQ ID No. 3; (c) A nucleic acid sequence encoding VEGFR-3-D1D2 having the sequence set forth in SEQ ID No. 9 operably linked to said nucleic acid sequence encoding the heavy chain of said hIL-6R antibody or antigen binding fragment or domain thereof; and (D) nucleic acid sequences encoding VEGFR-1-D2 and VEGFR-2-D3 having the sequences set forth in SEQ ID NOs 5 and 7 operably linked to the nucleic acid sequence encoding the light chain of the hIL-6R antibody or an antigen binding fragment or domain thereof. In some embodiments, the nucleic acid sequence encoding VEGFR-3-D1D2 is replaced with a nucleic acid sequence encoding at least one VEGFR-3 Ig-like domain selected from the group consisting of: VEGFR-3-D1, VEGFR-3-D2, and VEGFR3-D3.

In still another aspect, the invention provides an isolated nucleic acid molecule encoding the heavy chain of the antibody fusion protein, said isolated nucleic acid molecule having the sequence set forth in SEQ ID NO. 17, 21, 25, 29, 79, 83, 87, 91, 95 or 99; and an isolated nucleic acid molecule encoding the light chain of the fusion protein, the isolated nucleic acid molecule having the sequence set forth in SEQ ID NO. 19, 23, 27, 31, 81, 85, 89, 93, 97 or 101.

In yet another aspect, the isolated nucleic acid molecule may further comprise a leader nucleic acid sequence encoding a signal polypeptide. In certain embodiments, wherein the VEGF binding unit is attached to the C-terminus of the heavy or light chain of the antibody portion, the leader sequence precedes SEQ ID NOS: 1 and 3.

In another aspect, the invention provides an isolated nucleic acid molecule encoding the antibody fusion protein or chimeric protein; wherein the isolated nucleic acid molecule comprises a nucleic acid sequence that differs from one or more codons of a nucleic acid sequence listed in the disclosure due to the degeneracy of the genetic code. Such different nucleic acid sequences are within the scope of the invention.

In yet another aspect, the invention provides a vector comprising any of the nucleic acid molecules, including an expression vector comprising any of the nucleic acid molecules operably linked to an expression control sequence. Examples of vectors include nucleic acid sequences selected from the group consisting of: SEQ ID NO 17, SEQ ID NO 19, SEQ ID NO 21, SEQ ID NO 23, SEQ ID NO 25, SEQ ID NO 27, SEQ ID NO 29, SEQ ID NO 31, SEQ ID NO 59, SEQ ID NO 61, SEQ ID NO 63, SEQ ID NO 65, SEQ ID NO 75, SEQ ID NO 77, SEQ ID NO 79, SEQ ID NO 81, SEQ ID NO 83, SEQ ID NO 85, SEQ ID NO 87, SEQ ID NO 89, SEQ ID NO 91, SEQ ID NO 93, SEQ ID NO 95, SEQ ID NO 97, SEQ ID NO 99 and SEQ ID NO 101.

In one aspect, the invention provides the construction of nucleic acid molecules encoding the heavy and light chains of the antibody fusion proteins disclosed herein, inserted into vectors capable of expressing the antibody fusion proteins when introduced into a suitable host cell. Suitable host cells include, but are not limited to, bacterial cells, yeast cells, insect cells, and mammalian cells. Any method known to those skilled in the art for inserting a DNA fragment into a vector can be used to construct an expression vector encoding a chimeric polypeptide molecule under the control of a transcription/translation control signal. These methods may include recombinant DNA and synthetic techniques in vitro and recombinant (gene recombination) in vivo (see Sambrook et al, molecular cloning: laboratory Manual (Molecular Cloning, ALaboratory Manual), cold spring harbor laboratory Press (Cold Spring Harbor Press), current national institute of molecular biology (Current Protocols in Molecular Biology), editions, ausubel et al, green publishing Association (Greene publication. Assoc.), wiley International science Press (Wiley-Interscience), new York).

Expression of the nucleic acid molecule encoding the antibody fusion protein of the invention may be regulated by a second nucleic acid sequence (promoter) such that the antibody fusion protein is expressed in a host transformed with the nucleic acid molecule. For example, expression of the antibody fusion proteins described herein can be controlled by any promoter/enhancer element known in the art.

Typically, plasmid vectors containing replicon and control sequences derived from species compatible with the host cell are used in conjunction with these hosts. The vector typically carries a replication site and a marker sequence capable of providing phenotypic selection in the transformed cell. For example, E.coli (E.coli) is typically transformed with pBR322 (i.e., a plasmid derived from E.coli species) (see, e.g., bolivar et al, gene, 2:95 (1977)). Plasmid pBR322 contains ampicillin and tetracycline resistance genes and thus provides a simple method for identifying transformed cells. The pBR322 plasmid or other microbial plasmid or phage must also contain or be modified to contain promoters that can be used by the microbial organism to express the protein.

Those most commonly used in recombinant DNA construction include the beta-lactamase (penicillinase) and lactose promoter systems or tryptophan (trp) promoter systems (Goeddel et al, nucleic Acids research, 8:4057 (1980)). While these are most commonly used, other microbial promoters have been found and utilized. For example, the tac promoter is a synthetically produced DNA promoter produced from a combination of promoters from trp and lac operons (de Boer et al, proc. Natl. Acad. Sci. USA (PNAS), (1983-01-80 (1): 21-25 (1983)). It is commonly used for protein production in E.coli (Amann et al, gene 25:167 (1983)). Any of these promoters may be used in combination with the method of producing the antibody fusion protein of the invention.

In addition to prokaryotes, eukaryotic microorganisms, such as yeast cultures, may also be used. Saccharomyces cerevisiae (Saccharomyces cerevisiae) or Saccharomyces cerevisiae is the most commonly used among eukaryotic microorganisms, although many other strains are commonly available. For expression in Saccharomyces, for example, the plasmid YRp7 (Stinchcomb et al, nature, 282:39 (1979)) is generally used. Other exemplary plasmids are disclosed in U.S. patent 4,615,974; struhl et al, proc. Natl. Acad. Sci. USA, 76 (3): 1035 (1979). Plasmid YRp7 contains the trp1 gene which provides a selectable marker for a mutant strain of yeast lacking growth capacity in the absence of tryptophan, such as ATCC No. 44,076 or RH218 (Jones, genetics, 85:23 (1977)). The presence of trp1 lesions, which are characteristic of the yeast host cell genome, then provides an effective environment for detection of transformation by growth in the absence of tryptophan.

Suitable promoter sequences in Yeast vectors include 3-phosphoglycerate kinase (Hitzeman et al, J Biol chem.), 255:2073 (1980)) or promoters for other glycolytic enzymes, such as glyceraldehyde-3-phosphate dehydrogenase, hexokinase, pyruvate decarboxylase and glucokinase (Romanos et al, yeast (Yeast), 8:423 (1992), weinhandl et al, microbial cell factories (Microb Cell factories), 13:5 (2014)). In constructing a suitable expression plasmid, termination sequences associated with these genes are also ligated into the expression vector 3' of the sequence desired to be expressed to provide polyadenylation and termination of the mRNA. Other promoters with the additional advantage of transcription controlled by growth conditions, such as the promoter region of alcohol dehydrogenase 2, and the enzymes responsible for maltose and galactose utilization (Romanos et al, weinhandl et al, supra). Any plasmid vector containing a yeast compatible promoter, an origin of replication and a termination sequence is suitable.

In addition to microorganisms, cell cultures derived from multicellular organisms may also be used as hosts. In principle, any such cell culture, whether from vertebrate or invertebrate cultures, is possible. However, there is much interest in vertebrate cells, and in recent years, propagation of vertebrate cells in Culture (Tissue Culture) has become a routine procedure (Tissue Culture, academic Press, kruse and Patterson, editions (1973)). Examples of such useful host cell lines are VERO and HeLa cells, chinese Hamster Ovary (CHO) cell lines, and W138, BHK, COS-7, 293 and MDCK cell lines. Expression vectors for such cells typically include, if desired, an origin of replication, a promoter located in front of the gene to be expressed, any necessary ribosome binding sites, RNA splice sites, polyadenylation sites and transcription terminator sequences.

For use in mammalian cells, control functions on the expression vector are typically provided by viral material. For example, the commonly used promoters are derived from polyoma virus, adenovirus 2, and most commonly simian virus 40 (SV 40). The early and late promoters of SV40 virus are particularly useful because both can be readily obtained from the virus as fragments that also comprise the SV40 viral origin of replication (Fiers et al, nature 273:113 (1978)). Smaller or larger SV40 fragments may also be used, provided that they comprise an approximately 250bp sequence extending from the HindIII site toward the BglI site at the viral origin of replication. Furthermore, it may also be and often is desirable to utilize promoters or control sequences that are typically associated with the desired gene sequence, provided that such control sequences are compatible with the host cell system.

Thus, according to the invention, expression vectors capable of replication in bacterial, yeast, insect or mammalian cell hosts comprising nucleic acids encoding antibody fusion proteins as described herein are used to transfect hosts and thereby direct expression of such nucleic acids to produce fusion polypeptides, which can then be recovered in biologically active form. As used herein, a biologically active form includes a form capable of binding to at least one VEGF family member.

In some embodiments, the host cell may be an E.coli, COS cell, HEK 293 cell (also simply referred to as 293 cell), or Chinese hamster ovary ("CHO") cell. Preferably, the host cell is a HEK 293 or CHO cell.

Vector construction

Construction of a suitable vector containing the desired coding and control sequences employs standard ligation techniques. The isolated plasmid or DNA fragment is cut, sheared and ligated into the desired form to form the desired plasmid. The method employed is independent of the source of the DNA or the intended host. Cleavage is performed by treatment with one or more restriction enzymes in a suitable buffer.

Nucleic acid sequences substantially encoding one or more Ig-like domains of VEGFR-1, VEGFR-2 or VEGFR-3 may be generated according to the methods disclosed in U.S. Pat. No. 6,897,294.

In one embodiment, the nucleic acid sequences encoding substantially Ig-like domain 2 of VEGFR-1 and Ig-like domain 3 of VEGFR-2 are linked in tandem in the desired order. This construct is then ligated to the 3' end of the nucleic acid sequences encoding the heavy and light chains of the hIL-6R antibody. In another embodiment, this construct is linked to the 3' end of the nucleic acid sequence encoding the light chain of the hIL-6R antibody. Another nucleic acid construct comprises a nucleic acid sequence substantially encoding Ig-like domains 1 and 2, or 2 and 3, or 1, 2 and 3 of VEGFR-3 linked to the 3' end of the nucleic acid sequence encoding the heavy chain of a hIL-6R antibody. Such complete nucleic acid sequences are referred to as chimeric nucleic acid sequences.

The entire chimeric nucleic acid sequence is then placed in a vector comprising a promoter that is in frame with the gene and compatible with the intended host cell. Many plasmids, such as those described in the following: us patent 4,456,748;5,460,811;5,888,808; and 6,333,147, can be used to produce the antibody fusion proteins of the invention.

In one embodiment, the chimeric heavy and chimeric light chains of the antibody fusion proteins of the invention are produced according to the methods described in U.S. patent 7,070,959. The chimeric nucleic acid sequence of SEQ ID NO. 17, 19, 21, 23, 25, 27, 29, 59, 61, 63, 65, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99 or 101 was inserted into expression vector pEE14.1 (Lonza Biologics)) with a CMV promoter.

In one embodiment, CHO K1 cells are transfected with pEE14.1/SEQ ID NO:17 and pEE14.1/SEQ ID NO:19 constructs and then cultured. Antibody fusion proteins obtained from CHO cells can be purified and characterized by binding assays as described in us patent 7,070,959.

Similarly CHO K1 or HEK293 cells were transfected with the following vector pairs: pEE14.1/SEQ ID NO. 21 and pEE14.1/SEQ ID NO. 23; or pEE14.1/SEQ ID NO. 25 and pEE14.1/SEQ ID NO. 27; or pEE14.1/SEQ ID NO. 29 and pEE14.1/SEQ ID NO. 31; or pcDNA3.4/SEQ ID NO. 79 and pcDNA3.4/SEQ ID NO. 81; or pcDNA3.4/SEQ ID NO. 83 and pcDNA3.4/SEQ ID NO. 85; or pcDNA3.4/SEQ ID NO. 87 and pcDNA3.4/SEQ ID NO. 89; or pcDNA3.4/SEQ ID NO. 91 and pcDNA3.4/SEQ ID NO. 93; or pcDNA3.4/SEQ ID NO. 95 and pcDNA3.4/SEQ ID NO. 97; or pcDNA3.4/SEQ ID NO. 99 and pcDNA3.4/SEQ ID NO. 101. Antibody fusion proteins obtained from these CHO or HEK293 cells can be similarly purified and characterized.

In one embodiment, the antibody fusion proteins of the invention may be expressed as K _d ≤10 ^-9 M binds to hIL-6R and VEGF family members. In another embodiment, the antibody fusion proteins of the invention may be expressed as K _d ≤5×10 ^-10 M binds to VEGF family members. In yet another embodiment, the antibody fusion proteins of the invention may be expressed as K _d ≤10 ^-10 M binds to VEGF family members.

In one aspect, the invention provides compounds, compositions and methods for treating or controlling a disease, condition or disorder whose etiology is abnormal angiogenesis.

In another aspect, the invention provides a method of treating or controlling at least one ocular disease, condition, or disorder in a subject, the ocular disease, condition, or disorder having abnormal angiogenesis as a cause of the disease, condition, or disorder. The methods comprise administering to a subject in need of such treatment or control a composition comprising an antibody fusion protein disclosed herein. Such antibody fusion proteins comprise a heavy chain and light chain pair having: SEQ ID NOS 18 and 20; or SEQ ID NOS.22 and 24; or SEQ ID NOS 26 and 28; or SEQ ID NOS 30 and 32; or SEQ ID NOS 78 and 80; or SEQ ID NOS 82 and 84; or SEQ ID NOS 86 and 88; or SEQ ID NOS 90 and 100. In one embodiment, the antibody fusion proteins used in such methods may comprise pairs of proteins having the sequences set forth in SEQ ID NOs 60, 62, 64, 66, 74 or 76 or dimers of said proteins. In another embodiment, the antibody fusion protein used in such methods may comprise a protein pair having a sequence starting from amino acid 17 of SEQ ID NO. 60, 62, 64, 66, 74 or 76 or a dimer of said proteins.

In still another aspect, the ocular disease, condition, or disorder is selected from the group consisting of: choroidal neovascularization, neovascular age-related macular degeneration (wet age-related macular degeneration), polypoidal choroidal vasculopathy ("PCV"), myopic choroidal neovascularization, vascular leakage, macular edema caused by diabetes, uveitis, central and branch retinal vein occlusion, nonproliferative and proliferative diabetic retinopathy, retinopathy of prematurity, corneal neovascularization, corneal inflammation, and neovascular glaucoma.

In one embodiment, the fusion polypeptide is administered to the subject at a dose of about 25-4000 micrograms. In another embodiment, the subject is administered a dose of about 50-4000, about 100-4000, about 500-4000, about 1000-4000, about 2000-4000, about 50-3000, about 50-2000, about 50-1000, or about 50-500 micrograms of the fusion polypeptide.

In still another aspect, the composition comprising the fusion polypeptide is in the form of an eye drop or eye injection, such as an intravitreal injection, an intracameral (intra-anterior) injection, a periorbital injection, a subcapsular (subtenon) injection, a subretinal injection, or a suprachoroidal injection. Such compositions comprise ophthalmic compositions. The antibody fusion proteins of the invention may also be incorporated into medical devices that are implantable in or near diseased tissue.

In one embodiment, the invention provides a method or composition for treating or controlling an anterior-segment (anti-segment) disease, condition, or disorder; such as corneal neovascularization, corneal inflammation, or neovascular glaucoma. The composition comprising the fusion polypeptide may be in the form of eye drops or an intracameral or subconjunctival injection. In another embodiment, the invention provides a method or composition for treating or controlling a posterior-segment (posterior-segment) disease, condition, or disorder; such as choroidal neovascularization, neovascular age-related macular degeneration (wet age-related macular degeneration), polypoidal choriocaulopathy ("PCV"), myopic choroidal neovascularization, vascular leakage, macular edema caused by diabetes, uveitis, central and branch retinal vein occlusion, nonproliferative and proliferative diabetic retinopathy, retinopathy of prematurity. In this case, the composition comprising the fusion polypeptide may be administered in the form of an intravitreal injection.

In yet another aspect, the eye drops are administered to the subject at least once daily, at least once weekly, or at least once monthly until the disease, condition, or disorder is substantially treated or controlled.

In yet another aspect, the composition is administered to the subject by sustained drug release for a period of at least one month, at least two months, at least three months, or at least six months.

In still another aspect, intravitreal injection is administered to a subject or injection into or near diseased tissue according to a regimen recommended by a medical practitioner for a particular patient. For example, the injection may be administered at least once a month, at least once every two months, at least once every three months, or at least once every six months until the disease, condition, or disorder is substantially treated or controlled. In one embodiment, the treatment may be administered more frequently at the beginning and then reduced in frequency after a period of time. Such a period of time may be determined by a healthcare practitioner.

The concentration of the antibody fusion proteins of the invention in such ophthalmic compositions may range from about 0.1 to about 200mg/ml (or alternatively from about 0.25 to about 200mg/ml, or from about 0.25 to about 160mg/ml, or from about 0.5 to about 100mg/ml, or from about 0.25 to about 50mg/ml, or from about 0.5 to about 200mg/ml, or from about 0.5 to about 160mg/ml, or from about 0.5 to about 100mg/ml, or from about 0.5 to about 50mg/ml, or from about 1 to about 200mg/ml, or from 1 to about 160mg/ml, or from about 0.5 to about 100mg/ml, or from about 1 to about 50 mg/ml).

In yet another aspect, a method of preparing a composition of the present invention comprises combining: (a) an amount of an antibody fusion protein of the invention; and (b) a physiologically acceptable carrier (carrier).

In one embodiment, such a physiologically acceptable carrier may be a sterile saline solution or a physiologically acceptable buffer. In another embodiment, such carriers comprise a hydrophobic medium, such as a pharmaceutically acceptable oil. In yet another embodiment, the carrier comprises an emulsion of a hydrophobic material and water, for example. In yet another embodiment, the antibody fusion proteins of the invention may be associated or linked with high molecular weight materials to provide long circulation times.

Physiologically acceptable buffers include, but are not limited to, phosphate buffers or Tris-HCl buffers (including Tris (hydroxymethyl) aminomethane and HCl). For example, tris-HCl buffer at pH 7.4 contains 3g/l Tris (hydroxymethyl) aminomethane and 0.76g/l HCl. In yet another aspect, the buffer is 10X phosphate buffered saline ("PBS") or 5X PBS solution. Non-limiting examples of buffers for injectable compositions comprising biological products include phosphate, citric acid, acetic acid, tromethamine, histidine, arginine, gluconic acid, lactic acid, tartaric acid, aspartic acid, and glutamic acid.

In some cases, other buffers may also be found to be suitable or desirable, e.g., pK at 25℃ _a HEPES (N- { 2-hydroxyethyl } piperazine-N' - { 2-ethanesulfonic acid }) based buffer at 7.5 and a pH in the range of about 6.8-8.2; pK at 25 ℃ _a BES (N, N-bis { 2-hydroxyethyl } 2-aminoethanesulfonic acid) at 7.1 and a pH in the range of about 6.4-7.8; pK at 25 ℃ _a MOPS (3- { N-morpholino } propanesulfonic acid) at 7.2 and a pH in the range of about 6.5-7.9; pK at 25 ℃ _a TES (N-tris { hydroxymethyl } -methyl-2-aminoethanesulfonic acid) at 7.4 and a pH in the range of about 6.8-8.2; pK at 25 ℃ _a MOBS (4- { N-morpholino } butanesulfonic acid) of 7.6 and a pH in the range of about 6.9-8.3; pK at 25 ℃ _a DIPSO (3- (N, N-bis { 2-hydroxyethyl } amino) -2-hydroxypropane) at 7.52 and a pH in the range of about 7-8.2; pK at 25 ℃ _a TAPSO (2-hydroxy-3 { tris (hydroxymethyl) methylamino } -1-propanesulfonic acid) at 7.61 and pH in the range of about 7-8.2.

In certain embodiments, the compositions of the present invention are formulated in a buffer having an acidic pH (e.g., about 4 to about 6.8, or alternatively about 5 to about 6.8). In such embodiments, the buffering capacity of the composition desirably allows the composition to quickly reach physiological pH after being administered to a patient.

In addition to the buffer, the composition of the invention may comprise a material selected from the group consisting of: surfactants, stabilizers, preservatives, co-solvents, humectants, emollients, chelating agents, tonicity adjusting agents and antioxidants.

In one aspect, any of these materials that may be used in the compositions of the present invention are physiologically acceptable materials. In certain embodiments, any of these materials that may be used in the compositions of the present invention are ophthalmically acceptable materials.

Water-soluble preservatives that may be used include quaternary ammonium compounds such as benzalkonium chloride and various polyquaternary ammonium compounds. These agents may be present in individual amounts of about 0.001 wt.% to about 2 wt.% (preferably, about 0.01 wt.% to about 0.05 wt.%).

Non-limiting examples of surfactants include, but are not limited to, nonionic surfactants such as polysorbates (e.g., polysorbate 20, polysorbate 80), 4- (1, 3-tetramethylbutyl) phenol/poly (oxyethylene) polymers (e.g., polymers sold under the trademark Tyloxapol), poly (oxyethylene) -poly (oxypropylene) block copolymers, glycolate esters of fatty acids, and the like, and mixtures thereof.

In one aspect, the pH of the composition is in the range of about 4 to about 8. Alternatively, the pH of the composition is in the range of about 6 to about 8, or about 6.5 to about 7.5.

In another aspect, the pH of the composition is about 7. Alternatively, the pH of the composition is in the range of about 7 to about 7.5.

In still another aspect, the pH of the composition is about 7.4.

In yet another aspect, the composition may further comprise a viscosity modifying compound designed to facilitate administration of the composition into a subject or to facilitate bioavailability of the subject. In still another aspect, the viscosity modifying compound may be selected such that the composition is not readily dispersible after application to the ocular environment. Such compounds may enhance the viscosity of the composition and include, but are not limited to: monomeric polyols such as glycerol, propylene glycol, ethylene glycol; polymeric polyols such as polyethylene glycol; various polymers of the cellulose family, such as hydroxypropyl methylcellulose ("HPMC"), sodium carboxymethyl cellulose ("CMC"), hydroxypropyl cellulose ("HPC"); polysaccharides, such as hyaluronic acid and salts thereof, chondroitin sulfate and salts thereof, glucans, such as glucan 70; water-soluble proteins such as gelatin; vinyl polymers such as polyvinyl alcohol, polyvinylpyrrolidone, povidone; carbomers, such as carbomer 934P, carbomer 941, carbomer 940 or carbomer 974P; and an acrylic polymer. In general, the desired viscosity may be in the range of about 1 to about 400 centipoise ("cps") or mpa.s.

Non-limiting examples of chelating agents include ethylenediamine tetraacetic acid ("EDTA"), diethylenetriamine penta (methylphosphonic acid), hydroxyethylidene diphosphonic acid, tetra sodium salt of hydroxyethylidene diphosphonic acid (also known as "HAP").

While the buffer itself is a "tonicity adjuster" and "pH adjuster" that broadly maintains the ophthalmic solution at a specific ionic concentration and pH, additional "tonicity adjusters" may be added to adjust the final tonicity of the solution. Such tonicity adjusting agents are well known to those skilled in the art and include, but are not limited to, mannitol, sorbitol, dextrose, sucrose, urea, propylene glycol, and glycerin. In addition, various salts may be used, including halide salts of monovalent cations (e.g., naCl or KCl). Typically, the tonicity of the formulations of the present invention is in the range of about 200 to 400 mOsm/kg. Alternatively, the tonicity of the formulation of the invention is in the range of about 220 to 400mOsm/kg, or about 220 to 350mOsm/kg, or about 220 to 300mOsm/kg, or about 250 to 350 mOsm/kg.

Non-limiting examples of antioxidants include: ascorbic acid (vitamin C) and salts and esters thereof; tocopherols (e.g., alpha-tocopherol) and tocotrienols (vitamin E), as well as salts and esters thereof (e.g., vitamin E TGPS (D-alpha-tocopheryl polyethylene glycol 1000 succinate)); glutathione; lipoic acid; uric acid; tertiary butylated hydroxyanisole ("BHA"); tertiary butylated hydroxytoluene ("BHT"); tertiary butyl hydroquinone ("TBHQ"); and polyphenol antioxidants (such as gallic acid, cinnamic acid, flavonoids, and salts, esters, and derivatives thereof).

Non-limiting examples of stabilizers include sucrose, mannitol, sorbitol, and trehalose.

It will be appreciated that the proportions of the various components or mixtures in the examples below may be adjusted as appropriate.

In another aspect, the antibody fusion proteins of the invention and appropriate amounts of one or more desired excipients are incorporated into a formulation for topical administration or injection into a portion of the eye, such as the anterior or posterior segment or the vitreous humor. The injectable formulation may desirably contain a carrier that provides sustained release of the active ingredient, such as for a period of time exceeding about 1 week (or exceeding about 1, 2, 3, 4, 5, or 6 months). In certain embodiments, the antibody fusion proteins of the invention are included in a delivery device to provide sustained release of the active ingredient over a prolonged period of time, such as 4, 5, 6 months or longer. Examples of such delivery devices are described in U.S. patent nos. 8,399,006 and 9,417,238.

In still another aspect, a composition comprising an antibody fusion protein of the invention and a desired excipient is lyophilized and reconstituted with a physiologically acceptable liquid carrier substantially immediately prior to administration to a subject.

In one embodiment, the compounds or compositions of the invention may be injected with a fine gauge needle, such as a 25-35 gauge needle. Typically, an amount of about 25. Mu.l to about 100. Mu.l of a composition comprising about 25-4000. Mu.g of an antibody fusion protein of the invention is administered to a patient. In one embodiment, the antibody fusion protein has heavy and light chain amino acid sequences substantially as set forth below: SEQ ID NOS 18 and 20; or SEQ ID NOS.22 and 24; or SEQ ID NOS 26 and 28; or SEQ ID NOS 30 and 32; or SEQ ID NOS 78 and 80; or SEQ ID NOS 82 and 84; or SEQ ID NOS 86 and 88; or SEQ ID NOS 90 and 100. In another embodiment, the antibody fusion proteins used in such procedures may comprise pairs of proteins having sequences substantially as set forth in SEQ ID NOs 60, 62, 64, 66, 74 or 76 or dimers of said proteins. In yet another example, an antibody fusion protein for use in such a procedure may comprise a protein pair having a sequence starting at amino acid 17 of a sequence substantially as set forth in SEQ ID NOs 60, 62, 64, 66, 74 or 76, or a dimer of said protein. In yet another embodiment, the antibody fusion protein has the heavy and light chain amino acid sequences as set forth below: SEQ ID NOS 18 and 20; or SEQ ID NOS.22 and 24; or SEQ ID NOS 26 and 28; or SEQ ID NOS 30 and 32; or SEQ ID NOS 78 and 80; or SEQ ID NOS 82 and 84; or SEQ ID NOS 86 and 88; or SEQ ID NOS 90 and 100. In yet another example, an antibody fusion protein for use in such a procedure may comprise a protein pair having a sequence starting at amino acid 17 of the sequence set forth in SEQ ID NO 60, 62, 64, 66, 74 or 76, or a dimer of said protein. The concentration of such antibody fusion proteins is selected from the ranges disclosed above.

In yet another aspect, the antibody fusion proteins of the invention are incorporated into an ophthalmic device comprising a biodegradable material, and the device is implanted into the posterior segment tissue of a subject to provide long term (e.g., longer than about 1 week or longer than about 1, 2, 3, 4, 5, or 6 months) treatment or control of an angiogenic disease, condition, or disorder. Such devices may be implanted into the eye or periocular tissues of a subject by a skilled physician. Non-limiting examples of ophthalmic implant systems or devices for sustained release of active ingredients are disclosed in U.S. Pat. nos. 5,378,475;5,773,019;5,902,598;6,001,386;6,051,576; and 6,726,918.

In yet another aspect, a method of treating or controlling an ocular angiogenic disease, condition, or disorder comprises administering to a subject in need thereof a composition comprising an antibody fusion protein of the invention.

In still another aspect, the antibody fusion protein used in the method comprises an antibody or antigen-binding fragment or domain thereof directed against IL-6R; wherein at least one of the following is linked to a VEGF binding unit: (1) a light chain or antigen binding fragment or domain thereof; and (2) a heavy chain or antigen binding fragment or domain thereof, the VEGF binding unit comprising: (1) (a) Ig-like domain 2 or substantially Ig-like domain 2 of human VEGFR-1; and (b) Ig-like domain 3 or substantially Ig-like domain 3 of human VEGFR-2; or (2) at least one Ig-like domain selected from the group consisting of: ig-like domains 1, 2, and 3 or substantially Ig-like domains 1, 2, and 3 of human VEGFR-3. In one embodiment, the VEGF binding unit comprises: human VEGFR-3 (a) Ig like domains 1 and 2 or substantially Ig like domains 1 and 2; or (b) Ig-like domains 2 and 3 or substantially Ig-like domains 2 and 3; or (c) Ig-like domains 1, 2 and 3 or substantially Ig-like domains 1, 2 and 3.

In yet another aspect, a method of treating or controlling an ocular angiogenic disease, condition, or disorder comprises administering to a subject in need thereof a composition comprising an antibody fusion protein having heavy and light chain amino acid sequences as set forth in seq id no: SEQ ID NOS 18 and 20; or SEQ ID NOS.22 and 24; or SEQ ID NOS 26 and 28; SEQ ID NOS 30 and 32; SEQ ID NOS 78 and 80; SEQ ID NOS 82 and 84; SEQ ID NOS 86 and 88; SEQ ID NOS 90 and 92; SEQ ID NOS 94 and 96; or SEQ ID NOS 98 and 100; or an antibody fusion protein having an amino acid sequence as set forth in SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 74 or SEQ ID NO. 76. In still another aspect, the antibody fusion proteins used in such methods may comprise pairs of proteins having a sequence starting at amino acid 17 of the sequences set forth in SEQ ID NOs 60, 62, 64, 66, 74 or 76 or dimers of said proteins.

In yet another aspect, a method of treating or controlling an ocular angiogenic disease, condition, or disorder having aberrant angiogenesis in the etiology of the posterior segment of the eye comprises intravitreally injecting into a subject in need thereof a composition comprising an antibody fusion protein having the heavy and light chain amino acid sequences as set forth below: SEQ ID NOS 18 and 20; or SEQ ID NOS.22 and 24; or SEQ ID NOS 26 and 28; or SEQ ID NOS 30 and 32; SEQ ID NOS 78 and 80; SEQ ID NOS 82 and 84; SEQ ID NOS 86 and 88; SEQ ID NOS 90 and 92; SEQ ID NOS 94 and 96; or SEQ ID NOS 98 and 100; or an antibody fusion protein having an amino acid sequence as set forth in SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 74 or SEQ ID NO. 76. In still another aspect, the antibody fusion proteins used in such methods may comprise pairs of proteins having a sequence starting at amino acid 17 of the sequences set forth in SEQ ID NOs 60, 62, 64, 66, 74 or 76 or dimers of said proteins.

In another embodiment, such a disease, condition, or disorder is selected from the group consisting of: including neovascular age-related macular degeneration (wet age-related macular degeneration), polypoidal Choroidal Vasculopathy (PCV) and myopic choroidal neovascularization, vascular leakage, macular edema caused by diabetes, uveitis, central and branch retinal vein occlusion, nonproliferative and proliferative diabetic retinopathy, retinopathy of prematurity, corneal neovascularization, corneal inflammation and neovascular glaucoma.

In yet another aspect, the compositions of the invention are administered weekly, monthly, once a year, twice a year, four times a year, or at a frequency determined to be suitable for treating or controlling a pre-inflammatory disease, condition, or disorder.

In yet another aspect, the antibody fusion proteins of the invention may also be used to treat or control tumors, systemic inflammatory diseases or conditions, or autoimmune diseases, such as arthritis. Such treatment or control may be achieved by, for example, systemic administration. Dosages and regimens for treating such diseases or conditions may be determined or recommended by the healthcare practitioner for a particular disease or condition.

Example 1: an antibody fusion protein comprising VEGFR-1-D2, VEGFR-2-D3 and a monoclonal antibody (mAb) directed against IL-6R.

Six antibody fusion proteins of the invention were produced according to the methods disclosed herein, denoted B781401, B781402, B781403, B781404, B781405 and B781406.

B781401 consists of: a VEGF binding unit consisting of VEGFR-1-D2-VEGFR-2-D3 directly linked to the amino terminus of the heavy chain of tolizumab (mAb against IL-6R). The heavy chain of B781401 has the amino acid sequence SEQ ID NO:78 and the nucleic acid sequence SEQ ID NO: 79. The light chain of B781401 has the amino acid sequence SEQ ID NO. 80 and the nucleic acid sequence SEQ ID NO. 81.

Each of B781402, B781403 and B781404 consists of: a VEGF binding unit consisting of VEGFR-1-D2-VEGFR-2-D3 linked to the amino terminus of the heavy chain of tolizumab by a flexible linker. The heavy chains of B781402, B781403 and B781404 have the amino acid sequences SEQ ID NO. 82, SEQ ID NO. 86 and SEQ ID NO. 90, respectively; and have the nucleic acid sequences SEQ ID NO:83, SEQ ID NO:87 and SEQ ID NO:91, respectively. The light chains of B781402, B781403 and B781404 have the amino acid sequences SEQ ID NO. 84, SEQ ID NO. 88 and SEQ ID NO. 92, respectively, and have the nucleic acid sequences SEQ ID NO. 85, SEQ ID NO. 89 and SEQ ID NO. 93, respectively.

B781405 consists of: a VEGF binding unit consisting of VEGFR-1-D2-VEGFR-2-D3 directly linked to the amino terminus of the light chain of tolizumab. The heavy chain of B781405 has the amino acid sequence SEQ ID NO. 94 and the nucleic acid sequence SEQ ID NO. 95. The light chain of B781405 has the amino acid sequence SEQ ID NO. 96 and the nucleic acid sequence SEQ ID NO. 97.

B781406 consists of: a VEGF binding unit consisting of VEGFR-1-D2-VEGFR-2-D3 linked to the amino terminus of the light chain of tolizumab by a flexible linker. The heavy chain of B781406 has the amino acid sequence SEQ ID NO. 98 and the nucleic acid sequence SEQ ID NO. 99. The light chain of B781406 has the amino acid sequence SEQ ID NO. 100 and the nucleic acid sequence SEQ ID NO. 101.

The carboxy-terminus of the heavy chains of B781401, B781402, B781405 and B781406 did not have glycine and lysine amino acid residues. The carboxyl terminus of the heavy chain of B781404 does not have a lysine residue. The carboxy terminus of the heavy chain of B781403 includes glycine and lysine amino acid residues.

FIGS. 7A-D show schematic representations of antibody fusion proteins B78401-78406.

Example 2: antibody fusion proteins comprising IL-6R binding scFv linked to VEGFR-1-D2-VEGFR-2-D3

Four antibody fusion proteins of the invention were prepared according to the methods disclosed herein and are designated EB-DJ1, EB-vA, EB-vB, EB-vvC. Each of these fusion proteins comprises a pair of constructs, or a dimer of constructs, each of which comprises an IL-6R scFv, an Fc domain of IgG1, and VEGF binding units comprising human VEGFR-1-D2 and human VEGFR-2-D3. Specifically, each of EB-DJ1 and EB-vvA consists of a dimer of constructs, each of which consists of IL-6R scFv linked to the Fc domain of IgG 1. The carboxy terminus of the IgG1-Fc domain was linked to a VEGF binding unit consisting of VEGFR-1-D2-VEGFR-2-D3 via a flexible linker. The EB-DJ1 construct has the amino acid sequence SEQ ID NO:60 and the nucleic acid sequence SEQ ID NO:59. The construct of EB-vvA has the amino acid sequence SEQ ID NO. 74 and the nucleic acid sequence SEQ ID NO. 75.

EB-vvB consists of dimers of constructs, each of which consists of an IL-6R scFv linked by a flexible linker to a VEGF binding unit consisting of VEGFR-1-D2-VEGFR-2-D3. The carboxy terminus of the VEGF binding unit is directly linked to the IgG1-Fc domain. The construct of EB-vvB has the amino acid sequence SEQ ID NO. 62 and the nucleic acid sequence SEQ ID NO. 61.

EB-vvC consists of dimers of constructs, each of which consists of: a VEGF binding unit consisting of VEGFR-1-D2-VEGFR-2-D3 directly linked to an IgG1-Fc domain. The carboxy terminus of the IgG1-Fc domain is linked to the IL-6R scFv via a flexible linker. The construct of EB-vvC has the amino acid sequence SEQ ID NO 76 and the nucleic acid sequence SEQ ID NO 77.

Example 2: EB-DJ1, EB-vA, EB-vvB and EB-vvC vs recombinant human VEGF-A with Abelmoschus, B781403 and B781405 ₁₆₅ ELISA binding affinity of (C).

FIG. 8 shows schematic representations of antibody fusion proteins EB-DJ1, EB-vA, EB-vvB and EB-vvC.

Example 3: transient expression and purification of B78401-78406.

Genes encoding the amino acid sequences of B78401-78406 shown as SEQ ID NOs 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99 and 101 were synthesized, and an expression vector based on the vector pcDNA3.4 for expressing a protein was constructed. Expression vectors were used to transiently transfect HEK293 cells with a chemically defined medium. The produced protein was purified by a protein a affinity column, ultrafiltered and then sterile-filtered through 0.2 μm to obtain a large amount of high-purity protein. Expression of B78401-78406 in HEK293 cells produced a protein with a MW of about 200KDa (non-reduced form on SDS-PAGE) with about 100% purity when analyzed by SEC-HPLC. The SEC-HPLC chromatogram of B781401 is shown in fig. 9. The expression and purification results of B78401-78406 are shown in Table 3.

TABLE 3 expression and purification of B78401-78140 produced in HEK293 cells

Genes encoding the amino acid sequences of B78401-78406 shown as SEQ ID NOs 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99 and 101 were synthesized, and an expression vector based on the vector pcDNA3.4 for expressing a protein was constructed. The expression vector was used to transiently transfect CHO cells with a chemically defined medium. The produced protein was purified by a protein a affinity column, ultrafiltered and then sterile-filtered through 0.2 μm to obtain a large amount of high-purity protein. When analyzed by SEC-HPLC, the expression of B78401-78406 in CHO cells produced a protein with a MW of about 200kDa (non-reduced form on SDS-PAGE) with a purity of about 93%. The SEC-HPLC chromatogram of B781401 is shown in fig. 10. The expression and purification results of B78401-78406 are shown in Table 4.

TABLE 4 expression and purification of B78401-78140 produced in CHO cells

Example 4: comparison of B78401-78406 with Abelmoschus using enzyme-linked immunosorbent assay (ELISA)For recombinant human VEGF-A ₁₆₅ Is used for the binding affinity of (a) to the substrate.

Use of recombinant human VEGF-A coated at +4℃ ₁₆₅ ELISA assays were performed in 96-well plates (2. Mu.g/ml, 100. Mu.l/well) for 16 hours. After non-specific blocking with 1% BSA at 25 ℃ for 1 hour, a series of dilutions of test antibodies were added to the coated wells and incubated at 25 ℃ for 1 hour. Detection of bound antibody using HRP conjugated secondary antibody (goat anti-human IgG 1-Fc) followed by reading OD ₄₅₀ . B78401-78406 to recombinant human VEGF-A ₁₆₅ Is in the sub-nanomolar order and is comparable to aflibercept. Fig. 11 shows the results.

Example 5: b78401-78406 recombinant human VEGF-B with Abelmosil pairs ₁₆₇ ELISA binding affinity of (C).

Use of recombinant human VEGF-B coated at +4℃ ₁₆₇ ELISA assays were performed in 96-well plates (2. Mu.g/ml, 100. Mu.l/well) for 16 hours. After non-specific blocking with 1% BSA at 25 ℃ for 1 hour, a series of dilutions of test antibodies were added to the coated wells and incubated at 25 ℃ for 1 hour. Detection of bound antibody using HRP conjugated secondary antibody (goat anti-human IgG 1-Fc) followed by reading OD ₄₅₀ . B78401-78406 to recombinant human VEGF-A ₁₆₅ Is in the sub-nanomolar order and is comparable to aflibercept. The results are shown in fig. 12.

Example 6: comparison of ELISA binding affinity of B78401-78406 to Abelmoschus for recombinant human PlGF.

ELISA assays were performed at +4℃using96-well plates coated with recombinant human PlGF (2. Mu.g/ml, 100. Mu.l/well) for 16 hours. After non-specific blocking with 1% BSA at 25 ℃ for 1 hour, a series of dilutions of test antibodies were added to the coated wells And incubated at 25℃for 1 hour. Detection of bound antibody using HRP conjugated secondary antibody (goat anti-human IgG 1-Fc) followed by reading OD ₄₅₀ . B78401-78406 has a binding affinity for recombinant human pigf in the sub-nanomolar range and is comparable to aflibercept. The results are shown in fig. 13.

Example 7: comparison of ELISA binding affinity of B78401-78406 to Tozucchini antibody to recombinant human IL-6R.

ELISA assays were performed at +4℃using96-well plates coated with recombinant human IL-6R (2. Mu.g/ml, 100. Mu.l/well) for 16 hours. After non-specific blocking with 1% BSA at 25 ℃ for 1 hour, a series of dilutions of test antibodies were added to IL-6R coated wells and incubated at 25 ℃ for 1 hour. Detection of bound antibody using HRP conjugated secondary antibody (goat anti-human IgG 1-Fc) followed by reading OD ₄₅₀ . B78401-78406 has a binding affinity for recombinant human IL-6R at a sub-nanomolar level and is comparable to tolizumab. The results are shown in fig. 17.

Example 8: comparison of VEGF-A in VEGFR2-NFAT-RE luciferase reporter cells inhibited by B78401-78406 with Abelmoschus pair ₁₆₅ Effects of mediated VEGFR2 signaling.

Recombinant human VEGF-A ₁₆₅ Mix with serially diluted test abs, incubate at room temperature for 30 minutes, and then add to the kit containing 4 x 10 ⁴ VEGFR2 (KDR) -NFAT-RE luciferase was reported in the wells of cells/well followed by incubation at 37℃for 6 hours. After the addition of 50. Mu.l Bright-Lite, the luciferase signal was detected by a microplate reader. VEGFR2 signaling luciferase assay was validated using Bevacizumab (Avastin) as a positive control (see fig. 15A). B78401-78406 pair inhibits VEGF-A ₁₆₅ The effect of mediated VEGFR2 signaling was comparable to that of albessleeve (see fig. 15B).

Example 9: comparison of the effect of B78401-78406 and tobramycin on inhibition of IL-6R signaling.

Phosphorylation of Signal transduction and transcriptional activator 3 (STAT 3) in TF-1 cells in response to recombinant IL-6 stimulation was measured using a phosphorylated STAT3 (Tyr 705) cell kit from Cisbio according to manufacturer's instructions. Detection of phosphorylated STAT3 involves a sandwich immunoassay comprising an anti-phosphorylated STAT3 antibody in combination with an anti-total anti-antibody (anti-total anti-body) fluorescently labeled with a donor or acceptor. Activation of IL-6/IL-6R signaling in TF-1 cells results in an increase in Homogeneous Time Resolved Fluorescence (HTRF) signal, while inhibition will show the opposite effect. B781401, B781402, B781404 and B781405 showed an effect comparable to tolizumab in inhibiting STAT3 phosphorylation in TF-1 cells stimulated by recombinant human IL-6 ligand. The results are shown in fig. 16.

Example 10: the effect of B78401-78406 on inhibition of IL-6R signaling was compared to that of rituximab and tobulab.

According to the manufacturer's instructions, useLuminous cell viability assay measurements of IL-6 mediated TF-1 cell proliferation were performed with a kit obtained from Promega. Activation of IL-6R signaling in TF-1 cells results in proliferation of TF-1 cells, which is reflected by increased luminescent signaling, whereas inhibition of IL-6R signaling will show the opposite effect. B781404, B781405 and B781406 show comparable effects in inhibiting TF-1 cell proliferation stimulated by recombinant human IL-6 ligand. Setuximab was a mAb against IL-6. The results are shown in fig. 17.

Table 5 shows a summary of the transient expression of B78401-78406 in HEK293 and CHO cells, the binding affinities of ELISA to human VEGF-A165, VEGF-B167, plGF and IL-6R, and the inhibition in three cell-based functional assays.

TABLE 5

B78401-78406 profile summarization

Example 11: EB-DJ1, EB-vA, EB-vvB and EB-vvC vs recombinant human VEGF-A with Abelmoschus, B781403 and B781405 ₁₆₅ ELISA binding affinity of (C).

Use of recombinant human VEGF-A coated at +4℃ ₁₆₅ ELISA assays were performed in 96-well plates (2. Mu.g/ml, 100. Mu.l/well) for 16 hours. After non-specific blocking with 1% BSA at 25 ℃ for 1 hour, a series of dilutions of test antibodies were added to the coated wells and incubated at 25 ℃ for 1 hour. Detection of bound antibody using HRP conjugated secondary antibody (goat anti-human IgG 1-Fc) followed by reading OD ₄₅₀ . The binding affinities of EB-DJ1, EB-vA, EB-vvB and EB-vvC for recombinant human VEGF-A165 were at sub-nanomolar levels and comparable to Abelmoschus, B781403 and B781405. The results are shown in fig. 18.

Example 12: EB-DJ1, EB-vA, EB-vvB and EB-vvC pairs recombinant human VEGF-B with Abelmoschus, B781402, B781403 and B781405 pairs ₁₆₇ ELISA binding affinity of (C).

Use of recombinant human VEGF-B coated at +4℃ ₁₆₇ ELISA assays were performed in 96-well plates (2. Mu.g/ml, 100. Mu.l/well) for 16 hours. After non-specific blocking with 1% BSA at 25℃for 1 hour, a series of dilutions of test antibodies were added to VEGF-B ₁₆₇ The coated wells were incubated at 25℃for 1 hour. Detection of bound antibody using HRP conjugated secondary antibody (goat anti-human IgG 1-Fc) followed by reading OD ₄₅₀ . EB-DJ1, EB-vvA, EB-vvB and EB-vvC for recombinant human VEGF-B ₁₆₇ Is in the sub-nanomolar order and is comparable to aflibercept, B781402, B781403 and B781405. The results are shown in fig. 19.

Example 13: comparison of ELISA binding affinity of EB-DJ1, EB-vA, EB-vvB and EB-vvC with Abelmoschus, B781403 and B781405 for recombinant human PlGF.

ELISA assays were performed at +4℃using96-well plates coated with recombinant human PlGF (2. Mu.g/ml, 100. Mu.l/well) for 16 hours. After non-specific blocking with 1% BSA at 25℃for 1 hour, a series of dilutions of the test were performed Antibodies were added to the coated wells and incubated at 25 ℃ for 1 hour. Detection of bound antibody using HRP conjugated secondary antibody (goat anti-human IgG 1-Fc) followed by reading OD ₄₅₀ . The binding affinities of EB-DJ1, EB-vA, EB-vvB and EB-vvC for recombinant human PlGF are in the sub-nanomolar order and are comparable to Abelmosil, B781403 and B781405. The results are shown in fig. 20.

Example 14: comparison of ELISA binding affinity of EB-DJ1, EB-vA, EB-vvB and EB-vvC with Touzumab, B781402, B781403 and B781405 for recombinant human IL-6R.

ELISA assays were performed at +4℃using96-well plates coated with recombinant human IL-6R (2. Mu.g/ml, 100. Mu.l/well) for 16 hours. After non-specific blocking with 1% BSA at 25 ℃ for 1 hour, a series of dilutions of test antibodies were added to Il-6R coated wells and incubated at 25 ℃ for 1 hour. Detection of bound antibody using HRP conjugated secondary antibody (goat anti-human IgG 1-Fc) followed by reading OD ₄₅₀ . The binding affinities of EB-DJ1, EB-vA, EB-vvB and EB-vvC for recombinant human IL-6R were at sub-nanomolar levels and comparable to tobrazumab, B781402, B781403 and B781405. The results are shown in fig. 21.

A summary of binding affinities of EB-DJ1, EB-vA, EB-vvB and EB-vvC for human VEGF-A165, VEGF-B167, plGF and IL-6R is shown in Table 6.

TABLE 6 summary of EB-DJ1, EB-vA, EB-vvB and EB-vvC

Nucleic acid and amino acid sequence listing

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While particular embodiments of the present invention have been illustrated, it will be understood by those skilled in the art that various equivalents, modifications, substitutions and changes may be made thereto without departing from the spirit and scope of the invention as defined in the following claims.

Sequence listing

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<213> Homo sapiens (Homo sapiens)

<400> 2

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 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 Ile Cys Asn Val Asn His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 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 His Glu Asp

260 265 270

Pro Glu Val Lys 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 Ala Leu Pro Ala Pro 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 Arg Glu 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 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

<210> 3

<211> 642

<212> DNA

<213> Homo sapiens (Homo sapiens)

<400> 3

gacattcaaa tgactcagtc tccatccagt ctctccgctt ctgtggggga ccgagtaacc 60

ataacatgtc gggcatctca ggacataagc tcatacttga attggtatca gcagaaacca 120

gggaaggcgc ccaagcttct tatctactat acatcaagac ttcatagcgg ggtgccaagc 180

cgattcagtg gcagcggttc aggaacagac tttacgttca ccatttcatc tttgcagcca 240

gaagatatag ctacgtacta ctgtcagcaa ggaaatacgt tgccgtacac ctttggccag 300

ggcacaaaag tcgaaattaa gcgaaccgta gcagccccga gtgtctttat ctttcctccc 360

tcagatgagc aacttaaaag cgggacagcc tcagtagttt gcctcctgaa caatttctac 420

ccacgggaag ccaaggtgca gtggaaggtg gacaatgctc ttcagtccgg caactctcag 480

gaaagtgtta ccgagcaaga ctctaaagac tcaacttaca gcctcagctc caccctcact 540

ttgtccaagg ctgattacga aaaacataag gtatatgcct gcgaagttac gcaccaagga 600

ctttcatccc cggtgacaaa gagcttcaac agaggcgaat gt 642

<210> 4

<211> 214

<212> PRT

<213> Homo sapiens (Homo sapiens)

<400> 4

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 Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln 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> 5

<211> 306

<212> DNA

<213> Homo sapiens (Homo sapiens)

<400> 5

tccgacacag gacgcccctt cgtagaaatg tactctgaga ttccggaaat catccatatg 60

actgagggca gagagttggt cataccatgc agagtcactt caccaaatat aaccgtgacg 120

ttgaagaaat ttcccttgga cacgttgatt cccgatggta agcggattat atgggacagc 180

cgcaagggct ttataataag taatgcaaca tataaggaaa taggtctcct cacatgcgaa 240

gctacagtca acggccatct ctacaagaca aattatctta cccacaggca gacgaacaca 300

ataatt 306

<210> 6

<211> 102

<212> PRT

<213> Homo sapiens (Homo sapiens)

<400> 6

Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu

1 5 10 15

Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val

20 25 30

Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr

35 40 45

Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe

50 55 60

Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu

65 70 75 80

Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg

85 90 95

Gln Thr Asn Thr Ile Ile

100

<210> 7

<211> 309

<212> DNA

<213> Homo sapiens (Homo sapiens)

<400> 7

gacgtggttc tttcaccctc acacggtatt gagttgtcag tcggtgagaa gctggtcttg 60

aactgcacgg ccagaacgga attgaacgtc ggcattgatt ttaactggga atacccgtcc 120

tctaaacacc aacacaagaa gttggtcaac cgcgatctga agacccaatc cggaagtgaa 180

atgaagaaat tcttgtctac tttgaccatt gatggcgtca cgagatctga tcaagggctt 240

tacacctgcg ccgcgagctc tggtcttatg accaagaaga acagtacatt tgtgcgggta 300

catgaaaaa 309

<210> 8

<211> 103

<212> PRT

<213> Homo sapiens (Homo sapiens)

<400> 8

Asp Val Val Leu Ser Pro Ser His Gly Ile Glu Leu Ser Val Gly Glu

1 5 10 15

Lys Leu Val Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn Val Gly Ile

20 25 30

Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys His Gln His Lys Lys Leu

35 40 45

Val Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser Glu Met Lys Lys Phe

50 55 60

Leu Ser Thr Leu Thr Ile Asp Gly Val Thr Arg Ser Asp Gln Gly Leu

65 70 75 80

Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met Thr Lys Lys Asn Ser Thr

85 90 95

Phe Val Arg Val His Glu Lys

100

<210> 9

<211> 615

<212> DNA

<213> Homo sapiens (Homo sapiens)

<400> 9

tattctatga caccgccgac cttgaacata accgaggaat cacatgtaat agacacaggg 60

gactcacttt caatcagctg tcgaggccag caccccctgg aatgggcttg gccgggggca 120

caagaagcac ctgctactgg tgacaaggac agcgaagata cgggagtagt tagagactgt 180

gagggcacag acgctagacc ttactgcaag gtcctgcttt tgcatgaagt gcacgctaac 240

gacactggga gctatgtctg ctactacaag tatatcaaag cgcggataga gggaacgaca 300

gctgcgtcaa gttatgtgtt cgtcagagat tttgagcaac cgtttattaa taagcctgac 360

acgctgcttg taaatagaaa agacgccatg tgggtaccat gtctggtcag tatacctggt 420

ctcaatgtga ctcttcgctc tcaaagcagc gtgctgtggc cggacggcca ggaagtggtt 480

tgggatgaca ggcgggggat gcttgtttcc actccgcttc tccatgacgc cctctacctg 540

caatgtgaaa ccacgtgggg tgatcaagat ttcctgtcta atcccttctt ggtacatatc 600

accgggaacg aactc 615

<210> 10

<211> 205

<212> PRT

<213> Homo sapiens (Homo sapiens)

<400> 10

Tyr Ser Met Thr Pro Pro Thr Leu Asn Ile Thr Glu Glu Ser His Val

1 5 10 15

Ile Asp Thr Gly Asp Ser Leu Ser Ile Ser Cys Arg Gly Gln His Pro

20 25 30

Leu Glu Trp Ala Trp Pro Gly Ala Gln Glu Ala Pro Ala Thr Gly Asp

35 40 45

Lys Asp Ser Glu Asp Thr Gly Val Val Arg Asp Cys Glu Gly Thr Asp

50 55 60

Ala Arg Pro Tyr Cys Lys Val Leu Leu Leu His Glu Val His Ala Asn

65 70 75 80

Asp Thr Gly Ser Tyr Val Cys Tyr Tyr Lys Tyr Ile Lys Ala Arg Ile

85 90 95

Glu Gly Thr Thr Ala Ala Ser Ser Tyr Val Phe Val Arg Asp Phe Glu

100 105 110

Gln Pro Phe Ile Asn Lys Pro Asp Thr Leu Leu Val Asn Arg Lys Asp

115 120 125

Ala Met Trp Val Pro Cys Leu Val Ser Ile Pro Gly Leu Asn Val Thr

130 135 140

Leu Arg Ser Gln Ser Ser Val Leu Trp Pro Asp Gly Gln Glu Val Val

145 150 155 160

Trp Asp Asp Arg Arg Gly Met Leu Val Ser Thr Pro Leu Leu His Asp

165 170 175

Ala Leu Tyr Leu Gln Cys Glu Thr Thr Trp Gly Asp Gln Asp Phe Leu

180 185 190

Ser Asn Pro Phe Leu Val His Ile Thr Gly Asn Glu Leu

195 200 205

<210> 11

<211> 48

<212> DNA

<213> Artificial work

<220>

<223> Artificial joint

<400> 11

ggagaaggtt ccggtgatgg aggtgagggg agcggggatg gggaaggt 48

<210> 12

<211> 16

<212> PRT

<213> Artificial work

<220>

<223> Artificial joint

<400> 12

Gly Glu Gly Ser Gly Asp Gly Gly Glu Gly Ser Gly Asp Gly Glu Gly

1 5 10 15

<210> 13

<211> 33

<212> DNA

<213> Artificial work

<220>

<223> Artificial joint

<400> 13

ggaggctcag gtggcggtgg ttctggcgga gga 33

<210> 14

<211> 11

<212> PRT

<213> Artificial work

<220>

<223> Artificial joint

<400> 14

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

1 5 10

<210> 15

<211> 48

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 15

atgccgttgc tgctgctttt gccactcctt tgggccgggg ctttggca 48

<210> 16

<211> 16

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 16

Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala

1 5 10 15

<210> 17

<211> 2058

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 17

atgcctctcc tcctcctctt gcccctcctt tgggccggag ccctggctca ggtgcagctg 60

caggaatcag ggcctggttt ggtgcggccg agtcagacgc tcagcttgac ttgtacggtg 120

tcaggttact ctatcactag cgatcatgcc tggagctggg tacgacaacc accgggtcgg 180

ggtctcgaat ggataggtta cataagctac tcaggaatca cgacatacaa tccctccctt 240

aaaagtcggg tcaccatgct ccgagacact agtaaaaatc agttctccct gcggttgtcc 300

agcgtgactg ctgccgacac ggcggtctat tattgcgcaa gaagtctggc gcggacaacg 360

gcaatggact actggggaca aggttcactg gtaaccgtta gttcagcaag caccaagggt 420

ccgtctgtct ttccactcgc gccttctagc aagtcaacct caggggggac tgccgcgctt 480

ggatgtctgg tcaaagatta ttttcctgag ccggtaacag ttagctggaa ttcaggtgcc 540

ctcacatctg gggtacacac gtttcccgcc gtgcttcaga gctctggcct ctacagtctt 600

tctagcgtgg tcaccgtccc atcttcatca ttgggtacac aaacttacat ttgtaacgtt 660

aatcacaaac ctagcaacac taaggtggat aaaaaagtag agccaaagtc ctgcgacaag 720

actcacacct gtcctccctg tccagcaccc gaacttttgg gcggtccttc tgttttcctg 780

tttcctccta aacccaaaga tacactcatg atctccagaa ccccggaagt aacctgcgta 840

gtcgtggacg tatcccatga ggatcccgag gtaaaattca actggtacgt agacggggtc 900

gaggtgcaca atgccaagac taaacctagg gaagagcaat acaatagtac gtacagggtg 960

gtttccgtgc tgaccgtcct gcatcaggat tggctcaacg ggaaagagta taaatgtaag 1020

gtgtcaaaca aagctttgcc ggcaccaata gagaaaacca ttagtaaggc gaaaggacaa 1080

ccccgagagc cacaagtgta tacgttgcct cccagccgcg aggaaatgac gaagaatcaa 1140

gtctctctga cttgtctggt gaagggtttt tacccgtctg atatagctgt cgaatgggag 1200

tctaacggcc agccagagaa taattacaaa accactcctc cggtcttgga ttctgatggg 1260

agctttttcc tgtattccaa attgacagtt gataaaagtc ggtggcagca ggggaacgtc 1320

ttctcctgta gcgtcatgca tgaagcactg cataatcatt atacccaaaa aagtttgtcc 1380

ttgagccctg gtggcgaggg ttcaggggat ggaggcgagg ggtccgggga cggcgaaggc 1440

tcagataccg gaagaccatt tgtggagatg tattccgaaa taccggagat aatacatatg 1500

acggaaggtc gagaactcgt catcccatgt cgcgtaacct ctccaaatat caccgtaaca 1560

ctcaaaaaat tccctcttga cacgttgata ccggacggca aaagaataat atgggattca 1620

aggaaaggat ttataataag caacgccaca tacaaagaga ttgggctgct cacttgtgaa 1680

gccactgtta atgggcactt gtataagact aattatctca cccaccgcca gacgaatact 1740

ataatagatg tcgttctgag cccaagtcat gggattgaac tttctgttgg cgaaaagctc 1800

gtgttgaatt gcactgctag gacggagctg aatgttggta tagatttcaa ttgggaatat 1860

cctagctcta aacaccagca caaaaaactc gttaatcgcg acttgaagac gcagtcagga 1920

tcagagatga aaaagttcct ctcaacgctg actatagatg gagtaacgag atccgaccag 1980

ggattgtaca cctgcgccgc gtcttccggg ctcatgacaa aaaaaaacag cactttcgta 2040

cgcgtccatg aaaaatag 2058

<210> 18

<211> 685

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 18

Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala

1 5 10 15

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

20 25 30

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

35 40 45

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

50 55 60

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

65 70 75 80

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

85 90 95

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

100 105 110

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

115 120 125

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

130 135 140

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu

145 150 155 160

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

165 170 175

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu

180 185 190

Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

195 200 205

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

210 215 220

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys

225 230 235 240

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

245 250 255

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

260 265 270

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

275 280 285

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

290 295 300

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

305 310 315 320

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

325 330 335

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

340 345 350

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

355 360 365

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

370 375 380

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

385 390 395 400

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

405 410 415

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

420 425 430

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

435 440 445

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

450 455 460

Gly Glu Gly Ser Gly Asp Gly Gly Glu Gly Ser Gly Asp Gly Glu Gly

465 470 475 480

Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu

485 490 495

Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val

500 505 510

Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr

515 520 525

Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe

530 535 540

Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu

545 550 555 560

Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg

565 570 575

Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile

580 585 590

Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr

595 600 605

Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys

610 615 620

His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly

625 630 635 640

Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr

645 650 655

Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met

660 665 670

Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys

675 680 685

<210> 19

<211> 1356

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 19

atgcccttgc tgctgttgct gccccttctc tgggcagggg cgctggctga cattcaaatg 60

actcagtctc catccagtct ctccgcttct gtgggggacc gagtaaccat aacatgtcgg 120

gcatctcagg acataagctc atacttgaat tggtatcagc agaaaccagg gaaggcgccc 180

aagcttctta tctactatac atcaagactt catagcgggg tgccaagccg attcagtggc 240

agcggttcag gaacagactt tacgttcacc atttcatctt tgcagccaga agatatagct 300

acgtactact gtcagcaagg aaatacgttg ccgtacacct ttggccaggg cacaaaagtc 360

gaaattaagc gaaccgtagc agccccgagt gtctttatct ttcctccctc agatgagcaa 420

cttaaaagcg ggacagcctc agtagtttgc ctcctgaaca atttctaccc acgggaagcc 480

aaggtgcagt ggaaggtgga caatgctctt cagtccggca actctcagga aagtgttacc 540

gagcaagact ctaaagactc aacttacagc ctcagctcca ccctcacttt gtccaaggct 600

gattacgaaa aacataaggt atatgcctgc gaagttacgc accaaggact ttcatccccg 660

gtgacaaaga gcttcaacag aggcgaatgt ggagaggggt ccggcgacgg cggtgaaggg 720

tctggtgatg gggaaggttc cgataccggt cgacccttcg tcgagatgta ttctgagatt 780

ccggaaatca tccacatgac cgaaggacga gagcttgtaa ttccttgccg agttacatca 840

cccaacataa cggtgacact caagaagttt cctttggata cattgattcc ggacgggaag 900

cgcataattt gggatagtag aaagggtttt attatcagca acgctacgta taaggagata 960

ggtctgctca cttgtgaagc cactgtgaat gggcacctgt acaaaacaaa ttatctcacc 1020

caccgacaga ctaacaccat tatcgatgtt gttttgtctc catctcatgg aatcgaactt 1080

agtgtcggag aaaagctcgt actgaattgc acagcccgaa cggaacttaa tgttgggatt 1140

gactttaatt gggagtatcc gtcttctaag catcaacaca agaagcttgt taacagggat 1200

ctcaagacgc aatccggatc agaaatgaaa aaatttctct ccactcttac tatagatgga 1260

gtcacacgct ccgaccaagg tctctacacg tgcgcagcta gtagtggtct gatgaccaaa 1320

aagaactcta cgttcgtgag agtacatgag aagtag 1356

<210> 20

<211> 451

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 20

Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala

1 5 10 15

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

20 25 30

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

35 40 45

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

50 55 60

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

65 70 75 80

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

85 90 95

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

100 105 110

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

115 120 125

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

130 135 140

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

145 150 155 160

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

165 170 175

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

180 185 190

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

195 200 205

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

210 215 220

Phe Asn Arg Gly Glu Cys Gly Glu Gly Ser Gly Asp Gly Gly Glu Gly

225 230 235 240

Ser Gly Asp Gly Glu Gly Ser Asp Thr Gly Arg Pro Phe Val Glu Met

245 250 255

Tyr Ser Glu Ile Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu

260 265 270

Val Ile Pro Cys Arg Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys

275 280 285

Lys Phe Pro Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp

290 295 300

Asp Ser Arg Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile

305 310 315 320

Gly Leu Leu Thr Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr

325 330 335

Asn Tyr Leu Thr His Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu

340 345 350

Ser Pro Ser His Gly Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu

355 360 365

Asn Cys Thr Ala Arg Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp

370 375 380

Glu Tyr Pro Ser Ser Lys His Gln His Lys Lys Leu Val Asn Arg Asp

385 390 395 400

Leu Lys Thr Gln Ser Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu

405 410 415

Thr Ile Asp Gly Val Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala

420 425 430

Ala Ser Ser Gly Leu Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val

435 440 445

His Glu Lys

450

<210> 21

<211> 2043

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 21

atgcccctgc ttctcctctt gccgttgctc tgggctggtg ctttggcgca agtacaactt 60

caagaatcag gtcccgggct cgtgcggcct tcacaaacac ttagcctcac ctgcactgtg 120

tccgggtata gcataacaag tgaccacgcg tggagctggg tgcggcagcc tcctggtcgc 180

ggcctcgagt ggattggata catatcctac tcaggaatca ctacatataa tccaagtttg 240

aaatcccgag ttaccatgtt gagggacacg agtaaaaatc agttcagtct gaggttgtca 300

agcgtaacgg cggctgatac ggctgtttat tactgtgcaa gaagtttggc acgaacaacc 360

gcgatggact actggggtca aggctcattg gtaactgtga gctctgcgtc taccaagggc 420

cctagcgttt ttcctctggc cccttcctcc aagtccacgt ccggtggaac agctgctctc 480

ggctgtttgg taaaagatta tttcccagaa cccgttactg tgtcatggaa ctctggtgct 540

ttgacaagtg gagtccatac ttttcctgcc gttctgcaat caagtgggct ctatagcttg 600

tcctcagttg tcacagtacc atcatcaagc ctgggtacac agacttatat atgcaatgtg 660

aaccacaagc cttccaatac gaaagtcgac aagaaggtcg agcccaagtc atgcgacaag 720

acccatacct gccccccatg tccagccccc gaactgctgg gcggaccctc agtcttcctc 780

tttccaccaa agccgaaaga tacccttatg atctctagga cccccgaggt aacgtgcgtt 840

gtcgtcgatg tgtctcacga ggacccggag gtcaagttca attggtacgt cgatggcgtc 900

gaggttcata acgcgaagac taaaccgagg gaggaacaat acaactctac gtaccgagta 960

gtgtccgtgt tgacagtact gcatcaagat tggctcaatg gtaaagaata taaatgcaag 1020

gtctctaaca aagcgttgcc tgcgccaatc gaaaaaacta ttagcaaagc taagggtcaa 1080

ccgcgagagc ctcaggtata cacgcttcct ccgtcccgag aagagatgac gaaaaatcaa 1140

gtctccctga catgtcttgt taagggtttt tacccttctg acattgctgt cgaatgggag 1200

tccaatggcc agcccgagaa caactataag acgacgcctc ccgtcttgga tagtgacgga 1260

agctttttcc tgtattctaa attgaccgtg gacaagagcc ggtggcaaca gggtaacgtc 1320

ttttcatgct ccgtaatgca cgaggcgctt cataaccact acacccaaaa gagtctctca 1380

ttgtctcccg gtggcggttc aggtgggggg ggaagcggtg gtggatctga cactggacgg 1440

cctttcgttg agatgtactc agaaattccg gagatcattc acatgacaga agggagggag 1500

ttggtgatac cttgccgggt tacatcacca aacataactg taacactcaa aaaattcccc 1560

ctggatacac ttatccctga tggaaagcga ataatatggg acagtagaaa aggatttatc 1620

attagcaacg caacgtataa agaaatcgga ttgcttacct gcgaagcgac ggtgaatggc 1680

catctgtaca aaacgaacta cctcacgcac cgacaaacga acactatcat agatgtagtt 1740

ttgagtccta gtcacggtat tgagctcagc gtcggggaga aactggtcct taactgtact 1800

gctagaacgg aactcaacgt gggtatagat ttcaactggg agtacccgtc atccaaacat 1860

caacacaaga aacttgtcaa ccgagacctg aagacacaat ctggatcaga gatgaagaag 1920

tttttgtcta ctcttacaat tgatggggtc actcggtctg atcaaggact gtatacctgc 1980

gcagccagtt cagggttgat gactaaaaaa aattccacct tcgtacgagt ccacgagaag 2040

tag 2043

<210> 22

<211> 680

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 22

Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala

1 5 10 15

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

20 25 30

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

35 40 45

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

50 55 60

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

65 70 75 80

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

85 90 95

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

100 105 110

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

115 120 125

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

130 135 140

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu

145 150 155 160

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

165 170 175

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu

180 185 190

Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

195 200 205

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

210 215 220

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys

225 230 235 240

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

245 250 255

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

260 265 270

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

275 280 285

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

290 295 300

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

305 310 315 320

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

325 330 335

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

340 345 350

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

355 360 365

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

370 375 380

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

385 390 395 400

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

405 410 415

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

420 425 430

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

435 440 445

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

450 455 460

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Asp Thr Gly Arg

465 470 475 480

Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu Ile Ile His Met Thr

485 490 495

Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val Thr Ser Pro Asn Ile

500 505 510

Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu Ile Pro Asp Gly

515 520 525

Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser Asn Ala

530 535 540

Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala Thr Val Asn Gly

545 550 555 560

His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln Thr Asn Thr Ile

565 570 575

Ile Asp Val Val Leu Ser Pro Ser His Gly Ile Glu Leu Ser Val Gly

580 585 590

Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn Val Gly

595 600 605

Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys His Gln His Lys Lys

610 615 620

Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser Glu Met Lys Lys

625 630 635 640

Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr Arg Ser Asp Gln Gly

645 650 655

Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met Thr Lys Lys Asn Ser

660 665 670

Thr Phe Val Arg Val His Glu Lys

675 680

<210> 23

<211> 1341

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 23

atgcctctgc tccttctcct gccattgttg tgggctggtg cgctcgcaga tattcaaatg 60

actcagtctc cttcaagcct ttccgcctca gtcggcgaca gagtaacaat aacttgtcgg 120

gcgtctcaag atatctcctc atatttgaat tggtaccagc aaaaacccgg taaagcacca 180

aagcttctca tctactatac ctcaagactg cattccgggg tgccgagccg gtttagcgga 240

tctggatctg gaacagactt tacattcacg atttccagcc tgcagccgga ggatattgcc 300

acctattatt gtcagcaggg aaacacgttg ccttacactt tcggacaggg aaccaaagtg 360

gagataaaga ggactgttgc cgcaccgagc gtgtttatct ttcctccttc agatgagcag 420

cttaagtctg gtacagcctc agttgtatgt ttgctgaaca acttctaccc aagggaagct 480

aaagtacagt ggaaggttga taatgccctt caatccggga actctcaaga gtctgtaaca 540

gaacaagata gtaaggactc aacgtatagc ctttccagca cgttgacgct gagtaaggca 600

gactatgaaa agcacaaggt ctacgcgtgc gaggtgacac accaaggcct gtcttcccct 660

gtaaccaaaa gctttaacag gggtgagtgc ggtggaagcg gcggcggcgg ttctggaggc 720

gggtcagaca ctggtcgacc gtttgtcgag atgtattctg agatacctga gattatccac 780

atgacagaag gacgggaact ggtgatccct tgccgggtaa cctcacccaa tatcaccgtg 840

acattgaaaa agtttcccct tgacacactt atacctgacg gaaagaggat catttgggac 900

agtcgcaagg gtttcatcat ttccaacgca acatataaag agataggact tttgacgtgc 960

gaagcgacgg tcaatggtca cttgtacaag acgaactatt tgacccatag acaaacgaac 1020

actataatag atgttgtgct tagtccaagt cacgggatag aattgagtgt aggcgagaag 1080

cttgtactca attgtacggc ccgaaccgag ctcaacgttg gaatagactt caactgggag 1140

taccctagca gcaagcacca acataagaag cttgtaaacc gcgatttgaa gacgcagtca 1200

ggcagtgaaa tgaaaaagtt cttgtccact ttgacgattg atggtgttac gagatcagac 1260

cagggcttgt atacctgcgc agcgtcaagc gggctgatga cgaagaagaa ctcaactttt 1320

gtcagagttc acgaaaagta g 1341

<210> 24

<211> 446

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 24

Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala

1 5 10 15

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

20 25 30

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

35 40 45

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

50 55 60

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

65 70 75 80

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

85 90 95

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

100 105 110

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

115 120 125

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

130 135 140

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

145 150 155 160

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

165 170 175

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

180 185 190

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

195 200 205

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

210 215 220

Phe Asn Arg Gly Glu Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

225 230 235 240

Gly Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro

245 250 255

Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg

260 265 270

Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp

275 280 285

Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly

290 295 300

Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys

305 310 315 320

Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His

325 330 335

Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly

340 345 350

Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg

355 360 365

Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser

370 375 380

Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser

385 390 395 400

Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val

405 410 415

Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu

420 425 430

Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys

435 440 445

<210> 25

<211> 2043

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 25

atgccgcttc ttttgttgct ccccctgctg tgggcggggg ccctcgcgca agttcaactg 60

caggagagcg gcccgggttt ggtacgacca agccaaacac tctcacttac atgcaccgtg 120

tcagggtata gcattacctc agaccacgcg tggagctggg tacggcagcc gccgggtcga 180

ggcctcgagt ggatagggta tatctcttac tcaggtatta caacatacaa cccgtctctt 240

aagtctcgcg tgaccatgct gcgggataca agcaaaaacc agttctccct cagactgagc 300

tctgtcactg cggccgatac tgctgtctac tattgtgctc gaagtttggc gaggacaacg 360

gctatggact attggggcca aggatccctg gtaacagttt cttctgcaag tacgaaaggc 420

ccaagtgtgt ttccactggc tccctcctct aagagcactt ctgggggaac ggcagctctg 480

ggctgccttg tgaaggacta ctttcctgag ccagtaacag tctcctggaa ttcaggagcc 540

cttactagcg gtgttcatac gttcccggcc gttctgcaga gtagcgggct ttactctctg 600

tcatctgttg tgacggttcc atccagcagc ttgggcacac agacctacat atgcaatgtc 660

aatcacaaac cttctaatac aaaggtggat aaaaaagtcg agcctaagag ttgcgataag 720

acccatacct gtcctccatg tcccgcacca gaacttttgg gcgggccatc agtgtttctg 780

ttccccccca agcctaaaga tacccttatg attagtagaa cacccgaagt gacctgtgta 840

gtagtggatg ttagccatga ggaccctgaa gttaaattca attggtatgt cgatggggtt 900

gaagttcaca atgccaaaac taagccccgc gaagaacagt ataacagtac atatagggtc 960

gtttcagtac tgacagtatt gcaccaggac tggttgaacg gaaaggagta taagtgcaaa 1020

gtcagcaaca aagccctgcc tgcacctatc gaaaaaacca tcagtaaggc aaagggacag 1080

ccgagggaac cgcaggtgta cacgctcccc ccgtccagag aagagatgac aaagaaccag 1140

gtcagcctga catgtttggt caagggattc tatccgtcag acattgccgt cgagtgggag 1200

agtaatggcc agcccgagaa taattataaa actactccgc ccgtgcttga ctccgacggg 1260

tcatttttcc tctatagcaa actgaccgtg gataagtcaa gatggcaaca aggtaacgtc 1320

tttagttgta gtgttatgca tgaggcgctt cataaccact atacacagaa gagtttgagt 1380

ttgtcacctg gtggggggag cggtggtgga ggttctggtg gtggttatag catgactcca 1440

cccaccctga acatcactga agaatcacat gtcatcgaca ctggtgactc cttgtccata 1500

agttgccggg ggcaacaccc tctggaatgg gcctggcccg gtgcacagga ggccccagcg 1560

actggcgaca aggactcaga ggacacgggg gttgtcagag attgtgaggg gactgacgcg 1620

aggccgtatt gcaaagttct gctgcttcat gaagtgcacg caaacgatac gggatcttac 1680

gtgtgctact acaaatatat aaaggcccgg attgaaggta cgacagcggc ttcaagctac 1740

gtattcgtta gggatttcga gcaaccattc atcaacaagc ctgatacatt gttggttaac 1800

cgaaaagacg ccatgtgggt cccttgcctc gtctccattc cgggacttaa tgtaacactc 1860

aggagccaaa gttccgtctt gtggcccgac ggccaagaag tagtttggga cgacaggcga 1920

ggcatgctcg tgagtacgcc gctgcttcat gatgcgctgt accttcaatg cgagacgact 1980

tggggtgacc aagactttct ctctaaccct tttctggtcc atatcacagg gaacgagctc 2040

tag 2043

<210> 26

<211> 680

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 26

Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala

1 5 10 15

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

20 25 30

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

35 40 45

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

50 55 60

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

65 70 75 80

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

85 90 95

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

100 105 110

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

115 120 125

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

130 135 140

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu

145 150 155 160

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

165 170 175

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu

180 185 190

Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

195 200 205

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

210 215 220

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys

225 230 235 240

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

245 250 255

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

260 265 270

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

275 280 285

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

290 295 300

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

305 310 315 320

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

325 330 335

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

340 345 350

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

355 360 365

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

370 375 380

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

385 390 395 400

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

405 410 415

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

420 425 430

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

435 440 445

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

450 455 460

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Tyr Ser Met Thr Pro

465 470 475 480

Pro Thr Leu Asn Ile Thr Glu Glu Ser His Val Ile Asp Thr Gly Asp

485 490 495

Ser Leu Ser Ile Ser Cys Arg Gly Gln His Pro Leu Glu Trp Ala Trp

500 505 510

Pro Gly Ala Gln Glu Ala Pro Ala Thr Gly Asp Lys Asp Ser Glu Asp

515 520 525

Thr Gly Val Val Arg Asp Cys Glu Gly Thr Asp Ala Arg Pro Tyr Cys

530 535 540

Lys Val Leu Leu Leu His Glu Val His Ala Asn Asp Thr Gly Ser Tyr

545 550 555 560

Val Cys Tyr Tyr Lys Tyr Ile Lys Ala Arg Ile Glu Gly Thr Thr Ala

565 570 575

Ala Ser Ser Tyr Val Phe Val Arg Asp Phe Glu Gln Pro Phe Ile Asn

580 585 590

Lys Pro Asp Thr Leu Leu Val Asn Arg Lys Asp Ala Met Trp Val Pro

595 600 605

Cys Leu Val Ser Ile Pro Gly Leu Asn Val Thr Leu Arg Ser Gln Ser

610 615 620

Ser Val Leu Trp Pro Asp Gly Gln Glu Val Val Trp Asp Asp Arg Arg

625 630 635 640

Gly Met Leu Val Ser Thr Pro Leu Leu His Asp Ala Leu Tyr Leu Gln

645 650 655

Cys Glu Thr Thr Trp Gly Asp Gln Asp Phe Leu Ser Asn Pro Phe Leu

660 665 670

Val His Ile Thr Gly Asn Glu Leu

675 680

<210> 27

<211> 1356

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 27

atgcccttgc tcctgttgct ccccctgctc tgggcaggag ctcttgctga catacaaatg 60

actcaatctc ctagctcact ctccgctagt gtgggcgatc gggtaaccat cacatgtcgg 120

gccagccagg acatatcttc atatctgaat tggtatcagc agaagccagg gaaggcccct 180

aagctgctta tctactacac gtcaaggttg cactcaggtg tcccgtctcg gttctctggt 240

agtgggtccg ggactgactt tacattcaca attagtagcc tccagcccga ggacatagcg 300

acttactact gccaacaggg taataccttg ccctacactt tcggacaagg gaccaaggtt 360

gagattaagc gaacggtcgc tgctcccagt gtgttcattt ttcctccgtc tgatgaacag 420

ttgaaatccg ggaccgctag cgttgtgtgt ctcctgaata acttttaccc aagggaggcc 480

aaagttcaat ggaaagtaga taacgccttg cagagtggaa acagccagga gagtgttact 540

gagcaagact caaaagattc aacctatagc ctcagctcca ctctcacgct gagcaaagct 600

gactacgaaa agcacaaggt atatgcctgc gaagttactc atcaaggact gagctctcca 660

gtgacgaaga gtttcaaccg gggggaatgc ggcgaaggct ccggagacgg cggtgaggga 720

agcggcgatg gagaggggtc cgatactggc cgcccctttg tggagatgta ttctgagatc 780

ccggagatta tacacatgac tgagggacga gagctcgtta tcccatgtcg agtaacgagt 840

ccgaatataa cggtcacgct caaaaaattt cccttggata ccttgatacc agatggtaag 900

cgaataatct gggattctcg gaaagggttt attatctcaa acgctacgta caaagaaata 960

gggcttttga cttgtgaggc tacagttaat ggacatcttt ataaaacgaa ttatcttacg 1020

caccgacaga caaacaccat aatagatgtt gtcctttctc cctctcatgg aattgagttg 1080

agcgtgggtg aaaagttggt gctgaactgc accgctcgca ctgagcttaa tgtcggaatt 1140

gattttaatt gggagtaccc ttcaagcaaa catcagcata agaaactggt aaatagagat 1200

cttaaaacac agtcaggtag cgaaatgaaa aagttcctga gtacgttgac aatcgacggt 1260

gtgactagat ccgatcaagg tctctataca tgtgccgcca gttctggtct gatgaccaaa 1320

aagaatagta catttgttcg agttcacgag aaatag 1356

<210> 28

<211> 451

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 28

Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala

1 5 10 15

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

20 25 30

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

35 40 45

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

50 55 60

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

65 70 75 80

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

85 90 95

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

100 105 110

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

115 120 125

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

130 135 140

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

145 150 155 160

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

165 170 175

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

180 185 190

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

195 200 205

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

210 215 220

Phe Asn Arg Gly Glu Cys Gly Glu Gly Ser Gly Asp Gly Gly Glu Gly

225 230 235 240

Ser Gly Asp Gly Glu Gly Ser Asp Thr Gly Arg Pro Phe Val Glu Met

245 250 255

Tyr Ser Glu Ile Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu

260 265 270

Val Ile Pro Cys Arg Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys

275 280 285

Lys Phe Pro Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp

290 295 300

Asp Ser Arg Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile

305 310 315 320

Gly Leu Leu Thr Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr

325 330 335

Asn Tyr Leu Thr His Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu

340 345 350

Ser Pro Ser His Gly Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu

355 360 365

Asn Cys Thr Ala Arg Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp

370 375 380

Glu Tyr Pro Ser Ser Lys His Gln His Lys Lys Leu Val Asn Arg Asp

385 390 395 400

Leu Lys Thr Gln Ser Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu

405 410 415

Thr Ile Asp Gly Val Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala

420 425 430

Ala Ser Ser Gly Leu Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val

435 440 445

His Glu Lys

450

<210> 29

<211> 2043

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 29

atgcccctcc tccttttgct tcctctgctg tgggcgggcg cgctggcaca agtacaattg 60

caagagagcg gcccaggtct cgtaaggccg tcccagactt tgtctctgac atgcacagta 120

tcagggtatt ccatcactag tgatcacgct tggtcctggg tccgacagcc gcctgggaga 180

ggcctggagt ggatagggta catctcctac tccggaataa cgacgtacaa cccgagtctg 240

aagtctcgag taaccatgct gagggataca agcaagaatc agttttcatt gaggctctca 300

tccgttacag ccgccgacac agctgtctat tattgcgctc gcagtttggc cagaaccact 360

gcaatggatt actggggcca aggatccctg gttaccgtca gctcagctag cacgaaaggt 420

ccatctgttt tcccacttgc accgtccagt aagtccacct caggcggaac cgctgccctt 480

ggatgcctgg tcaaggatta tttccccgag ccagtcacag tcagctggaa ctctggagcc 540

ctcaccagcg gagttcacac gtttcccgct gtcttgcaaa gttccgggct ctacagtctg 600

agctctgtag taaccgtgcc cagttcaagc cttgggaccc aaacttacat atgtaatgta 660

aatcacaagc caagcaacac taaggtggat aaaaaagtcg agccgaaatc ctgcgacaaa 720

acacacacgt gtcctccgtg tccggctccc gaattgcttg gcggcccctc cgtgtttctg 780

ttcccaccga agccaaagga cactctgatg atctctcgca cgccagaagt gacatgcgtc 840

gttgtagacg tatcacacga agaccccgaa gttaagttta actggtatgt ggatggagtc 900

gaagtacata atgccaagac gaaaccaagg gaagaacaat acaattctac atatcgggtc 960

gtgagtgttc tgacggtatt gcatcaagat tggctcaacg gtaaagaata caaatgtaag 1020

gtgagtaata aagcgcttcc cgctccaata gagaagacaa tatccaaagc taaaggtcag 1080

ccacgggagc cgcaagttta taccttgccg ccttcaagag aagagatgac aaaaaaccag 1140

gtttccctta cgtgcctggt gaagggattt tacccaagtg atatagcagt tgaatgggag 1200

agcaacggtc aaccagaaaa caactacaag actactcccc cagttctcga ctctgatggg 1260

tctttctttt tgtactcaaa actcaccgtt gacaaatcaa gatggcagca aggcaacgtt 1320

ttttcatgta gcgtcatgca tgaggccttg cacaaccact acacgcaaaa aagcctcagt 1380

ttgagtcccg ggggtggtag tggcggtggc ggttccggcg gtgggtattc tatgacacca 1440

cccacgctca atattacaga ggagagccac gtaattgata caggtgattc tctgtccatt 1500

agttgcaggg gtcaacatcc gctggaatgg gcctggccgg gtgcgcaaga agcacccgca 1560

acaggagata aagactccga agatacgggg gtggtcagag attgtgaagg gacagatgca 1620

aggccttatt gtaaggtttt gcttctccac gaggtacatg cgaacgatac tgggtcttac 1680

gtgtgttact acaagtatat caaagctagg atcgagggga ctaccgccgc gagttcttat 1740

gtttttgtcc gagacttcga gcagccgttc atcaataaac ctgacacact gttggtaaac 1800

cggaaagacg ccatgtgggt gccttgtctt gtttctatcc cgggtctgaa cgtcactctt 1860

aggagtcagt ccagcgtcct ctggcccgat ggccaggagg tcgtctggga tgacagaagg 1920

ggcatgttgg tatccactcc gcttttgcac gatgcgctgt accttcagtg tgagaccact 1980

tggggtgacc aagattttct ctcaaatccc tttctggtcc acataaccgg caacgagctc 2040

tag 2043

<210> 30

<211> 680

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 30

Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala

1 5 10 15

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

20 25 30

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

35 40 45

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

50 55 60

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

65 70 75 80

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

85 90 95

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

100 105 110

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

115 120 125

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

130 135 140

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu

145 150 155 160

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

165 170 175

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu

180 185 190

Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

195 200 205

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

210 215 220

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys

225 230 235 240

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

245 250 255

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

260 265 270

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

275 280 285

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

290 295 300

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

305 310 315 320

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

325 330 335

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

340 345 350

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

355 360 365

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

370 375 380

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

385 390 395 400

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

405 410 415

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

420 425 430

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

435 440 445

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

450 455 460

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Tyr Ser Met Thr Pro

465 470 475 480

Pro Thr Leu Asn Ile Thr Glu Glu Ser His Val Ile Asp Thr Gly Asp

485 490 495

Ser Leu Ser Ile Ser Cys Arg Gly Gln His Pro Leu Glu Trp Ala Trp

500 505 510

Pro Gly Ala Gln Glu Ala Pro Ala Thr Gly Asp Lys Asp Ser Glu Asp

515 520 525

Thr Gly Val Val Arg Asp Cys Glu Gly Thr Asp Ala Arg Pro Tyr Cys

530 535 540

Lys Val Leu Leu Leu His Glu Val His Ala Asn Asp Thr Gly Ser Tyr

545 550 555 560

Val Cys Tyr Tyr Lys Tyr Ile Lys Ala Arg Ile Glu Gly Thr Thr Ala

565 570 575

Ala Ser Ser Tyr Val Phe Val Arg Asp Phe Glu Gln Pro Phe Ile Asn

580 585 590

Lys Pro Asp Thr Leu Leu Val Asn Arg Lys Asp Ala Met Trp Val Pro

595 600 605

Cys Leu Val Ser Ile Pro Gly Leu Asn Val Thr Leu Arg Ser Gln Ser

610 615 620

Ser Val Leu Trp Pro Asp Gly Gln Glu Val Val Trp Asp Asp Arg Arg

625 630 635 640

Gly Met Leu Val Ser Thr Pro Leu Leu His Asp Ala Leu Tyr Leu Gln

645 650 655

Cys Glu Thr Thr Trp Gly Asp Gln Asp Phe Leu Ser Asn Pro Phe Leu

660 665 670

Val His Ile Thr Gly Asn Glu Leu

675 680

<210> 31

<211> 1341

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 31

atgccgctcc tgcttcttct cccactcctc tgggccggag cgcttgccga catacagatg 60

acccagtccc ctagtagcct cagcgcaagc gttggagatc gggtgactat aacgtgccga 120

gcgtcccaag acatttcttc ttatttgaat tggtatcaac aaaaaccagg gaaagccccg 180

aaactgctga tttattacac cagtcgactg cactccggag tccctagtcg gttcagcggg 240

tctggatcag gtactgattt tacctttact ataagctcac tccagccaga ggacattgcg 300

acctattatt gccagcaggg aaacacactt ccgtacacgt ttggccaggg gaccaaagtt 360

gaaatcaaga ggaccgtggc agccccctca gttttcatat tccctccgtc tgacgagcag 420

ttgaagtcag ggactgcatc cgtggtgtgt ctgctgaata atttctaccc acgcgaggcc 480

aaggtgcagt ggaaggtaga taatgctctc caatccggga acagccaaga gtctgttact 540

gaacaagatt ccaaagactc tacctatagc ctctcaagca cccttacact tagtaaggcg 600

gattacgaaa aacacaaagt ctacgcatgt gaagtgaccc atcagggtct cagcagcccg 660

gtcactaaaa gctttaacag gggggaatgt ggggggagtg gtggtggagg tagcggcggt 720

ggctccgaca ccggaaggcc tttcgtagag atgtattcag aaattcccga aattatacat 780

atgacggaag gcagagagct ggtcataccg tgtagagtaa catcacccaa cataactgtt 840

acgcttaaaa agttcccact tgacacactt atacccgacg gcaagagaat aatctgggac 900

agcagaaaag gtttcatcat ctccaatgct acttataaag agatcgggct cctgacgtgc 960

gaggcgaccg taaacgggca tttgtacaaa accaactatc tcactcatag acaaacaaac 1020

actattattg atgtggtgct cagcccctct catgggatcg agctttccgt aggtgaaaag 1080

ctggtcctga actgcacagc acggactgag ttgaatgtag ggatagattt caactgggaa 1140

tacccgtctt caaaacatca gcacaaaaag cttgtgaatc gcgacctcaa gacacaatca 1200

gggtcagaaa tgaaaaagtt tctctcaacg ctgactatcg acggcgtcac gcggtccgat 1260

cagggccttt acacttgtgc ggcctcttct gggttgatga cgaagaaaaa cagtacgttt 1320

gtacgcgtac atgagaagta g 1341

<210> 32

<211> 446

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 32

Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala

1 5 10 15

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

20 25 30

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

35 40 45

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

50 55 60

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

65 70 75 80

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

85 90 95

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

100 105 110

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

115 120 125

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

130 135 140

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

145 150 155 160

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

165 170 175

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

180 185 190

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

195 200 205

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

210 215 220

Phe Asn Arg Gly Glu Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

225 230 235 240

Gly Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro

245 250 255

Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg

260 265 270

Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp

275 280 285

Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly

290 295 300

Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys

305 310 315 320

Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His

325 330 335

Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly

340 345 350

Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg

355 360 365

Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser

370 375 380

Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser

385 390 395 400

Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val

405 410 415

Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu

420 425 430

Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys

435 440 445

<210> 33

<211> 2010

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 33

caggtgcagc tgcaggaatc agggcctggt ttggtgcggc cgagtcagac gctcagcttg 60

acttgtacgg tgtcaggtta ctctatcact agcgatcatg cctggagctg ggtacgacaa 120

ccaccgggtc ggggtctcga atggataggt tacataagct actcaggaat cacgacatac 180

aatccctccc ttaaaagtcg ggtcaccatg ctccgagaca ctagtaaaaa tcagttctcc 240

ctgcggttgt ccagcgtgac tgctgccgac acggcggtct attattgcgc aagaagtctg 300

gcgcggacaa cggcaatgga ctactgggga caaggttcac tggtaaccgt tagttcagca 360

agcaccaagg gtccgtctgt ctttccactc gcgccttcta gcaagtcaac ctcagggggg 420

actgccgcgc ttggatgtct ggtcaaagat tattttcctg agccggtaac agttagctgg 480

aattcaggtg ccctcacatc tggggtacac acgtttcccg ccgtgcttca gagctctggc 540

ctctacagtc tttctagcgt ggtcaccgtc ccatcttcat cattgggtac acaaacttac 600

atttgtaacg ttaatcacaa acctagcaac actaaggtgg ataaaaaagt agagccaaag 660

tcctgcgaca agactcacac ctgtcctccc tgtccagcac ccgaactttt gggcggtcct 720

tctgttttcc tgtttcctcc taaacccaaa gatacactca tgatctccag aaccccggaa 780

gtaacctgcg tagtcgtgga cgtatcccat gaggatcccg aggtaaaatt caactggtac 840

gtagacgggg tcgaggtgca caatgccaag actaaaccta gggaagagca atacaatagt 900

acgtacaggg tggtttccgt gctgaccgtc ctgcatcagg attggctcaa cgggaaagag 960

tataaatgta aggtgtcaaa caaagctttg ccggcaccaa tagagaaaac cattagtaag 1020

gcgaaaggac aaccccgaga gccacaagtg tatacgttgc ctcccagccg cgaggaaatg 1080

acgaagaatc aagtctctct gacttgtctg gtgaagggtt tttacccgtc tgatatagct 1140

gtcgaatggg agtctaacgg ccagccagag aataattaca aaaccactcc tccggtcttg 1200

gattctgatg ggagcttttt cctgtattcc aaattgacag ttgataaaag tcggtggcag 1260

caggggaacg tcttctcctg tagcgtcatg catgaagcac tgcataatca ttatacccaa 1320

aaaagtttgt ccttgagccc tggtggcgag ggttcagggg atggaggcga ggggtccggg 1380

gacggcgaag gctcagatac cggaagacca tttgtggaga tgtattccga aataccggag 1440

ataatacata tgacggaagg tcgagaactc gtcatcccat gtcgcgtaac ctctccaaat 1500

atcaccgtaa cactcaaaaa attccctctt gacacgttga taccggacgg caaaagaata 1560

atatgggatt caaggaaagg atttataata agcaacgcca catacaaaga gattgggctg 1620

ctcacttgtg aagccactgt taatgggcac ttgtataaga ctaattatct cacccaccgc 1680

cagacgaata ctataataga tgtcgttctg agcccaagtc atgggattga actttctgtt 1740

ggcgaaaagc tcgtgttgaa ttgcactgct aggacggagc tgaatgttgg tatagatttc 1800

aattgggaat atcctagctc taaacaccag cacaaaaaac tcgttaatcg cgacttgaag 1860

acgcagtcag gatcagagat gaaaaagttc ctctcaacgc tgactataga tggagtaacg 1920

agatccgacc agggattgta cacctgcgcc gcgtcttccg ggctcatgac aaaaaaaaac 1980

agcactttcg tacgcgtcca tgaaaaatag 2010

<210> 34

<211> 669

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 34

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 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 Ile Cys Asn Val Asn His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 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 His Glu Asp

260 265 270

Pro Glu Val Lys 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 Ala Leu Pro Ala Pro 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 Arg Glu 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 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Gly Glu Gly Ser Gly Asp Gly Gly Glu Gly Ser Gly Asp Gly Glu Gly

450 455 460

Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu

465 470 475 480

Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val

485 490 495

Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr

500 505 510

Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe

515 520 525

Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu

530 535 540

Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg

545 550 555 560

Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile

565 570 575

Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr

580 585 590

Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys

595 600 605

His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly

610 615 620

Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr

625 630 635 640

Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met

645 650 655

Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys

660 665

<210> 35

<211> 1308

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 35

gacattcaaa tgactcagtc tccatccagt ctctccgctt ctgtggggga ccgagtaacc 60

ataacatgtc gggcatctca ggacataagc tcatacttga attggtatca gcagaaacca 120

gggaaggcgc ccaagcttct tatctactat acatcaagac ttcatagcgg ggtgccaagc 180

cgattcagtg gcagcggttc aggaacagac tttacgttca ccatttcatc tttgcagcca 240

gaagatatag ctacgtacta ctgtcagcaa ggaaatacgt tgccgtacac ctttggccag 300

ggcacaaaag tcgaaattaa gcgaaccgta gcagccccga gtgtctttat ctttcctccc 360

tcagatgagc aacttaaaag cgggacagcc tcagtagttt gcctcctgaa caatttctac 420

ccacgggaag ccaaggtgca gtggaaggtg gacaatgctc ttcagtccgg caactctcag 480

gaaagtgtta ccgagcaaga ctctaaagac tcaacttaca gcctcagctc caccctcact 540

ttgtccaagg ctgattacga aaaacataag gtatatgcct gcgaagttac gcaccaagga 600

ctttcatccc cggtgacaaa gagcttcaac agaggcgaat gtggagaggg gtccggcgac 660

ggcggtgaag ggtctggtga tggggaaggt tccgataccg gtcgaccctt cgtcgagatg 720

tattctgaga ttccggaaat catccacatg accgaaggac gagagcttgt aattccttgc 780

cgagttacat cacccaacat aacggtgaca ctcaagaagt ttcctttgga tacattgatt 840

ccggacggga agcgcataat ttgggatagt agaaagggtt ttattatcag caacgctacg 900

tataaggaga taggtctgct cacttgtgaa gccactgtga atgggcacct gtacaaaaca 960

aattatctca cccaccgaca gactaacacc attatcgatg ttgttttgtc tccatctcat 1020

ggaatcgaac ttagtgtcgg agaaaagctc gtactgaatt gcacagcccg aacggaactt 1080

aatgttggga ttgactttaa ttgggagtat ccgtcttcta agcatcaaca caagaagctt 1140

gttaacaggg atctcaagac gcaatccgga tcagaaatga aaaaatttct ctccactctt 1200

actatagatg gagtcacacg ctccgaccaa ggtctctaca cgtgcgcagc tagtagtggt 1260

ctgatgacca aaaagaactc tacgttcgtg agagtacatg agaagtag 1308

<210> 36

<211> 435

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 36

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 Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln 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 Gly Glu Gly Ser Gly Asp Gly Gly Glu Gly

210 215 220

Ser Gly Asp Gly Glu Gly Ser Asp Thr Gly Arg Pro Phe Val Glu Met

225 230 235 240

Tyr Ser Glu Ile Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu

245 250 255

Val Ile Pro Cys Arg Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys

260 265 270

Lys Phe Pro Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp

275 280 285

Asp Ser Arg Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile

290 295 300

Gly Leu Leu Thr Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr

305 310 315 320

Asn Tyr Leu Thr His Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu

325 330 335

Ser Pro Ser His Gly Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu

340 345 350

Asn Cys Thr Ala Arg Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp

355 360 365

Glu Tyr Pro Ser Ser Lys His Gln His Lys Lys Leu Val Asn Arg Asp

370 375 380

Leu Lys Thr Gln Ser Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu

385 390 395 400

Thr Ile Asp Gly Val Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala

405 410 415

Ala Ser Ser Gly Leu Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val

420 425 430

His Glu Lys

435

<210> 37

<211> 1995

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 37

caagtacaac ttcaagaatc aggtcccggg ctcgtgcggc cttcacaaac acttagcctc 60

acctgcactg tgtccgggta tagcataaca agtgaccacg cgtggagctg ggtgcggcag 120

cctcctggtc gcggcctcga gtggattgga tacatatcct actcaggaat cactacatat 180

aatccaagtt tgaaatcccg agttaccatg ttgagggaca cgagtaaaaa tcagttcagt 240

ctgaggttgt caagcgtaac ggcggctgat acggctgttt attactgtgc aagaagtttg 300

gcacgaacaa ccgcgatgga ctactggggt caaggctcat tggtaactgt gagctctgcg 360

tctaccaagg gccctagcgt ttttcctctg gccccttcct ccaagtccac gtccggtgga 420

acagctgctc tcggctgttt ggtaaaagat tatttcccag aacccgttac tgtgtcatgg 480

aactctggtg ctttgacaag tggagtccat acttttcctg ccgttctgca atcaagtggg 540

ctctatagct tgtcctcagt tgtcacagta ccatcatcaa gcctgggtac acagacttat 600

atatgcaatg tgaaccacaa gccttccaat acgaaagtcg acaagaaggt cgagcccaag 660

tcatgcgaca agacccatac ctgcccccca tgtccagccc ccgaactgct gggcggaccc 720

tcagtcttcc tctttccacc aaagccgaaa gataccctta tgatctctag gacccccgag 780

gtaacgtgcg ttgtcgtcga tgtgtctcac gaggacccgg aggtcaagtt caattggtac 840

gtcgatggcg tcgaggttca taacgcgaag actaaaccga gggaggaaca atacaactct 900

acgtaccgag tagtgtccgt gttgacagta ctgcatcaag attggctcaa tggtaaagaa 960

tataaatgca aggtctctaa caaagcgttg cctgcgccaa tcgaaaaaac tattagcaaa 1020

gctaagggtc aaccgcgaga gcctcaggta tacacgcttc ctccgtcccg agaagagatg 1080

acgaaaaatc aagtctccct gacatgtctt gttaagggtt tttacccttc tgacattgct 1140

gtcgaatggg agtccaatgg ccagcccgag aacaactata agacgacgcc tcccgtcttg 1200

gatagtgacg gaagcttttt cctgtattct aaattgaccg tggacaagag ccggtggcaa 1260

cagggtaacg tcttttcatg ctccgtaatg cacgaggcgc ttcataacca ctacacccaa 1320

aagagtctct cattgtctcc cggtggcggt tcaggtgggg ggggaagcgg tggtggatct 1380

gacactggac ggcctttcgt tgagatgtac tcagaaattc cggagatcat tcacatgaca 1440

gaagggaggg agttggtgat accttgccgg gttacatcac caaacataac tgtaacactc 1500

aaaaaattcc ccctggatac acttatccct gatggaaagc gaataatatg ggacagtaga 1560

aaaggattta tcattagcaa cgcaacgtat aaagaaatcg gattgcttac ctgcgaagcg 1620

acggtgaatg gccatctgta caaaacgaac tacctcacgc accgacaaac gaacactatc 1680

atagatgtag ttttgagtcc tagtcacggt attgagctca gcgtcgggga gaaactggtc 1740

cttaactgta ctgctagaac ggaactcaac gtgggtatag atttcaactg ggagtacccg 1800

tcatccaaac atcaacacaa gaaacttgtc aaccgagacc tgaagacaca atctggatca 1860

gagatgaaga agtttttgtc tactcttaca attgatgggg tcactcggtc tgatcaagga 1920

ctgtatacct gcgcagccag ttcagggttg atgactaaaa aaaattccac cttcgtacga 1980

gtccacgaga agtag 1995

<210> 38

<211> 664

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 38

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 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 Ile Cys Asn Val Asn His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 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 His Glu Asp

260 265 270

Pro Glu Val Lys 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 Ala Leu Pro Ala Pro 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 Arg Glu 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 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Asp Thr Gly Arg

450 455 460

Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu Ile Ile His Met Thr

465 470 475 480

Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val Thr Ser Pro Asn Ile

485 490 495

Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu Ile Pro Asp Gly

500 505 510

Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser Asn Ala

515 520 525

Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala Thr Val Asn Gly

530 535 540

His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln Thr Asn Thr Ile

545 550 555 560

Ile Asp Val Val Leu Ser Pro Ser His Gly Ile Glu Leu Ser Val Gly

565 570 575

Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn Val Gly

580 585 590

Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys His Gln His Lys Lys

595 600 605

Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser Glu Met Lys Lys

610 615 620

Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr Arg Ser Asp Gln Gly

625 630 635 640

Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met Thr Lys Lys Asn Ser

645 650 655

Thr Phe Val Arg Val His Glu Lys

660

<210> 39

<211> 1293

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 39

gatattcaaa tgactcagtc tccttcaagc ctttccgcct cagtcggcga cagagtaaca 60

ataacttgtc gggcgtctca agatatctcc tcatatttga attggtacca gcaaaaaccc 120

ggtaaagcac caaagcttct catctactat acctcaagac tgcattccgg ggtgccgagc 180

cggtttagcg gatctggatc tggaacagac tttacattca cgatttccag cctgcagccg 240

gaggatattg ccacctatta ttgtcagcag ggaaacacgt tgccttacac tttcggacag 300

ggaaccaaag tggagataaa gaggactgtt gccgcaccga gcgtgtttat ctttcctcct 360

tcagatgagc agcttaagtc tggtacagcc tcagttgtat gtttgctgaa caacttctac 420

ccaagggaag ctaaagtaca gtggaaggtt gataatgccc ttcaatccgg gaactctcaa 480

gagtctgtaa cagaacaaga tagtaaggac tcaacgtata gcctttccag cacgttgacg 540

ctgagtaagg cagactatga aaagcacaag gtctacgcgt gcgaggtgac acaccaaggc 600

ctgtcttccc ctgtaaccaa aagctttaac aggggtgagt gcggtggaag cggcggcggc 660

ggttctggag gcgggtcaga cactggtcga ccgtttgtcg agatgtattc tgagatacct 720

gagattatcc acatgacaga aggacgggaa ctggtgatcc cttgccgggt aacctcaccc 780

aatatcaccg tgacattgaa aaagtttccc cttgacacac ttatacctga cggaaagagg 840

atcatttggg acagtcgcaa gggtttcatc atttccaacg caacatataa agagatagga 900

cttttgacgt gcgaagcgac ggtcaatggt cacttgtaca agacgaacta tttgacccat 960

agacaaacga acactataat agatgttgtg cttagtccaa gtcacgggat agaattgagt 1020

gtaggcgaga agcttgtact caattgtacg gcccgaaccg agctcaacgt tggaatagac 1080

ttcaactggg agtaccctag cagcaagcac caacataaga agcttgtaaa ccgcgatttg 1140

aagacgcagt caggcagtga aatgaaaaag ttcttgtcca ctttgacgat tgatggtgtt 1200

acgagatcag accagggctt gtatacctgc gcagcgtcaa gcgggctgat gacgaagaag 1260

aactcaactt ttgtcagagt tcacgaaaag tag 1293

<210> 40

<211> 430

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 40

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 Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln 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 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

210 215 220

Gly Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro

225 230 235 240

Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg

245 250 255

Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp

260 265 270

Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly

275 280 285

Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys

290 295 300

Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His

305 310 315 320

Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly

325 330 335

Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg

340 345 350

Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser

355 360 365

Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser

370 375 380

Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val

385 390 395 400

Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu

405 410 415

Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys

420 425 430

<210> 41

<211> 1995

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 41

caagttcaac tgcaggagag cggcccgggt ttggtacgac caagccaaac actctcactt 60

acatgcaccg tgtcagggta tagcattacc tcagaccacg cgtggagctg ggtacggcag 120

ccgccgggtc gaggcctcga gtggataggg tatatctctt actcaggtat tacaacatac 180

aacccgtctc ttaagtctcg cgtgaccatg ctgcgggata caagcaaaaa ccagttctcc 240

ctcagactga gctctgtcac tgcggccgat actgctgtct actattgtgc tcgaagtttg 300

gcgaggacaa cggctatgga ctattggggc caaggatccc tggtaacagt ttcttctgca 360

agtacgaaag gcccaagtgt gtttccactg gctccctcct ctaagagcac ttctggggga 420

acggcagctc tgggctgcct tgtgaaggac tactttcctg agccagtaac agtctcctgg 480

aattcaggag cccttactag cggtgttcat acgttcccgg ccgttctgca gagtagcggg 540

ctttactctc tgtcatctgt tgtgacggtt ccatccagca gcttgggcac acagacctac 600

atatgcaatg tcaatcacaa accttctaat acaaaggtgg ataaaaaagt cgagcctaag 660

agttgcgata agacccatac ctgtcctcca tgtcccgcac cagaactttt gggcgggcca 720

tcagtgtttc tgttcccccc caagcctaaa gataccctta tgattagtag aacacccgaa 780

gtgacctgtg tagtagtgga tgttagccat gaggaccctg aagttaaatt caattggtat 840

gtcgatgggg ttgaagttca caatgccaaa actaagcccc gcgaagaaca gtataacagt 900

acatataggg tcgtttcagt actgacagta ttgcaccagg actggttgaa cggaaaggag 960

tataagtgca aagtcagcaa caaagccctg cctgcaccta tcgaaaaaac catcagtaag 1020

gcaaagggac agccgaggga accgcaggtg tacacgctcc ccccgtccag agaagagatg 1080

acaaagaacc aggtcagcct gacatgtttg gtcaagggat tctatccgtc agacattgcc 1140

gtcgagtggg agagtaatgg ccagcccgag aataattata aaactactcc gcccgtgctt 1200

gactccgacg ggtcattttt cctctatagc aaactgaccg tggataagtc aagatggcaa 1260

caaggtaacg tctttagttg tagtgttatg catgaggcgc ttcataacca ctatacacag 1320

aagagtttga gtttgtcacc tggtgggggg agcggtggtg gaggttctgg tggtggttat 1380

agcatgactc cacccaccct gaacatcact gaagaatcac atgtcatcga cactggtgac 1440

tccttgtcca taagttgccg ggggcaacac cctctggaat gggcctggcc cggtgcacag 1500

gaggccccag cgactggcga caaggactca gaggacacgg gggttgtcag agattgtgag 1560

gggactgacg cgaggccgta ttgcaaagtt ctgctgcttc atgaagtgca cgcaaacgat 1620

acgggatctt acgtgtgcta ctacaaatat ataaaggccc ggattgaagg tacgacagcg 1680

gcttcaagct acgtattcgt tagggatttc gagcaaccat tcatcaacaa gcctgataca 1740

ttgttggtta accgaaaaga cgccatgtgg gtcccttgcc tcgtctccat tccgggactt 1800

aatgtaacac tcaggagcca aagttccgtc ttgtggcccg acggccaaga agtagtttgg 1860

gacgacaggc gaggcatgct cgtgagtacg ccgctgcttc atgatgcgct gtaccttcaa 1920

tgcgagacga cttggggtga ccaagacttt ctctctaacc cttttctggt ccatatcaca 1980

gggaacgagc tctag 1995

<210> 42

<211> 664

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 42

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 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 Ile Cys Asn Val Asn His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 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 His Glu Asp

260 265 270

Pro Glu Val Lys 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 Ala Leu Pro Ala Pro 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 Arg Glu 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 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Tyr Ser Met Thr Pro

450 455 460

Pro Thr Leu Asn Ile Thr Glu Glu Ser His Val Ile Asp Thr Gly Asp

465 470 475 480

Ser Leu Ser Ile Ser Cys Arg Gly Gln His Pro Leu Glu Trp Ala Trp

485 490 495

Pro Gly Ala Gln Glu Ala Pro Ala Thr Gly Asp Lys Asp Ser Glu Asp

500 505 510

Thr Gly Val Val Arg Asp Cys Glu Gly Thr Asp Ala Arg Pro Tyr Cys

515 520 525

Lys Val Leu Leu Leu His Glu Val His Ala Asn Asp Thr Gly Ser Tyr

530 535 540

Val Cys Tyr Tyr Lys Tyr Ile Lys Ala Arg Ile Glu Gly Thr Thr Ala

545 550 555 560

Ala Ser Ser Tyr Val Phe Val Arg Asp Phe Glu Gln Pro Phe Ile Asn

565 570 575

Lys Pro Asp Thr Leu Leu Val Asn Arg Lys Asp Ala Met Trp Val Pro

580 585 590

Cys Leu Val Ser Ile Pro Gly Leu Asn Val Thr Leu Arg Ser Gln Ser

595 600 605

Ser Val Leu Trp Pro Asp Gly Gln Glu Val Val Trp Asp Asp Arg Arg

610 615 620

Gly Met Leu Val Ser Thr Pro Leu Leu His Asp Ala Leu Tyr Leu Gln

625 630 635 640

Cys Glu Thr Thr Trp Gly Asp Gln Asp Phe Leu Ser Asn Pro Phe Leu

645 650 655

Val His Ile Thr Gly Asn Glu Leu

660

<210> 43

<211> 1308

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 43

gacatacaaa tgactcaatc tcctagctca ctctccgcta gtgtgggcga tcgggtaacc 60

atcacatgtc gggccagcca ggacatatct tcatatctga attggtatca gcagaagcca 120

gggaaggccc ctaagctgct tatctactac acgtcaaggt tgcactcagg tgtcccgtct 180

cggttctctg gtagtgggtc cgggactgac tttacattca caattagtag cctccagccc 240

gaggacatag cgacttacta ctgccaacag ggtaatacct tgccctacac tttcggacaa 300

gggaccaagg ttgagattaa gcgaacggtc gctgctccca gtgtgttcat ttttcctccg 360

tctgatgaac agttgaaatc cgggaccgct agcgttgtgt gtctcctgaa taacttttac 420

ccaagggagg ccaaagttca atggaaagta gataacgcct tgcagagtgg aaacagccag 480

gagagtgtta ctgagcaaga ctcaaaagat tcaacctata gcctcagctc cactctcacg 540

ctgagcaaag ctgactacga aaagcacaag gtatatgcct gcgaagttac tcatcaagga 600

ctgagctctc cagtgacgaa gagtttcaac cggggggaat gcggcgaagg ctccggagac 660

ggcggtgagg gaagcggcga tggagagggg tccgatactg gccgcccctt tgtggagatg 720

tattctgaga tcccggagat tatacacatg actgagggac gagagctcgt tatcccatgt 780

cgagtaacga gtccgaatat aacggtcacg ctcaaaaaat ttcccttgga taccttgata 840

ccagatggta agcgaataat ctgggattct cggaaagggt ttattatctc aaacgctacg 900

tacaaagaaa tagggctttt gacttgtgag gctacagtta atggacatct ttataaaacg 960

aattatctta cgcaccgaca gacaaacacc ataatagatg ttgtcctttc tccctctcat 1020

ggaattgagt tgagcgtggg tgaaaagttg gtgctgaact gcaccgctcg cactgagctt 1080

aatgtcggaa ttgattttaa ttgggagtac ccttcaagca aacatcagca taagaaactg 1140

gtaaatagag atcttaaaac acagtcaggt agcgaaatga aaaagttcct gagtacgttg 1200

acaatcgacg gtgtgactag atccgatcaa ggtctctata catgtgccgc cagttctggt 1260

ctgatgacca aaaagaatag tacatttgtt cgagttcacg agaaatag 1308

<210> 44

<211> 435

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 44

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 Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln 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 Gly Glu Gly Ser Gly Asp Gly Gly Glu Gly

210 215 220

Ser Gly Asp Gly Glu Gly Ser Asp Thr Gly Arg Pro Phe Val Glu Met

225 230 235 240

Tyr Ser Glu Ile Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu

245 250 255

Val Ile Pro Cys Arg Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys

260 265 270

Lys Phe Pro Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp

275 280 285

Asp Ser Arg Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile

290 295 300

Gly Leu Leu Thr Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr

305 310 315 320

Asn Tyr Leu Thr His Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu

325 330 335

Ser Pro Ser His Gly Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu

340 345 350

Asn Cys Thr Ala Arg Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp

355 360 365

Glu Tyr Pro Ser Ser Lys His Gln His Lys Lys Leu Val Asn Arg Asp

370 375 380

Leu Lys Thr Gln Ser Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu

385 390 395 400

Thr Ile Asp Gly Val Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala

405 410 415

Ala Ser Ser Gly Leu Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val

420 425 430

His Glu Lys

435

<210> 45

<211> 1995

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 45

caagtacaat tgcaagagag cggcccaggt ctcgtaaggc cgtcccagac tttgtctctg 60

acatgcacag tatcagggta ttccatcact agtgatcacg cttggtcctg ggtccgacag 120

ccgcctggga gaggcctgga gtggataggg tacatctcct actccggaat aacgacgtac 180

aacccgagtc tgaagtctcg agtaaccatg ctgagggata caagcaagaa tcagttttca 240

ttgaggctct catccgttac agccgccgac acagctgtct attattgcgc tcgcagtttg 300

gccagaacca ctgcaatgga ttactggggc caaggatccc tggttaccgt cagctcagct 360

agcacgaaag gtccatctgt tttcccactt gcaccgtcca gtaagtccac ctcaggcgga 420

accgctgccc ttggatgcct ggtcaaggat tatttccccg agccagtcac agtcagctgg 480

aactctggag ccctcaccag cggagttcac acgtttcccg ctgtcttgca aagttccggg 540

ctctacagtc tgagctctgt agtaaccgtg cccagttcaa gccttgggac ccaaacttac 600

atatgtaatg taaatcacaa gccaagcaac actaaggtgg ataaaaaagt cgagccgaaa 660

tcctgcgaca aaacacacac gtgtcctccg tgtccggctc ccgaattgct tggcggcccc 720

tccgtgtttc tgttcccacc gaagccaaag gacactctga tgatctctcg cacgccagaa 780

gtgacatgcg tcgttgtaga cgtatcacac gaagaccccg aagttaagtt taactggtat 840

gtggatggag tcgaagtaca taatgccaag acgaaaccaa gggaagaaca atacaattct 900

acatatcggg tcgtgagtgt tctgacggta ttgcatcaag attggctcaa cggtaaagaa 960

tacaaatgta aggtgagtaa taaagcgctt cccgctccaa tagagaagac aatatccaaa 1020

gctaaaggtc agccacggga gccgcaagtt tataccttgc cgccttcaag agaagagatg 1080

acaaaaaacc aggtttccct tacgtgcctg gtgaagggat tttacccaag tgatatagca 1140

gttgaatggg agagcaacgg tcaaccagaa aacaactaca agactactcc cccagttctc 1200

gactctgatg ggtctttctt tttgtactca aaactcaccg ttgacaaatc aagatggcag 1260

caaggcaacg ttttttcatg tagcgtcatg catgaggcct tgcacaacca ctacacgcaa 1320

aaaagcctca gtttgagtcc cgggggtggt agtggcggtg gcggttccgg cggtgggtat 1380

tctatgacac cacccacgct caatattaca gaggagagcc acgtaattga tacaggtgat 1440

tctctgtcca ttagttgcag gggtcaacat ccgctggaat gggcctggcc gggtgcgcaa 1500

gaagcacccg caacaggaga taaagactcc gaagatacgg gggtggtcag agattgtgaa 1560

gggacagatg caaggcctta ttgtaaggtt ttgcttctcc acgaggtaca tgcgaacgat 1620

actgggtctt acgtgtgtta ctacaagtat atcaaagcta ggatcgaggg gactaccgcc 1680

gcgagttctt atgtttttgt ccgagacttc gagcagccgt tcatcaataa acctgacaca 1740

ctgttggtaa accggaaaga cgccatgtgg gtgccttgtc ttgtttctat cccgggtctg 1800

aacgtcactc ttaggagtca gtccagcgtc ctctggcccg atggccagga ggtcgtctgg 1860

gatgacagaa ggggcatgtt ggtatccact ccgcttttgc acgatgcgct gtaccttcag 1920

tgtgagacca cttggggtga ccaagatttt ctctcaaatc cctttctggt ccacataacc 1980

ggcaacgagc tctag 1995

<210> 46

<211> 664

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 46

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 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 Ile Cys Asn Val Asn His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 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 His Glu Asp

260 265 270

Pro Glu Val Lys 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 Ala Leu Pro Ala Pro 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 Arg Glu 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 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Tyr Ser Met Thr Pro

450 455 460

Pro Thr Leu Asn Ile Thr Glu Glu Ser His Val Ile Asp Thr Gly Asp

465 470 475 480

Ser Leu Ser Ile Ser Cys Arg Gly Gln His Pro Leu Glu Trp Ala Trp

485 490 495

Pro Gly Ala Gln Glu Ala Pro Ala Thr Gly Asp Lys Asp Ser Glu Asp

500 505 510

Thr Gly Val Val Arg Asp Cys Glu Gly Thr Asp Ala Arg Pro Tyr Cys

515 520 525

Lys Val Leu Leu Leu His Glu Val His Ala Asn Asp Thr Gly Ser Tyr

530 535 540

Val Cys Tyr Tyr Lys Tyr Ile Lys Ala Arg Ile Glu Gly Thr Thr Ala

545 550 555 560

Ala Ser Ser Tyr Val Phe Val Arg Asp Phe Glu Gln Pro Phe Ile Asn

565 570 575

Lys Pro Asp Thr Leu Leu Val Asn Arg Lys Asp Ala Met Trp Val Pro

580 585 590

Cys Leu Val Ser Ile Pro Gly Leu Asn Val Thr Leu Arg Ser Gln Ser

595 600 605

Ser Val Leu Trp Pro Asp Gly Gln Glu Val Val Trp Asp Asp Arg Arg

610 615 620

Gly Met Leu Val Ser Thr Pro Leu Leu His Asp Ala Leu Tyr Leu Gln

625 630 635 640

Cys Glu Thr Thr Trp Gly Asp Gln Asp Phe Leu Ser Asn Pro Phe Leu

645 650 655

Val His Ile Thr Gly Asn Glu Leu

660

<210> 47

<211> 1292

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 47

gacatacaga tgacccagtc ccctagtagc ctcagcgcaa gcgttggaga tcgggtgact 60

ataacgtgcc gagcgtccca agacatttct tcttatttga attggtatca acaaaaacca 120

gggaaagccc cgaaactgct gatttattac accagtcgac tgcactccgg agtccctagt 180

cggttcagcg ggtctggatc aggtactgat tttaccttta ctataagctc actccagcca 240

gaggacattg cgacctatta ttgccagcag ggaaacacac ttccgtacac gtttggccag 300

gggaccaaag ttgaaatcaa gaggaccgtg gcagcccctc agttttcata ttccctccgt 360

ctgacgagca gttgaagtca gggactgcat ccgtggtgtg tctgctgaat aatttctacc 420

cacgcgaggc caaggtgcag tggaaggtag ataatgctct ccaatccggg aacagccaag 480

agtctgttac tgaacaagat tccaaagact ctacctatag cctctcaagc acccttacac 540

ttagtaaggc ggattacgaa aaacacaaag tctacgcatg tgaagtgacc catcagggtc 600

tcagcagccc ggtcactaaa agctttaaca ggggggaatg tggggggagt ggtggtggag 660

gtagcggcgg tggctccgac accggaaggc ctttcgtaga gatgtattca gaaattcccg 720

aaattataca tatgacggaa ggcagagagc tggtcatacc gtgtagagta acatcaccca 780

acataactgt tacgcttaaa aagttcccac ttgacacact tatacccgac ggcaagagaa 840

taatctggga cagcagaaaa ggtttcatca tctccaatgc tacttataaa gagatcgggc 900

tcctgacgtg cgaggcgacc gtaaacgggc atttgtacaa aaccaactat ctcactcata 960

gacaaacaaa cactattatt gatgtggtgc tcagcccctc tcatgggatc gagctttccg 1020

taggtgaaaa gctggtcctg aactgcacag cacggactga gttgaatgta gggatagatt 1080

tcaactggga atacccgtct tcaaaacatc agcacaaaaa gcttgtgaat cgcgacctca 1140

agacacaatc agggtcagaa atgaaaaagt ttctctcaac gctgactatc gacggcgtca 1200

cgcggtccga tcagggcctt tacacttgtg cggcctcttc tgggttgatg acgaagaaaa 1260

acagtacgtt tgtacgcgta catgagaagt ag 1292

<210> 48

<211> 430

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 48

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 Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln 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 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

210 215 220

Gly Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro

225 230 235 240

Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg

245 250 255

Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp

260 265 270

Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly

275 280 285

Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys

290 295 300

Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His

305 310 315 320

Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly

325 330 335

Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg

340 345 350

Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser

355 360 365

Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser

370 375 380

Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val

385 390 395 400

Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu

405 410 415

Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys

420 425 430

<210> 49

<211> 446

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 49

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Thr Phe Asp Asp Tyr

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Ser Trp Asn Ser Gly Arg Ile Gly Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Ser Leu Phe

65 70 75 80

Leu Gln Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Gly Arg Asp Ser Phe Asp Ile Trp Gly Gln Gly Thr Met Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu 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 His Glu Asp Pro Glu Val

260 265 270

Lys 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 Ala Leu Pro Ala Pro 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 Arg Asp Glu Leu 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 Gln 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 Pro Gly Lys

435 440 445

<210> 50

<211> 214

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 50

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Ser Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu 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> 51

<211> 443

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 51

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly His Ser Ile Ser His Asp

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Glu Gly Leu Glu Trp

35 40 45

Ile Gly Phe Ile Ser Tyr Ser Gly Ile Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Gln Gly Arg Val 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 Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr 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 Ser Ser Lys Ser Thr Ser Gly Gly 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 Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys Val Glu

210 215 220

Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu

225 230 235 240

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

245 250 255

Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln

260 265 270

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

275 280 285

Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu

290 295 300

Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

305 310 315 320

Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys

325 330 335

Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

340 345 350

Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

355 360 365

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

370 375 380

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly

385 390 395 400

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

405 410 415

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala

420 425 430

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440

<210> 52

<211> 214

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 52

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Ser Val Thr Ile Thr Cys Gln Ala Ser Thr Asp Ile Ser Ser His

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Glu Leu Leu Ile

35 40 45

Tyr Tyr Gly Ser His Leu Leu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Glu Ala

65 70 75 80

Glu Asp Ala Ala Thr Tyr Tyr Cys Gly Gln Gly Asn Arg Leu Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Glu 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> 53

<211> 6

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 53

Ser Asp His Ala Trp Ser

1 5

<210> 54

<211> 16

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 54

Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser

1 5 10 15

<210> 55

<211> 10

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 55

Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr

1 5 10

<210> 56

<211> 11

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 56

Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn

1 5 10

<210> 57

<211> 7

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 57

Tyr Thr Ser Arg Leu His Ser

1 5

<210> 58

<211> 9

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 58

Gln Gln Gly Asn Thr Leu Pro Tyr Thr

1 5

<210> 59

<211> 2103

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 59

atgccgctct tgctccttct tccattgctc tgggcgggcg cactggccga tatccaaatg 60

acgcaaagtc caagttctct ttcagccagc gtcggagata gagtcactat aacatgccgc 120

gcgagccagg atatatcaag ctaccttaat tggtatcaac aaaaaccggg taaagcgccg 180

aaactcttga tttattatac cagtaggctc cactccggtg taccaagtcg gttcagtggc 240

tccgggagtg gaaccgactt cacatttaca ataagctctt tgcaaccaga ggatattgca 300

acttactatt gccagcaagg caacacgttg ccttacacgt ttggacaggg aacaaaggtt 360

gagataaagc gagggggcgg tggcagtggt ggagggggta gcggaggcgg ggggagtcaa 420

gtccagctcc aagagtccgg accaggcttg gtcagaccta gccagacgct tagcttgaca 480

tgtacggtga gtggctattc aattacatcc gatcatgctt ggagctgggt ccggcaacct 540

ccaggcagag gattggagtg gattggttat atctcttatt ctggtattac cacatataac 600

ccatcactca aaagtcgggt tactatgctg cgggacacct ccaaaaacca attttccctt 660

cggctgtcat cagtgaccgc ggcggataca gcggtgtatt attgtgcgcg cagcttggcc 720

cgcacaactg caatggatta ctggggtcaa ggttctcttg ttactgttag ttcagataaa 780

actcatacgt gtcccccttg tccagcacca gaattgctgg gaggcccctc tgtgtttttg 840

tttcctccca agccaaaaga cacccttatg atcagtcgga ctccagaagt cacgtgcgtt 900

gtggttgatg tgtcacacga ggatccagaa gtgaaattca actggtacgt tgatggcgtt 960

gaggtccata atgcaaaaac caaaccaaga gaagaacaat ataacagcac ataccgggtg 1020

gtctccgttc tgactgtgtt gcaccaggac tggttgaatg gtaaggaata taagtgcaag 1080

gtgtcaaaca aagcgttgcc tgctccgatc gaaaaaacaa tatccaaggc aaaaggtcaa 1140

ccccgcgagc ctcaagtata tactctccct cctagccgcg acgagttgac aaagaaccag 1200

gtttccttga catgtcttgt caaagggttc tacccgtccg atatagctgt tgaatgggaa 1260

agtaatggcc agccggaaaa taattataaa actactccac cggtacttga ctcagatggt 1320

tcattcttcc tttactccaa acttacagtt gacaaatcca ggtggcaaca gggaaatgta 1380

ttttcttgta gtgttatgca cgaggcgctg cacaatcact atacacaaaa aagcctttct 1440

cttagcccag gagggggctc tggagggggt gggagtggcg gtggcagcga caccggacga 1500

ccgttcgtag agatgtactc tgaaatacca gagataatcc acatgactga aggacgggag 1560

ctggtgatac cctgcagggt aacatctccc aacattacgg tgactctcaa gaagttccct 1620

cttgatacac tgattccgga tggtaaacgg atcatatggg atagtcgaaa aggttttata 1680

atcagcaatg caacctataa ggagattggg ctcttgacct gcgaagccac tgttaatggg 1740

catctttata agacgaacta tcttacccat cgccagacaa acaccattat agatgtggtt 1800

ttgtccccta gtcacgggat agaactctca gtgggcgaga agctggtcct caattgtact 1860

gccaggaccg aacttaatgt gggtatcgat ttcaattggg aatatccatc ttcaaaacac 1920

caacacaaaa agctcgttaa cagggacttg aagacccaat ctggatctga gatgaagaag 1980

ttcctttcta cattgacaat tgacggcgtt acgcgaagcg accaaggctt gtatacttgc 2040

gcagcgtcat ccggtctgat gaccaaaaaa aacagcactt ttgtaagagt tcacgaaaag 2100

tag 2103

<210> 60

<211> 700

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 60

Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala

1 5 10 15

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

20 25 30

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

35 40 45

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

50 55 60

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

65 70 75 80

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

85 90 95

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

100 105 110

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln

130 135 140

Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln Thr Leu Ser Leu Thr

145 150 155 160

Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser Trp

165 170 175

Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile Ser

180 185 190

Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr

195 200 205

Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser Ser

210 215 220

Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu Ala

225 230 235 240

Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr Val

245 250 255

Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

260 265 270

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

275 280 285

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

290 295 300

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

305 310 315 320

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

325 330 335

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

340 345 350

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

355 360 365

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

370 375 380

Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

385 390 395 400

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

405 410 415

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

420 425 430

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

435 440 445

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

450 455 460

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

465 470 475 480

Leu Ser Pro Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser

485 490 495

Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu Ile

500 505 510

Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val Thr

515 520 525

Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu

530 535 540

Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile

545 550 555 560

Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala

565 570 575

Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln

580 585 590

Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile Glu

595 600 605

Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr Glu

610 615 620

Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys His

625 630 635 640

Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser

645 650 655

Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr Arg

660 665 670

Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met Thr

675 680 685

Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys

690 695 700

<210> 61

<211> 2151

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 61

atgccgctgc ttttgctgct ccccctgttg tgggcgggtg cacttgccga catacagatg 60

acacagtccc cgtcatcact gagcgcatcc gtaggggacc gcgtcactat cacctgccgg 120

gcctctcaag acatatcctc ttaccttaac tggtaccaac aaaagccagg gaaggccccg 180

aaactcctca tatattatac aagccggctc catagcgggg tacccagtcg gtttagtggg 240

tccggctccg gaacggattt tacgtttact atcagtagcc tgcagccgga ggacattgcc 300

acgtactatt gtcagcaggg aaatactctc ccctatacat ttggacaagg cacgaaagtc 360

gaaattaaac gcggcggcgg tggatctggc gggggaggct cagggggtgg agggagccag 420

gtgcagctcc aggaatctgg gccagggttg gtaaggccct cccagacttt gagtctcaca 480

tgcaccgtct ctgggtattc tataacgtct gaccacgcgt ggagctgggt gcggcagccg 540

cctggacgcg gtctggagtg gataggatac atctcttaca gtggcatcac tacgtacaat 600

ccgtcactta agagccgcgt cactatgctc cgggacactt caaaaaacca gttttccctc 660

cgcttgtcta gtgtcacggc ggcggatacg gccgtctact attgtgcacg gtctttggca 720

cgaacaactg cgatggacta ttggggccaa ggttccctcg tgacggtctc cagtggtgga 780

tcagggggcg gaggatccgg cggcggtagc gggggtggtg gttccgacac ggggaggccc 840

tttgtggaaa tgtacagtga aataccagag attattcata tgacggaggg acgggaactc 900

gtaataccct gccgggtaac atcaccgaat attacggtta ctctcaaaaa attccccctc 960

gacacactca tcccagatgg caagagaata atatgggata gccggaaagg ctttatcatc 1020

tctaacgcga cctataaaga gataggcctg cttacgtgcg aggcgacagt taatggacat 1080

ctttataaaa cgaattacct tactcaccgg cagacgaaca cgataatcga cgtcgtcctg 1140

agtccttccc atggcataga gcttagcgtg ggagagaagt tggtcttgaa ttgcaccgcg 1200

cgcacagaat tgaatgtagg gattgacttt aactgggagt acccatcctc aaaacatcaa 1260

cataaaaagc tggtgaaccg ggatttgaag actcagagcg gatctgagat gaaaaagttc 1320

ctgtcaactc tcaccatcga tggagtaacc cgaagtgacc agggtcttta tacatgtgca 1380

gctagttcag gtcttatgac caagaaaaac tcaacgttcg ttcgcgtgca cgaaaagggt 1440

ggcagcggtg ggggagggag cggtggaggg gacaagaccc atacttgccc cccatgtcct 1500

gccccggaat tgctcggtgg gccatctgta ttccttttcc cacctaagcc caaggacacc 1560

ctcatgatta gccgaacacc ggaagtaact tgcgttgtcg tagatgtgtc tcacgaggat 1620

cccgaagtca aattcaactg gtacgtcgac ggcgtagagg tccataatgc taaaactaag 1680

ccccgcgaag aacaatataa ttccacgtac cgagtagtga gtgtgcttac cgtgcttcac 1740

caggactggt tgaacggaaa ggagtacaag tgtaaggtta gcaacaaggc gctcccggct 1800

ccgatagaaa agactatctc aaaggccaaa gggcagccaa gggagccgca ggtgtacaca 1860

ttgcctccct caagggatga gcttactaaa aaccaagtct ctctcacctg tctcgtaaag 1920

gggttttatc cctctgatat cgctgtggaa tgggaaagta acgggcaacc agaaaataat 1980

tacaaaacga ctccgccggt actggatagt gacggtagct tctttttgta cagcaagttg 2040

acagtagata aatctaggtg gcaacaaggt aacgtatttt cctgctcagt aatgcacgaa 2100

gcgctgcaca accattacac tcaaaaaagt ctgtcattgt cccctggcta g 2151

<210> 62

<211> 716

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 62

Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala

1 5 10 15

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

20 25 30

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

35 40 45

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

50 55 60

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

65 70 75 80

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

85 90 95

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

100 105 110

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln

130 135 140

Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln Thr Leu Ser Leu Thr

145 150 155 160

Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser Trp

165 170 175

Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile Ser

180 185 190

Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr

195 200 205

Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser Ser

210 215 220

Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu Ala

225 230 235 240

Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr Val

245 250 255

Ser Ser Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly

260 265 270

Gly Gly Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile

275 280 285

Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys

290 295 300

Arg Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu

305 310 315 320

Asp Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys

325 330 335

Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr

340 345 350

Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr

355 360 365

His Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His

370 375 380

Gly Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala

385 390 395 400

Arg Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser

405 410 415

Ser Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln

420 425 430

Ser Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly

435 440 445

Val Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly

450 455 460

Leu Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys Gly

465 470 475 480

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Asp Lys Thr His Thr Cys

485 490 495

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu

500 505 510

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

515 520 525

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

530 535 540

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

545 550 555 560

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

565 570 575

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

580 585 590

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys

595 600 605

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

610 615 620

Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

625 630 635 640

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

645 650 655

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

660 665 670

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

675 680 685

Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

690 695 700

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

705 710 715

<210> 63

<211> 2799

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 63

atgccattgc ttctcttgct gccactcctt tgggctggag ccctcgctga cattcaaatg 60

acccagagtc cgtcttcact ttctgcctcc gttggggata gagtgacgat cacgtgccgc 120

gcgtcacaag acatctctag ttacctcaac tggtatcagc aaaagcccgg taaagctcca 180

aaacttctca tctactatac ttctagattg cactccggcg taccgtctag gttttcaggt 240

agtggtagcg gcaccgactt cacttttacg atatcctctt tgcagcccga ggatatcgct 300

acttactatt gtcaacaagg aaacacgctt ccgtacacct tcggtcaagg gaccaaggta 360

gaaatcaaaa ggggtggcgg tggatcaggt ggcgggggat ccggaggggg tggatcccag 420

gtacaattgc aagagtctgg ccccggtctc gtcaggccat cccaaacttt gtcactgact 480

tgtacggtta gcggttacag tataaccagc gatcacgcgt ggagctgggt ccgacagccc 540

cccgggcggg gattggaatg gatcgggtat atctcctact caggaataac cacttacaat 600

ccatccctga aatcccgagt tacgatgctt agggatacaa gtaaaaacca gttctctctg 660

aggcttagct ctgtgactgc cgccgacaca gcggtttatt actgtgcacg gtcactggcg 720

aggaccacgg cgatggacta ttggggccag ggatcactcg tgactgtaag ctcagggggg 780

tcaggaggtg gtggctcagg tggtggaagt ggtgggggcg ggtcagacac gggaaggccg 840

tttgtagaaa tgtatagtga gataccggaa attatacaca tgaccgaagg ccgagaactc 900

gtcataccct gcagagttac ttcacctaac ataacggtca cgcttaaaaa atttcccctg 960

gacaccctga tacctgacgg gaaacggatc atatgggact caaggaaagg gtttatcatc 1020

tccaatgcta cttataaaga gatcgggctc ctgacttgtg aagccaccgt aaacggtcat 1080

ctttataaga ccaactacct cactcatcga cagacgaata cgataattga tgtcgtgctt 1140

agtccaagcc acggtattga gttgtcagtg ggcgagaaac tggtgctcaa ttgcacagca 1200

agaacggagc ttaacgtggg tatagacttc aactgggagt atccctccag taaacaccaa 1260

cacaaaaaac tcgttaatag agatttgaag acccaaagcg gatcagagat gaagaaattt 1320

ttgagcactc tcacgataga tggcgtgacg cggtcagatc aggggctcta tacctgcgct 1380

gcctcctccg gtctcatgac aaaaaagaat agcacttttg ttagggtgca cgaaaaaggc 1440

ggcagcggag gggggggatc aggtggtgga gacaagacac atacttgccc accgtgtccc 1500

gctccggaac tgcttggcgg gcctagcgtc ttcctcttcc cgcctaagcc gaaagacacc 1560

cttatgatct cacgaacgcc cgaggtgacg tgcgtcgttg ttgatgtgag ccacgaagat 1620

ccagaagtta agttcaattg gtacgtcgac ggggtggaag tacacaatgc gaagaccaaa 1680

ccgagggagg agcagtataa ttcaacatac agagtcgttt ctgtcctcac ggttctccac 1740

caggattggt tgaacggcaa agaatataaa tgcaaagtga gcaataaggc tctccccgct 1800

cccatcgaaa agacaatctc taaggctaaa ggccagccga gagaaccgca ggtttatacc 1860

ctcccaccct cacgcgacga gttgactaag aaccaggtca gccttacgtg tttggtgaag 1920

gggttctatc cgtctgacat cgcggtcgaa tgggaatcta acggtcaacc cgagaataac 1980

tataaaacta ccccaccagt tttggactca gacgggtcct ttttcctgta cagcaagctc 2040

acggtcgaca aatcccggtg gcagcaggga aatgttttca gttgcagtgt catgcacgaa 2100

gcattgcata atcattacac acaaaaatca ctcagcctga gccctggggg gggtagtggc 2160

gggggaggaa gcggtggagg atactctatg actccgccaa cacttaacat tactgaggag 2220

agccacgtca ttgatacggg ggactctttg tccatttcct gcagaggcca gcatccgctc 2280

gaatgggcct ggcccggagc tcaagaggcc ccggcgactg gtgataaaga cagcgaggat 2340

acgggagtag taagagactg cgagggcact gacgcccgac cgtactgcaa ggtactcctc 2400

ctccatgaag tccatgctaa tgatacaggg agttacgtct gttactacaa atacatcaaa 2460

gcgaggatag aaggtacgac cgcggcttca tcttacgttt ttgttagaga ttttgagcaa 2520

ccctttataa ataaacccga taccctcctg gtcaatcgca aggacgccat gtgggtcccg 2580

tgcctggtgt caatcccagg acttaacgtc actctcagat ctcaaagctc tgtgctttgg 2640

cctgacggac aggaggttgt ttgggacgac agacggggca tgctcgtgtc aacccctctg 2700

cttcatgatg ccctctattt gcagtgtgag acgacgtggg gtgaccagga ttttctgtca 2760

aacccttttc tggtgcacat cacgggcaat gagctctag 2799

<210> 64

<211> 932

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 64

Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala

1 5 10 15

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

20 25 30

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

35 40 45

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

50 55 60

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

65 70 75 80

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

85 90 95

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

100 105 110

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln

130 135 140

Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln Thr Leu Ser Leu Thr

145 150 155 160

Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser Trp

165 170 175

Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile Ser

180 185 190

Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr

195 200 205

Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser Ser

210 215 220

Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu Ala

225 230 235 240

Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr Val

245 250 255

Ser Ser Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly

260 265 270

Gly Gly Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile

275 280 285

Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys

290 295 300

Arg Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu

305 310 315 320

Asp Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys

325 330 335

Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr

340 345 350

Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr

355 360 365

His Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His

370 375 380

Gly Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala

385 390 395 400

Arg Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser

405 410 415

Ser Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln

420 425 430

Ser Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly

435 440 445

Val Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly

450 455 460

Leu Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys Gly

465 470 475 480

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Asp Lys Thr His Thr Cys

485 490 495

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu

500 505 510

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

515 520 525

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

530 535 540

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

545 550 555 560

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

565 570 575

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

580 585 590

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys

595 600 605

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

610 615 620

Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

625 630 635 640

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

645 650 655

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

660 665 670

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

675 680 685

Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

690 695 700

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Ser Gly

705 710 715 720

Gly Gly Gly Ser Gly Gly Gly Tyr Ser Met Thr Pro Pro Thr Leu Asn

725 730 735

Ile Thr Glu Glu Ser His Val Ile Asp Thr Gly Asp Ser Leu Ser Ile

740 745 750

Ser Cys Arg Gly Gln His Pro Leu Glu Trp Ala Trp Pro Gly Ala Gln

755 760 765

Glu Ala Pro Ala Thr Gly Asp Lys Asp Ser Glu Asp Thr Gly Val Val

770 775 780

Arg Asp Cys Glu Gly Thr Asp Ala Arg Pro Tyr Cys Lys Val Leu Leu

785 790 795 800

Leu His Glu Val His Ala Asn Asp Thr Gly Ser Tyr Val Cys Tyr Tyr

805 810 815

Lys Tyr Ile Lys Ala Arg Ile Glu Gly Thr Thr Ala Ala Ser Ser Tyr

820 825 830

Val Phe Val Arg Asp Phe Glu Gln Pro Phe Ile Asn Lys Pro Asp Thr

835 840 845

Leu Leu Val Asn Arg Lys Asp Ala Met Trp Val Pro Cys Leu Val Ser

850 855 860

Ile Pro Gly Leu Asn Val Thr Leu Arg Ser Gln Ser Ser Val Leu Trp

865 870 875 880

Pro Asp Gly Gln Glu Val Val Trp Asp Asp Arg Arg Gly Met Leu Val

885 890 895

Ser Thr Pro Leu Leu His Asp Ala Leu Tyr Leu Gln Cys Glu Thr Thr

900 905 910

Trp Gly Asp Gln Asp Phe Leu Ser Asn Pro Phe Leu Val His Ile Thr

915 920 925

Gly Asn Glu Leu

930

<210> 65

<211> 2805

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 65

atgccgctgc tgttgcttct tcccctgctc tgggctgggg cactggccga catacaaatg 60

acccagtcac caagtagtct ctctgcaagc gtcggagacc gggtcacgat aacctgtcga 120

gcaagtcagg acattagtag ctacctgaac tggtatcagc agaagcctgg caaagccccg 180

aagctcctca tatactatac cagcagactg cacagtggtg taccatcccg attctccggc 240

tcaggatccg gaaccgactt cacgttcacc ataagcagtc ttcaacccga ggacatcgca 300

acttattact gtcaacaagg taacacactt ccatatacat tcggccaggg taccaaagtt 360

gagatcaaaa gaggaggcgg tggttccggg ggtggaggct ctggaggtgg cggatcccag 420

gtccagctcc aggaaagcgg tccgggtttg gtgagaccat ctcagacact gagcttgacg 480

tgtacggtaa gtggttactc tataacttcc gatcatgcgt ggtcctgggt acggcaaccc 540

cctggcagag gtctcgaatg gataggctat attagctatt ctggaattac cacatacaac 600

ccaagcctga aatctcgcgt caccatgctg cgcgatactt ccaagaatca attttctctg 660

cggttgtcaa gtgttacggc ggctgacact gccgtctact actgtgctcg atccctcgcg 720

cggacaacag ccatggatta ctggggccaa gggtcccttg tgacggtatc ctccggcggg 780

agtggtggcg ggggttccgg gggaggtagt ggtggggggg gttcagacac aggacgccca 840

tttgtcgaga tgtacagtga gatacctgaa ataattcaca tgacggaagg acgcgagctt 900

gtcataccat gccgcgtgac tagccctaat attacggtaa cactgaaaaa attcccactt 960

gatactctga ttccggacgg caagcgaatc atttgggact caaggaaagg tttcataata 1020

tccaacgcaa catataagga aatcggactc ctgacgtgcg aggcgacggt aaacggccac 1080

ctttataaga caaactatct tacgcaccgg caaactaata ctattataga cgttgtcctt 1140

tctccctctc acggcataga gttgagtgtc ggtgaaaaat tggtacttaa ttgcaccgcg 1200

agaacggaac ttaatgtcgg aattgatttc aattgggaat acccaagtag taaacaccag 1260

cataagaagc ttgtaaaccg cgatttgaaa acgcaatctg gatcagaaat gaaaaaattt 1320

ctcagtacgc ttacaataga tggggtaacc cgaagcgatc aaggactgta tacctgcgca 1380

gcgtctagtg gcctcatgac aaagaagaat tcaacattcg taagagttca cgagaagggt 1440

ggcggtggtt caggtggggg atcaggcggg ggcggttata gcatgacgcc cccgacattg 1500

aacattacag aagagtctca cgtaatagat acgggggatt ccctcagtat ttcctgccgc 1560

gggcaacacc cacttgaatg ggcgtggccc ggggctcaag aagcaccagc aaccggagac 1620

aaagatagcg aggatactgg tgtcgttcga gactgtgaag ggaccgatgc ccggccgtac 1680

tgtaaggttc tcctgttgca tgaggttcat gctaatgata cgggcagcta tgtgtgctac 1740

tataagtaca tcaaagcgcg gatcgaaggc actaccgccg cgtcttctta tgttttcgtg 1800

cgagattttg aacaaccatt tataaacaag ccggacactt tgctcgtcaa taggaaagac 1860

gccatgtggg ttccctgctt ggtgtccata cccggcctga atgttacact taggtcacag 1920

agctctgttt tgtggcctga cggacaggag gttgtttggg atgatagacg aggcatgctc 1980

gtgtcaactc cacttcttca cgatgcgctg tatctccaat gcgagactac gtggggagat 2040

caagactttc ttagcaatcc cttcctggtc cacattactg gaaatgagct tggtgggagc 2100

ggaggtgggg gctcaggagg tggggataag acccatactt gcccaccctg cccggcacct 2160

gaacttctcg gaggtccgtc agtgtttttg tttccgccaa agcctaaaga cacactgatg 2220

atttctcgga cgcccgaggt aacttgtgta gtcgtagacg tgtcccatga ggaccctgaa 2280

gttaaattca actggtacgt ggacggggtt gaagtacata atgcaaagac aaaaccccgg 2340

gaggagcagt ataacagtac ttacagagta gtctccgtgc tcaccgtact ccaccaagat 2400

tggctcaacg gcaaggagta caaatgcaaa gtgtcaaata aagcgttgcc tgctccaatt 2460

gaaaaaacaa tatccaaggc gaaggggcaa ccccgagagc ctcaggttta cacattgccg 2520

ccaagtcgag acgaattgac aaagaaccaa gttagcttga cctgcctcgt gaagggtttt 2580

tatccgagcg atatagccgt tgaatgggag tctaacgggc aaccggaaaa taactataaa 2640

accactccgc cggtgcttga cagcgacggt tcttttttcc tgtacagtaa actcaccgtt 2700

gataaatcta ggtggcagca gggtaacgtc tttagttgca gcgttatgca tgaggctctt 2760

cataatcatt atactcaaaa atctttgagt ctgtctcccg gatag 2805

<210> 66

<211> 934

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 66

Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala

1 5 10 15

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

20 25 30

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

35 40 45

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

50 55 60

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

65 70 75 80

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

85 90 95

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

100 105 110

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln

130 135 140

Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln Thr Leu Ser Leu Thr

145 150 155 160

Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser Trp

165 170 175

Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile Ser

180 185 190

Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr

195 200 205

Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser Ser

210 215 220

Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu Ala

225 230 235 240

Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr Val

245 250 255

Ser Ser Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly

260 265 270

Gly Gly Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile

275 280 285

Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys

290 295 300

Arg Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu

305 310 315 320

Asp Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys

325 330 335

Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr

340 345 350

Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr

355 360 365

His Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His

370 375 380

Gly Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala

385 390 395 400

Arg Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser

405 410 415

Ser Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln

420 425 430

Ser Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly

435 440 445

Val Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly

450 455 460

Leu Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys Gly

465 470 475 480

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Tyr Ser Met Thr

485 490 495

Pro Pro Thr Leu Asn Ile Thr Glu Glu Ser His Val Ile Asp Thr Gly

500 505 510

Asp Ser Leu Ser Ile Ser Cys Arg Gly Gln His Pro Leu Glu Trp Ala

515 520 525

Trp Pro Gly Ala Gln Glu Ala Pro Ala Thr Gly Asp Lys Asp Ser Glu

530 535 540

Asp Thr Gly Val Val Arg Asp Cys Glu Gly Thr Asp Ala Arg Pro Tyr

545 550 555 560

Cys Lys Val Leu Leu Leu His Glu Val His Ala Asn Asp Thr Gly Ser

565 570 575

Tyr Val Cys Tyr Tyr Lys Tyr Ile Lys Ala Arg Ile Glu Gly Thr Thr

580 585 590

Ala Ala Ser Ser Tyr Val Phe Val Arg Asp Phe Glu Gln Pro Phe Ile

595 600 605

Asn Lys Pro Asp Thr Leu Leu Val Asn Arg Lys Asp Ala Met Trp Val

610 615 620

Pro Cys Leu Val Ser Ile Pro Gly Leu Asn Val Thr Leu Arg Ser Gln

625 630 635 640

Ser Ser Val Leu Trp Pro Asp Gly Gln Glu Val Val Trp Asp Asp Arg

645 650 655

Arg Gly Met Leu Val Ser Thr Pro Leu Leu His Asp Ala Leu Tyr Leu

660 665 670

Gln Cys Glu Thr Thr Trp Gly Asp Gln Asp Phe Leu Ser Asn Pro Phe

675 680 685

Leu Val His Ile Thr Gly Asn Glu Leu Gly Gly Ser Gly Gly Gly Gly

690 695 700

Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

705 710 715 720

Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

725 730 735

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

740 745 750

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

755 760 765

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

770 775 780

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

785 790 795 800

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

805 810 815

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

820 825 830

Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys

835 840 845

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

850 855 860

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

865 870 875 880

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

885 890 895

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

900 905 910

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

915 920 925

Leu Ser Leu Ser Pro Gly

930

<210> 67

<211> 45

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 67

gggggcggtg gcagtggtgg agggggtagc ggaggcgggg ggagt 45

<210> 68

<211> 15

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 68

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

1 5 10 15

<210> 69

<211> 48

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 69

ggtggatcag ggggcggagg atccggcggc ggtagcgggg gtggtggt 48

<210> 70

<211> 16

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 70

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly

1 5 10 15

<210> 71

<211> 39

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 71

ggtggcggtg gttcaggtgg gggatcaggc gggggcggt 39

<210> 72

<211> 13

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 72

Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly

1 5 10

<210> 73

<211> 121

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 73

Glu 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 Ser Val Phe Lys Ile Asn

20 25 30

Val Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val

35 40 45

Ala Gly Ile Ile Ser Gly Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Phe Ile Thr Thr Glu Ser Asp Tyr Asp Leu Gly Arg Arg Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 74

<211> 711

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 74

Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala

1 5 10 15

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

20 25 30

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

35 40 45

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

50 55 60

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

65 70 75 80

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

85 90 95

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

100 105 110

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln

130 135 140

Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln Thr Leu Ser Leu Thr

145 150 155 160

Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser Trp

165 170 175

Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile Ser

180 185 190

Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr

195 200 205

Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser Ser

210 215 220

Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu Ala

225 230 235 240

Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr Val

245 250 255

Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

260 265 270

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

275 280 285

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

290 295 300

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

305 310 315 320

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

325 330 335

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

340 345 350

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

355 360 365

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

370 375 380

Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

385 390 395 400

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

405 410 415

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

420 425 430

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

435 440 445

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

450 455 460

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

465 470 475 480

Leu Ser Pro Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser

485 490 495

Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Thr Gly Arg Pro

500 505 510

Phe Val Glu Met Tyr Ser Glu Ile Pro Glu Ile Ile His Met Thr Glu

515 520 525

Gly Arg Glu Leu Val Ile Pro Cys Arg Val Thr Ser Pro Asn Ile Thr

530 535 540

Val Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu Ile Pro Asp Gly Lys

545 550 555 560

Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser Asn Ala Thr

565 570 575

Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala Thr Val Asn Gly His

580 585 590

Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln Thr Asn Thr Ile Ile

595 600 605

Asp Val Val Leu Ser Pro Ser His Gly Ile Glu Leu Ser Val Gly Glu

610 615 620

Lys Leu Val Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn Val Gly Ile

625 630 635 640

Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys His Gln His Lys Lys Leu

645 650 655

Val Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser Glu Met Lys Lys Phe

660 665 670

Leu Ser Thr Leu Thr Ile Asp Gly Val Thr Arg Ser Asp Gln Gly Leu

675 680 685

Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met Thr Lys Lys Asn Ser Thr

690 695 700

Phe Val Arg Val His Glu Lys

705 710

<210> 75

<211> 2133

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 75

atgccgctct tgctccttct tccattgctc tgggcgggcg cactggccga tatccaaatg 60

acgcaaagtc caagttctct ttcagccagc gtcggagata gagtcactat aacatgccgc 120

gcgagccagg atatatcaag ctaccttaat tggtatcaac aaaaaccggg taaagcgccg 180

aaactcttga tttattatac cagtaggctc cactccggtg taccaagtcg gttcagtggc 240

tccgggagtg gaaccgactt cacatttaca ataagctctt tgcaaccaga ggatattgca 300

acttactatt gccagcaagg caacacgttg ccttacacgt ttggacaggg aacaaaggtt 360

gagataaagc gagggggcgg tggcagtggt ggagggggta gcggaggcgg ggggagtcaa 420

gtccagctcc aagagtccgg accaggcttg gtcagaccta gccagacgct tagcttgaca 480

tgtacggtga gtggctattc aattacatcc gatcatgctt ggagctgggt ccggcaacct 540

ccaggcagag gattggagtg gattggttat atctcttatt ctggtattac cacatataac 600

ccatcactca aaagtcgggt tactatgctg cgggacacct ccaaaaacca attttccctt 660

cggctgtcat cagtgaccgc ggcggataca gcggtgtatt attgtgcgcg cagcttggcc 720

cgcacaactg caatggatta ctggggtcaa ggttctcttg ttactgttag ttcagataaa 780

actcatacgt gtcccccttg tccagcacca gaattgctgg gaggcccctc tgtgtttttg 840

tttcctccca agccaaaaga cacccttatg atcagtcgga ctccagaagt cacgtgcgtt 900

gtggttgatg tgtcacacga ggatccagaa gtgaaattca actggtacgt tgatggcgtt 960

gaggtccata atgcaaaaac caaaccaaga gaagaacaat ataacagcac ataccgggtg 1020

gtctccgttc tgactgtgtt gcaccaggac tggttgaatg gtaaggaata taagtgcaag 1080

gtgtcaaaca aagcgttgcc tgctccgatc gaaaaaacaa tatccaaggc aaaaggtcaa 1140

ccccgcgagc ctcaagtata tactctccct cctagccgcg acgagttgac aaagaaccag 1200

gtttccttga catgtcttgt caaagggttc tacccgtccg atatagctgt tgaatgggaa 1260

agtaatggcc agccggaaaa taattataaa actactccac cggtacttga ctcagatggt 1320

tcattcttcc tttactccaa acttacagtt gacaaatcca ggtggcaaca gggaaatgta 1380

ttttcttgta gtgttatgca cgaggcgctg cacaatcact atacacaaaa aagcctttct 1440

cttagcccag gagggggctc tggaggagga agcggcggag gcggaagcgg agggggaggt 1500

ggctccggag gcggtggcag cgacaccgga cgaccgttcg tagagatgta ctctgaaata 1560

ccagagataa tccacatgac tgaaggacgg gagctggtga taccctgcag ggtaacatct 1620

cccaacatta cggtgactct caagaagttc cctcttgata cactgattcc ggatggtaaa 1680

cggatcatat gggatagtcg aaaaggtttt ataatcagca atgcaaccta taaggagatt 1740

gggctcttga cctgcgaagc cactgttaat gggcatcttt ataagacgaa ctatcttacc 1800

catcgccaga caaacaccat tatagatgtg gttttgtccc ctagtcacgg gatagaactc 1860

tcagtgggcg agaagctggt cctcaattgt actgccagga ccgaacttaa tgtgggtatc 1920

gatttcaatt gggaatatcc atcttcaaaa caccaacaca aaaagctcgt taacagggac 1980

ttgaagaccc aatctggatc tgagatgaag aagttccttt ctacattgac aattgacggc 2040

gttacgcgaa gcgaccaagg cttgtatact tgcgcagcgt catccggtct gatgaccaaa 2100

aaaaacagca cttttgtaag agttcacgaa aag 2133

<210> 76

<211> 711

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 76

Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala

1 5 10 15

Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu

20 25 30

Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val

35 40 45

Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr

50 55 60

Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe

65 70 75 80

Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu

85 90 95

Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg

100 105 110

Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile

115 120 125

Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr

130 135 140

Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys

145 150 155 160

His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly

165 170 175

Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr

180 185 190

Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met

195 200 205

Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys Asp Lys Thr

210 215 220

His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser

225 230 235 240

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

245 250 255

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro

260 265 270

Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

275 280 285

Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val

290 295 300

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

305 310 315 320

Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr

325 330 335

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

340 345 350

Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys

355 360 365

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

370 375 380

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

385 390 395 400

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser

405 410 415

Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

420 425 430

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly

435 440 445

Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly

450 455 460

Ser Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu

465 470 475 480

Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln

485 490 495

Asp Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala

500 505 510

Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro

515 520 525

Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile

530 535 540

Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly

545 550 555 560

Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

565 570 575

Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

580 585 590

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

595 600 605

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

610 615 620

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

625 630 635 640

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

645 650 655

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

660 665 670

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

675 680 685

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

690 695 700

Ser Leu Val Thr Val Ser Ser

705 710

<210> 77

<211> 2133

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 77

atgccgctct tgctccttct tccattgctc tgggcgggcg cactggccag cgacaccgga 60

cgaccgttcg tagagatgta ctctgaaata ccagagataa tccacatgac tgaaggacgg 120

gagctggtga taccctgcag ggtaacatct cccaacatta cggtgactct caagaagttc 180

cctcttgata cactgattcc ggatggtaaa cggatcatat gggatagtcg aaaaggtttt 240

ataatcagca atgcaaccta taaggagatt gggctcttga cctgcgaagc cactgttaat 300

gggcatcttt ataagacgaa ctatcttacc catcgccaga caaacaccat tatagatgtg 360

gttttgtccc ctagtcacgg gatagaactc tcagtgggcg agaagctggt cctcaattgt 420

actgccagga ccgaacttaa tgtgggtatc gatttcaatt gggaatatcc atcttcaaaa 480

caccaacaca aaaagctcgt taacagggac ttgaagaccc aatctggatc tgagatgaag 540

aagttccttt ctacattgac aattgacggc gttacgcgaa gcgaccaagg cttgtatact 600

tgcgcagcgt catccggtct gatgaccaaa aaaaacagca cttttgtaag agttcacgaa 660

aaggataaaa ctcatacgtg tcccccttgt ccagcaccag aattgctggg aggcccctct 720

gtgtttttgt ttcctcccaa gccaaaagac acccttatga tcagtcggac tccagaagtc 780

acgtgcgttg tggttgatgt gtcacacgag gatccagaag tgaaattcaa ctggtacgtt 840

gatggcgttg aggtccataa tgcaaaaacc aaaccaagag aagaacaata taacagcaca 900

taccgggtgg tctccgttct gactgtgttg caccaggact ggttgaatgg taaggaatat 960

aagtgcaagg tgtcaaacaa agcgttgcct gctccgatcg aaaaaacaat atccaaggca 1020

aaaggtcaac cccgcgagcc tcaagtatat actctccctc ctagccgcga cgagttgaca 1080

aagaaccagg tttccttgac atgtcttgtc aaagggttct acccgtccga tatagctgtt 1140

gaatgggaaa gtaatggcca gccggaaaat aattataaaa ctactccacc ggtacttgac 1200

tcagatggtt cattcttcct ttactccaaa cttacagttg acaaatccag gtggcaacag 1260

ggaaatgtat tttcttgtag tgttatgcac gaggcgctgc acaatcacta tacacaaaaa 1320

agcctttctc ttagcccagg agggggctct ggaggaggaa gcggcggagg cggaagcgga 1380

gggggaggtg gctccggagg cggtggcgat atccaaatga cgcaaagtcc aagttctctt 1440

tcagccagcg tcggagatag agtcactata acatgccgcg cgagccagga tatatcaagc 1500

taccttaatt ggtatcaaca aaaaccgggt aaagcgccga aactcttgat ttattatacc 1560

agtaggctcc actccggtgt accaagtcgg ttcagtggct ccgggagtgg aaccgacttc 1620

acatttacaa taagctcttt gcaaccagag gatattgcaa cttactattg ccagcaaggc 1680

aacacgttgc cttacacgtt tggacaggga acaaaggttg agataaagcg agggggcggt 1740

ggcagtggtg gagggggtag cggaggcggg gggagtcaag tccagctcca agagtccgga 1800

ccaggcttgg tcagacctag ccagacgctt agcttgacat gtacggtgag tggctattca 1860

attacatccg atcatgcttg gagctgggtc cggcaacctc caggcagagg attggagtgg 1920

attggttata tctcttattc tggtattacc acatataacc catcactcaa aagtcgggtt 1980

actatgctgc gggacacctc caaaaaccaa ttttcccttc ggctgtcatc agtgaccgcg 2040

gcggatacag cggtgtatta ttgtgcgcgc agcttggccc gcacaactgc aatggattac 2100

tggggtcaag gttctcttgt tactgttagt tca 2133

<210> 78

<211> 652

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 78

Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu

1 5 10 15

Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val

20 25 30

Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr

35 40 45

Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe

50 55 60

Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu

65 70 75 80

Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg

85 90 95

Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile

100 105 110

Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr

115 120 125

Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys

130 135 140

His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly

145 150 155 160

Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr

165 170 175

Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met

180 185 190

Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys Gln Val Gln

195 200 205

Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln Thr Leu Ser

210 215 220

Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp

225 230 235 240

Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr

245 250 255

Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg

260 265 270

Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu

275 280 285

Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser

290 295 300

Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val

305 310 315 320

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

325 330 335

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

340 345 350

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

355 360 365

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

370 375 380

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

385 390 395 400

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

405 410 415

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

420 425 430

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

435 440 445

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

450 455 460

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

465 470 475 480

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

485 490 495

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

500 505 510

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

515 520 525

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

530 535 540

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

545 550 555 560

Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

565 570 575

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

580 585 590

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

595 600 605

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

610 615 620

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

625 630 635 640

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

645 650

<210> 79

<211> 1956

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 79

agcgacaccg gcagaccctt cgtggagatg tacagcgaga tccccgagat catccacatg 60

accgagggca gagagctggt gatcccctgc agagtgacca gccccaacat caccgtgacc 120

ctgaagaagt tccccctgga caccctgatc cccgacggca agagaatcat ctgggacagc 180

agaaagggct tcatcatcag caacgccacc tacaaggaga tcggcctgct gacctgcgag 240

gccaccgtga acggccacct gtacaagacc aactacctga cccacagaca gaccaacacc 300

atcatcgacg tggtgctgag ccccagccac ggcatcgagc tgagcgtggg cgagaagctg 360

gtgctgaact gcaccgccag aaccgagctg aacgtgggca tcgacttcaa ctgggagtac 420

cccagcagca agcaccagca caagaagctg gtgaacagag acctgaagac ccagagcggc 480

agcgagatga agaagttcct gagcaccctg accatcgacg gcgtgaccag aagcgaccag 540

ggcctgtaca cctgcgccgc cagcagcggc ctgatgacca agaagaacag caccttcgtg 600

agagtgcacg agaagcaggt gcagctgcag gagagcggcc ccggactggt gaggccttcc 660

cagaccctga gcctgacatg cacagtgagc ggctacagca tcacaagcga ccacgcctgg 720

agctgggtga gacagccccc cggaagaggc ctggaatgga tcggatatat ctcctactca 780

ggcattacca cctacaaccc ctctctgaaa agcagagtga ccatgctgag agatactagc 840

aagaaccagt ttagcctgag actgtctagc gtgactgccg ccgacaccgc cgtgtactac 900

tgcgccagat ccctggcccg gaccacagcc atggattact ggggccaggg aagcctggtg 960

acagtgtcct ccgctagcac caagggccca tcggtcttcc ccctggcacc ctcctccaag 1020

agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 1080

gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 1140

ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcagcttg 1200

ggcacccaga cctacatctg caacgtgaat cacaagccca gcaacaccaa ggtggacaag 1260

aaagttgagc ccaaatcttg tgacaaaact cacacatgcc caccgtgccc agcacctgaa 1320

ctcctggggg gaccgtcagt cttcctcttc cccccaaaac ccaaggacac cctcatgatc 1380

tcccggaccc ccgaggtcac atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc 1440

aagttcaact ggtacgtgga cggcgtggag gtgcataatg ccaagacaaa gccgcgggag 1500

gagcagtaca acagcacgta ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 1560

ctgaatggca aggagtacaa gtgcaaggtc tccaacaaag ccctcccagc ccccatcgag 1620

aaaaccatct ccaaagccaa agggcagccc cgagaaccac aggtgtacac cctgccccca 1680

tcccgggagg agatgaccaa gaaccaggtc agcctgacct gcctggtcaa aggcttctat 1740

cccagcgaca tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc 1800

acgcctcccg tgctggactc cgacggctcc ttcttcctct acagcaagct caccgtggac 1860

aagagcaggt ggcagcaggg gaacgtcttc tcatgctccg tgatgcatga ggctctgcac 1920

aaccactaca cgcagaagag cctctccctg tctccg 1956

<210> 80

<211> 214

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 80

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 Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln 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> 81

<211> 642

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 81

gacattcaga tgacccagag ccccagcagc ctgagcgcca gcgtgggaga cagagtgacc 60

atcacctgca gagccagcca ggacatctcc agctacctga actggtatca gcagaaaccc 120

ggcaaagccc caaaactgct gatctactac accagtagac tgcacagcgg cgtgcccagc 180

agattctcag gaagcggctc cggaaccgac ttcaccttca ctatcagcag cctgcagccc 240

gaagatattg ctacttacta ctgccagcag gggaacaccc tgccctatac cttcggccag 300

ggcaccaagg tggagatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360

tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420

cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480

gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540

ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600

ctgagttcgc ccgtcacaaa gagcttcaac aggggagagt gt 642

<210> 82

<211> 674

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 82

Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu

1 5 10 15

Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val

20 25 30

Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr

35 40 45

Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe

50 55 60

Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu

65 70 75 80

Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg

85 90 95

Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile

100 105 110

Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr

115 120 125

Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys

130 135 140

His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly

145 150 155 160

Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr

165 170 175

Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met

180 185 190

Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys Gly Gly Ser

195 200 205

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Ser Gly

210 215 220

Gly Gly Gly Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg

225 230 235 240

Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile

245 250 255

Thr Ser Asp His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly

260 265 270

Leu Glu Trp Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn

275 280 285

Pro Ser Leu Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn

290 295 300

Gln Phe Ser Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val

305 310 315 320

Tyr Tyr Cys Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp

325 330 335

Gly Gln Gly Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro

340 345 350

Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr

355 360 365

Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr

370 375 380

Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro

385 390 395 400

Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr

405 410 415

Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn

420 425 430

His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser

435 440 445

Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu

450 455 460

Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu

465 470 475 480

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

485 490 495

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu

500 505 510

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr

515 520 525

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn

530 535 540

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro

545 550 555 560

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

565 570 575

Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val

580 585 590

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

595 600 605

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

610 615 620

Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr

625 630 635 640

Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val

645 650 655

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

660 665 670

Ser Pro

<210> 83

<211> 2022

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 83

agcgacaccg gcagaccctt cgtggagatg tacagcgaga tccccgagat catccacatg 60

accgagggca gagagctggt gatcccctgc agagtgacca gccccaacat caccgtgacc 120

ctgaagaagt tccccctgga caccctgatc cccgacggca agagaatcat ctgggacagc 180

agaaagggct tcatcatcag caacgccacc tacaaggaga tcggcctgct gacctgcgag 240

gccaccgtga acggccacct gtacaagacc aactacctga cccacagaca gaccaacacc 300

atcatcgacg tggtgctgag ccccagccac ggcatcgagc tgagcgtggg cgagaagctg 360

gtgctgaact gcaccgccag aaccgagctg aacgtgggca tcgacttcaa ctgggagtac 420

cccagcagca agcaccagca caagaagctg gtgaacagag acctgaagac ccagagcggc 480

agcgagatga agaagttcct gagcaccctg accatcgacg gcgtgaccag aagcgaccag 540

ggcctgtaca cctgcgccgc cagcagcggc ctgatgacca agaagaacag caccttcgtg 600

agagtgcacg agaagggagg aagcggagga ggaagcgggg gaggaggaag tggaggagga 660

ggagggagcg gaggaggggg acaggtgcag ctgcaggaga gcggccccgg actggtgagg 720

ccttcccaga ccctgagcct gacatgcaca gtgagcggct acagcatcac aagcgaccac 780

gcctggagct gggtgagaca gccccccgga agaggcctgg aatggatcgg atatatctcc 840

tactcaggca ttaccaccta caacccctct ctgaaaagca gagtgaccat gctgagagat 900

actagcaaga accagtttag cctgagactg tctagcgtga ctgccgccga caccgccgtg 960

tactactgcg ccagatccct ggcccggacc acagccatgg attactgggg ccagggaagc 1020

ctggtgacag tgtcctccgc tagcaccaag ggcccatcgg tcttccccct ggcaccctcc 1080

tccaagagca cctctggggg cacagcggcc ctgggctgcc tggtcaagga ctacttcccc 1140

gaaccggtga cggtgtcgtg gaactcaggc gccctgacca gcggcgtgca caccttcccg 1200

gctgtcctac agtcctcagg actctactcc ctcagcagcg tggtgaccgt gccctccagc 1260

agcttgggca cccagaccta catctgcaac gtgaatcaca agcccagcaa caccaaggtg 1320

gacaagaaag ttgagcccaa atcttgtgac aaaactcaca catgcccacc gtgcccagca 1380

cctgaactcc tggggggacc gtcagtcttc ctcttccccc caaaacccaa ggacaccctc 1440

atgatctccc ggacccccga ggtcacatgc gtggtggtgg acgtgagcca cgaagaccct 1500

gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 1560

cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 1620

gactggctga atggcaagga gtacaagtgc aaggtctcca acaaagccct cccagccccc 1680

atcgagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 1740

cccccatccc gggaggagat gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc 1800

ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac 1860

aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc 1920

gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcatgaggct 1980

ctgcacaacc actacacgca gaagagcctc tccctgtctc cg 2022

<210> 84

<211> 214

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 84

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 Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln 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> 85

<211> 642

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 85

gacattcaga tgacccagag ccccagcagc ctgagcgcca gcgtgggaga cagagtgacc 60

atcacctgca gagccagcca ggacatctcc agctacctga actggtatca gcagaaaccc 120

ggcaaagccc caaaactgct gatctactac accagtagac tgcacagcgg cgtgcccagc 180

agattctcag gaagcggctc cggaaccgac ttcaccttca ctatcagcag cctgcagccc 240

gaagatattg ctacttacta ctgccagcag gggaacaccc tgccctatac cttcggccag 300

ggcaccaagg tggagatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360

tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420

cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480

gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540

ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600

ctgagttcgc ccgtcacaaa gagcttcaac aggggagagt gt 642

<210> 86

<211> 676

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 86

Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu

1 5 10 15

Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val

20 25 30

Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr

35 40 45

Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe

50 55 60

Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu

65 70 75 80

Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg

85 90 95

Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile

100 105 110

Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr

115 120 125

Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys

130 135 140

His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly

145 150 155 160

Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr

165 170 175

Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met

180 185 190

Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys Gly Gly Ser

195 200 205

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Ser Gly

210 215 220

Gly Gly Gly Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg

225 230 235 240

Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile

245 250 255

Thr Ser Asp His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly

260 265 270

Leu Glu Trp Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn

275 280 285

Pro Ser Leu Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn

290 295 300

Gln Phe Ser Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val

305 310 315 320

Tyr Tyr Cys Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp

325 330 335

Gly Gln Gly Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro

340 345 350

Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr

355 360 365

Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr

370 375 380

Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro

385 390 395 400

Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr

405 410 415

Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn

420 425 430

His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser

435 440 445

Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu

450 455 460

Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu

465 470 475 480

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

485 490 495

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu

500 505 510

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr

515 520 525

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn

530 535 540

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro

545 550 555 560

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

565 570 575

Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val

580 585 590

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

595 600 605

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

610 615 620

Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr

625 630 635 640

Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val

645 650 655

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

660 665 670

Ser Pro Gly Lys

675

<210> 87

<211> 2028

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 87

agcgacaccg gcagaccctt cgtggagatg tacagcgaga tccccgagat catccacatg 60

accgagggca gagagctggt gatcccctgc agagtgacca gccccaacat caccgtgacc 120

ctgaagaagt tccccctgga caccctgatc cccgacggca agagaatcat ctgggacagc 180

agaaagggct tcatcatcag caacgccacc tacaaggaga tcggcctgct gacctgcgag 240

gccaccgtga acggccacct gtacaagacc aactacctga cccacagaca gaccaacacc 300

atcatcgacg tggtgctgag ccccagccac ggcatcgagc tgagcgtggg cgagaagctg 360

gtgctgaact gcaccgccag aaccgagctg aacgtgggca tcgacttcaa ctgggagtac 420

cccagcagca agcaccagca caagaagctg gtgaacagag acctgaagac ccagagcggc 480

agcgagatga agaagttcct gagcaccctg accatcgacg gcgtgaccag aagcgaccag 540

ggcctgtaca cctgcgccgc cagcagcggc ctgatgacca agaagaacag caccttcgtg 600

agagtgcacg agaagggagg aagcggagga ggaagcgggg gaggaggaag tggaggagga 660

ggagggagcg gaggaggggg acaggtgcag ctgcaggaga gcggccccgg actggtgagg 720

ccttcccaga ccctgagcct gacatgcaca gtgagcggct acagcatcac aagcgaccac 780

gcctggagct gggtgagaca gccccccgga agaggcctgg aatggatcgg atatatctcc 840

tactcaggca ttaccaccta caacccctct ctgaaaagca gagtgaccat gctgagagat 900

actagcaaga accagtttag cctgagactg tctagcgtga ctgccgccga caccgccgtg 960

tactactgcg ccagatccct ggcccggacc acagccatgg attactgggg ccagggaagc 1020

ctggtgacag tgtcctccgc tagcaccaag ggcccatcgg tcttccccct ggcaccctcc 1080

tccaagagca cctctggggg cacagcggcc ctgggctgcc tggtcaagga ctacttcccc 1140

gaaccggtga cggtgtcgtg gaactcaggc gccctgacca gcggcgtgca caccttcccg 1200

gctgtcctac agtcctcagg actctactcc ctcagcagcg tggtgaccgt gccctccagc 1260

agcttgggca cccagaccta catctgcaac gtgaatcaca agcccagcaa caccaaggtg 1320

gacaagaaag ttgagcccaa atcttgtgac aaaactcaca catgcccacc gtgcccagca 1380

cctgaactcc tggggggacc gtcagtcttc ctcttccccc caaaacccaa ggacaccctc 1440

atgatctccc ggacccccga ggtcacatgc gtggtggtgg acgtgagcca cgaagaccct 1500

gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 1560

cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 1620

gactggctga atggcaagga gtacaagtgc aaggtctcca acaaagccct cccagccccc 1680

atcgagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 1740

cccccatccc gggaggagat gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc 1800

ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac 1860

aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc 1920

gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcatgaggct 1980

ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggtaaa 2028

<210> 88

<211> 214

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 88

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 Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln 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> 89

<211> 642

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 89

gacattcaga tgacccagag ccccagcagc ctgagcgcca gcgtgggaga cagagtgacc 60

atcacctgca gagccagcca ggacatctcc agctacctga actggtatca gcagaaaccc 120

ggcaaagccc caaaactgct gatctactac accagtagac tgcacagcgg cgtgcccagc 180

agattctcag gaagcggctc cggaaccgac ttcaccttca ctatcagcag cctgcagccc 240

gaagatattg ctacttacta ctgccagcag gggaacaccc tgccctatac cttcggccag 300

ggcaccaagg tggagatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360

tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420

cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480

gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540

ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600

ctgagttcgc ccgtcacaaa gagcttcaac aggggagagt gt 642

<210> 90

<211> 675

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 90

Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu

1 5 10 15

Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val

20 25 30

Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr

35 40 45

Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe

50 55 60

Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu

65 70 75 80

Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg

85 90 95

Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile

100 105 110

Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr

115 120 125

Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys

130 135 140

His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly

145 150 155 160

Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr

165 170 175

Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met

180 185 190

Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys Gly Gly Ser

195 200 205

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Ser Gly

210 215 220

Gly Gly Gly Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg

225 230 235 240

Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile

245 250 255

Thr Ser Asp His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly

260 265 270

Leu Glu Trp Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn

275 280 285

Pro Ser Leu Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn

290 295 300

Gln Phe Ser Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val

305 310 315 320

Tyr Tyr Cys Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp

325 330 335

Gly Gln Gly Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro

340 345 350

Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr

355 360 365

Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr

370 375 380

Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro

385 390 395 400

Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr

405 410 415

Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn

420 425 430

His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser

435 440 445

Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu

450 455 460

Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu

465 470 475 480

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

485 490 495

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu

500 505 510

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr

515 520 525

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn

530 535 540

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro

545 550 555 560

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

565 570 575

Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val

580 585 590

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

595 600 605

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

610 615 620

Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr

625 630 635 640

Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val

645 650 655

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

660 665 670

Ser Pro Gly

675

<210> 91

<211> 2025

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 91

agcgacaccg gcagaccctt cgtggagatg tacagcgaga tccccgagat catccacatg 60

accgagggca gagagctggt gatcccctgc agagtgacca gccccaacat caccgtgacc 120

ctgaagaagt tccccctgga caccctgatc cccgacggca agagaatcat ctgggacagc 180

agaaagggct tcatcatcag caacgccacc tacaaggaga tcggcctgct gacctgcgag 240

gccaccgtga acggccacct gtacaagacc aactacctga cccacagaca gaccaacacc 300

atcatcgacg tggtgctgag ccccagccac ggcatcgagc tgagcgtggg cgagaagctg 360

gtgctgaact gcaccgccag aaccgagctg aacgtgggca tcgacttcaa ctgggagtac 420

cccagcagca agcaccagca caagaagctg gtgaacagag acctgaagac ccagagcggc 480

agcgagatga agaagttcct gagcaccctg accatcgacg gcgtgaccag aagcgaccag 540

ggcctgtaca cctgcgccgc cagcagcggc ctgatgacca agaagaacag caccttcgtg 600

agagtgcacg agaagggagg aagcggagga ggaagcgggg gaggaggaag tggaggagga 660

ggagggagcg gaggaggggg acaggtgcag ctgcaggaga gcggccccgg actggtgagg 720

ccttcccaga ccctgagcct gacatgcaca gtgagcggct acagcatcac aagcgaccac 780

gcctggagct gggtgagaca gccccccgga agaggcctgg aatggatcgg atatatctcc 840

tactcaggca ttaccaccta caacccctct ctgaaaagca gagtgaccat gctgagagat 900

actagcaaga accagtttag cctgagactg tctagcgtga ctgccgccga caccgccgtg 960

tactactgcg ccagatccct ggcccggacc acagccatgg attactgggg ccagggaagc 1020

ctggtgacag tgtcctccgc tagcaccaag ggcccatcgg tcttccccct ggcaccctcc 1080

tccaagagca cctctggggg cacagcggcc ctgggctgcc tggtcaagga ctacttcccc 1140

gaaccggtga cggtgtcgtg gaactcaggc gccctgacca gcggcgtgca caccttcccg 1200

gctgtcctac agtcctcagg actctactcc ctcagcagcg tggtgaccgt gccctccagc 1260

agcttgggca cccagaccta catctgcaac gtgaatcaca agcccagcaa caccaaggtg 1320

gacaagaaag ttgagcccaa atcttgtgac aaaactcaca catgcccacc gtgcccagca 1380

cctgaactcc tggggggacc gtcagtcttc ctcttccccc caaaacccaa ggacaccctc 1440

atgatctccc ggacccccga ggtcacatgc gtggtggtgg acgtgagcca cgaagaccct 1500

gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 1560

cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 1620

gactggctga atggcaagga gtacaagtgc aaggtctcca acaaagccct cccagccccc 1680

atcgagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 1740

cccccatccc gggaggagat gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc 1800

ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac 1860

aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc 1920

gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcatgaggct 1980

ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggt 2025

<210> 92

<211> 214

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 92

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 Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln 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> 93

<211> 642

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 93

gacattcaga tgacccagag ccccagcagc ctgagcgcca gcgtgggaga cagagtgacc 60

atcacctgca gagccagcca ggacatctcc agctacctga actggtatca gcagaaaccc 120

ggcaaagccc caaaactgct gatctactac accagtagac tgcacagcgg cgtgcccagc 180

agattctcag gaagcggctc cggaaccgac ttcaccttca ctatcagcag cctgcagccc 240

gaagatattg ctacttacta ctgccagcag gggaacaccc tgccctatac cttcggccag 300

ggcaccaagg tggagatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360

tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420

cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480

gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540

ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600

ctgagttcgc ccgtcacaaa gagcttcaac aggggagagt gt 642

<210> 94

<211> 447

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 94

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 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 Ile Cys Asn Val Asn His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 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 His Glu Asp

260 265 270

Pro Glu Val Lys 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 Ala Leu Pro Ala Pro 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 Arg Glu 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 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

<210> 95

<211> 1341

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 95

caggtgcagc tgcaggagag cggccccgga ctggtgaggc cttcccagac cctgagcctg 60

acatgcacag tgagcggcta cagcatcaca agcgaccacg cctggagctg ggtgagacag 120

ccccccggaa gaggcctgga atggatcgga tatatctcct actcaggcat taccacctac 180

aacccctctc tgaaaagcag agtgaccatg ctgagagata ctagcaagaa ccagtttagc 240

ctgagactgt ctagcgtgac tgccgccgac accgccgtgt actactgcgc cagatccctg 300

gcccggacca cagccatgga ttactggggc cagggaagcc tggtgacagt gtcctccgct 360

agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420

acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480

aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540

ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600

atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 660

tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720

tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccccgag 780

gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840

gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900

acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960

tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020

gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggaggagatg 1080

accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140

gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200

gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1260

caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320

aagagcctct ccctgtctcc g 1341

<210> 96

<211> 419

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 96

Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu

1 5 10 15

Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val

20 25 30

Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr

35 40 45

Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe

50 55 60

Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu

65 70 75 80

Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg

85 90 95

Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile

100 105 110

Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr

115 120 125

Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys

130 135 140

His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly

145 150 155 160

Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr

165 170 175

Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met

180 185 190

Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys Asp Ile Gln

195 200 205

Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val

210 215 220

Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp

225 230 235 240

Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr

245 250 255

Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser

260 265 270

Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile

275 280 285

Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly

290 295 300

Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val

305 310 315 320

Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser

325 330 335

Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln

340 345 350

Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val

355 360 365

Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu

370 375 380

Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu

385 390 395 400

Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg

405 410 415

Gly Glu Cys

<210> 97

<211> 1257

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 97

agcgacaccg gcagaccctt cgtggagatg tacagcgaga tccccgagat catccacatg 60

accgagggca gagagctggt gatcccctgc agagtgacca gccccaacat caccgtgacc 120

ctgaagaagt tccccctgga caccctgatc cccgacggca agagaatcat ctgggacagc 180

agaaagggct tcatcatcag caacgccacc tacaaggaga tcggcctgct gacctgcgag 240

gccaccgtga acggccacct gtacaagacc aactacctga cccacagaca gaccaacacc 300

atcatcgacg tggtgctgag ccccagccac ggcatcgagc tgagcgtggg cgagaagctg 360

gtgctgaact gcaccgccag aaccgagctg aacgtgggca tcgacttcaa ctgggagtac 420

cccagcagca agcaccagca caagaagctg gtgaacagag acctgaagac ccagagcggc 480

agcgagatga agaagttcct gagcaccctg accatcgacg gcgtgaccag aagcgaccag 540

ggcctgtaca cctgcgccgc cagcagcggc ctgatgacca agaagaacag caccttcgtg 600

agagtgcacg agaaggacat tcagatgacc cagagcccca gcagcctgag cgccagcgtg 660

ggagacagag tgaccatcac ctgcagagcc agccaggaca tctccagcta cctgaactgg 720

tatcagcaga aacccggcaa agccccaaaa ctgctgatct actacaccag tagactgcac 780

agcggcgtgc ccagcagatt ctcaggaagc ggctccggaa ccgacttcac cttcactatc 840

agcagcctgc agcccgaaga tattgctact tactactgcc agcaggggaa caccctgccc 900

tataccttcg gccagggcac caaggtggag atcaaacgta cggtggctgc accatctgtc 960

ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 1020

ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 1080

tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 1140

agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 1200

gtcacccatc agggcctgag ttcgcccgtc acaaagagct tcaacagggg agagtgt 1257

<210> 98

<211> 447

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 98

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 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 Ile Cys Asn Val Asn His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 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 His Glu Asp

260 265 270

Pro Glu Val Lys 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 Ala Leu Pro Ala Pro 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 Arg Glu 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 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

<210> 99

<211> 1341

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 99

caggtgcagc tgcaggagag cggccccgga ctggtgaggc cttcccagac cctgagcctg 60

acatgcacag tgagcggcta cagcatcaca agcgaccacg cctggagctg ggtgagacag 120

ccccccggaa gaggcctgga atggatcgga tatatctcct actcaggcat taccacctac 180

aacccctctc tgaaaagcag agtgaccatg ctgagagata ctagcaagaa ccagtttagc 240

ctgagactgt ctagcgtgac tgccgccgac accgccgtgt actactgcgc cagatccctg 300

gcccggacca cagccatgga ttactggggc cagggaagcc tggtgacagt gtcctccgct 360

agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420

acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480

aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540

ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600

atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 660

tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720

tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccccgag 780

gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840

gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900

acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960

tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020

gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggaggagatg 1080

accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140

gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200

gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1260

caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320

aagagcctct ccctgtctcc g 1341

<210> 100

<211> 441

<212> PRT

<213> Artificial work

<220>

<223> Artificial sequence

<400> 100

Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu

1 5 10 15

Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val

20 25 30

Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr

35 40 45

Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe

50 55 60

Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu

65 70 75 80

Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg

85 90 95

Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile

100 105 110

Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr

115 120 125

Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys

130 135 140

His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly

145 150 155 160

Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr

165 170 175

Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met

180 185 190

Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys Gly Gly Ser

195 200 205

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Ser Gly

210 215 220

Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala

225 230 235 240

Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile

245 250 255

Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys

260 265 270

Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg

275 280 285

Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser

290 295 300

Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr

305 310 315 320

Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr

325 330 335

Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu

340 345 350

Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro

355 360 365

Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly

370 375 380

Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr

385 390 395 400

Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His

405 410 415

Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val

420 425 430

Thr Lys Ser Phe Asn Arg Gly Glu Cys

435 440

<210> 101

<211> 1323

<212> DNA

<213> Artificial work

<220>

<223> Artificial sequence

<400> 101

agcgacaccg gcagaccctt cgtggagatg tacagcgaga tccccgagat catccacatg 60

accgagggca gagagctggt gatcccctgc agagtgacca gccccaacat caccgtgacc 120

ctgaagaagt tccccctgga caccctgatc cccgacggca agagaatcat ctgggacagc 180

agaaagggct tcatcatcag caacgccacc tacaaggaga tcggcctgct gacctgcgag 240

gccaccgtga acggccacct gtacaagacc aactacctga cccacagaca gaccaacacc 300

atcatcgacg tggtgctgag ccccagccac ggcatcgagc tgagcgtggg cgagaagctg 360

gtgctgaact gcaccgccag aaccgagctg aacgtgggca tcgacttcaa ctgggagtac 420

cccagcagca agcaccagca caagaagctg gtgaacagag acctgaagac ccagagcggc 480

agcgagatga agaagttcct gagcaccctg accatcgacg gcgtgaccag aagcgaccag 540

ggcctgtaca cctgcgccgc cagcagcggc ctgatgacca agaagaacag caccttcgtg 600

agagtgcacg agaagggagg aagcggagga ggaagcgggg gaggaggaag tggaggagga 660

ggagggagcg gaggaggggg agacattcag atgacccaga gccccagcag cctgagcgcc 720

agcgtgggag acagagtgac catcacctgc agagccagcc aggacatctc cagctacctg 780

aactggtatc agcagaaacc cggcaaagcc ccaaaactgc tgatctacta caccagtaga 840

ctgcacagcg gcgtgcccag cagattctca ggaagcggct ccggaaccga cttcaccttc 900

actatcagca gcctgcagcc cgaagatatt gctacttact actgccagca ggggaacacc 960

ctgccctata ccttcggcca gggcaccaag gtggagatca aacgtacggt ggctgcacca 1020

tctgtcttca tcttcccgcc atctgatgag cagttgaaat ctggaactgc ctctgttgtg 1080

tgcctgctga ataacttcta tcccagagag gccaaagtac agtggaaggt ggataacgcc 1140

ctccaatcgg gtaactccca ggagagtgtc acagagcagg acagcaagga cagcacctac 1200

agcctcagca gcaccctgac gctgagcaaa gcagactacg agaaacacaa agtctacgcc 1260

tgcgaagtca cccatcaggg cctgagttcg cccgtcacaa agagcttcaa caggggagag 1320

tgt 1323

<210> 102

<211> 306

<212> PRT

<213> Homo sapiens (Homo sapiens)

<400> 102

Tyr Ser Met Thr Pro Pro Thr Leu Asn Ile Thr Glu Glu Ser His Val

1 5 10 15

Ile Asp Thr Gly Asp Ser Leu Ser Ile Ser Cys Arg Gly Gln His Pro

20 25 30

Leu Glu Trp Ala Trp Pro Gly Ala Gln Glu Ala Pro Ala Thr Gly Asp

35 40 45

Lys Asp Ser Glu Asp Thr Gly Val Val Arg Asp Cys Glu Gly Thr Asp

50 55 60

Ala Arg Pro Tyr Cys Lys Val Leu Leu Leu His Glu Val His Ala Asn

65 70 75 80

Asp Thr Gly Ser Tyr Val Cys Tyr Tyr Lys Tyr Ile Lys Ala Arg Ile

85 90 95

Glu Gly Thr Thr Ala Ala Ser Ser Tyr Val Phe Val Arg Asp Phe Glu

100 105 110

Gln Pro Phe Ile Asn Lys Pro Asp Thr Leu Leu Val Asn Arg Lys Asp

115 120 125

Ala Met Trp Val Pro Cys Leu Val Ser Ile Pro Gly Leu Asn Val Thr

130 135 140

Leu Arg Ser Gln Ser Ser Val Leu Trp Pro Asp Gly Gln Glu Val Val

145 150 155 160

Trp Asp Asp Arg Arg Gly Met Leu Val Ser Thr Pro Leu Leu His Asp

165 170 175

Ala Leu Tyr Leu Gln Cys Glu Thr Thr Trp Gly Asp Gln Asp Phe Leu

180 185 190

Ser Asn Pro Phe Leu Val His Ile Thr Gly Asn Glu Leu Tyr Asp Ile

195 200 205

Gln Leu Leu Pro Arg Lys Ser Leu Glu Leu Leu Val Gly Glu Lys Leu

210 215 220

Val Leu Asn Cys Thr Val Trp Ala Glu Phe Asn Ser Gly Val Thr Phe

225 230 235 240

Asp Trp Asp Tyr Pro Gly Lys Gln Ala Glu Arg Gly Lys Trp Val Pro

245 250 255

Glu Arg Arg Ser Gln Gln Thr His Thr Glu Leu Ser Ser Ile Leu Thr

260 265 270

Ile His Asn Val Ser Gln His Asp Leu Gly Ser Tyr Val Cys Lys Ala

275 280 285

Asn Asn Gly Ile Gln Arg Phe Arg Glu Ser Thr Glu Val Ile Val His

290 295 300

Glu Asn

305

<210> 103

<211> 918

<212> DNA

<213> Homo sapiens (Homo sapiens)

<400> 103

tacagcatga cccctcctac cctgaacatc accgaggaga gccacgtgat cgacaccggc 60

gacagcctga gcatcagctg cagaggccag catcctttag agtgggcctg gcccggcgcc 120

caggaggctc ctgccaccgg cgacaaggac agcgaggaca ccggcgtggt gagagactgc 180

gagggcaccg acgccagacc ctactgcaag gtgctgctgc tgcacgaggt gcacgccaac 240

gacaccggca gctacgtgtg ctactacaag tacatcaagg ccagaatcga gggcaccacc 300

gccgccagca gctacgtgtt cgtgagagac ttcgagcagc ccttcatcaa caagcccgac 360

accctgctgg tgaacagaaa ggacgccatg tgggtgccct gcctggtgag catccccggc 420

ctgaacgtga ccctgagaag ccagagcagc gtgctgtggc ccgacggcca ggaggtggtg 480

tgggacgaca gaagaggcat gctggtgagc actcctctgc tgcacgacgc cctgtacctg 540

cagtgcgaga ccacctgggg cgaccaggac ttcctgagca accccttcct ggtgcacatc 600

accggcaacg agctgtacga catccagctg ctgcccagga agagcctgga gctgctggtg 660

ggcgagaagc tggtgctgaa ctgcaccgtg tgggccgagt tcaactccgg cgtgaccttt 720

gactgggact accccggcaa gcaggccgaa aggggaaaat gggtgcccga aagaagaagt 780

cagcagaccc acacagaact gagctccatc ctgacaatcc acaacgtgag ccagcacgac 840

ctgggcagct atgtgtgcaa agctaacaac ggcatccaga gattcagaga gagcaccgag 900

gtgatcgtgc acgaaaat 918

Claims

1. An antibody fusion protein, or antigen binding fragment or domain thereof, capable of substantially binding to IL-6R and one or more VEGF family members.

2. The antibody fusion protein of claim 1, comprising an antibody or antigen-binding fragment or domain thereof directed against IL-6R linked to a VEGF binding unit comprising an Ig-like domain selected from the group consisting of: an Ig-like domain of a first VEGF receptor, an Ig-like domain of a second VEGF receptor, an Ig-like domain of a third VEGF receptor, and combinations thereof.

3. The antibody fusion protein of claim 1, comprising an antibody or antigen-binding fragment or domain thereof directed against IL-6R; wherein at least one of (1) a light chain or antigen binding fragment or domain thereof and (2) a heavy chain or antigen binding fragment or domain thereof is linked to a VEGF binding unit comprising a plurality of Ig-like domains selected from the group consisting of: an Ig-like domain of a first VEGF receptor, an Ig-like domain of a second VEGF receptor, an Ig-like domain of a third VEGF receptor, and combinations thereof.

4. The antibody fusion protein of claim 3, wherein the IL-6R is human IL-6R.

5. The antibody fusion protein of claim 4; wherein the VEGF binding unit comprises: (1) (a) Ig-like domain 2 or substantially Ig-like domain 2 of human VEGFR-1; and (b) Ig-like domain 3 or substantially Ig-like domain 3 of human VEGFR-2; or (2) (a) Ig-like domains 1 and 2 or substantially Ig-like domains 1 and 2 of human VEGFR-3; or (b) Ig-like domains 2 and 3 or substantially Ig-like domains 2 and 3 of human VEGFR-3; or (c) Ig-like domains 1, 2 and 3 or substantially Ig-like domains 1, 2 and 3 of human VEGFR-3.

6. The antibody fusion protein of claim 4; wherein the light chain or antigen-binding fragment or domain thereof and the heavy chain or antigen-binding fragment or domain thereof of the IL-6R antibody moiety are linked to a VEGF binding unit comprising: (a) Ig-like domain 2 or substantially Ig-like domain 2 of human VEGFR-1; and (b) human VEGFR-2 Ig like domain 3 or substantially Ig like domain 3.

7. The antibody fusion protein of claim 4; wherein (1) the light chain of the IL-6R antibody portion or antigen-binding fragment or domain thereof is linked to a first VEGF-binding unit comprising: (a) Ig-like domain 2 or substantially Ig-like domain 2 of human VEGFR-1; and (b) Ig-like domain 3 or substantially Ig-like domain 3 of human VEGFR-2; and (2) the heavy chain of the antibody fusion protein or antigen binding fragment or domain thereof is linked to a second VEGF binding unit comprising: (a) Ig-like domains 1 and 2 or substantially Ig-like domains 1 and 2 of human VEGFR-3; or (b) Ig-like domains 2 and 3 or substantially Ig-like domains 2 and 3 of human VEGFR-3; or (c) Ig-like domains 1, 2 and 3 or substantially Ig-like domains 1, 2 and 3 of human VEGFR-3.

8. The antibody fusion protein of claim 6; wherein said heavy chain thereof has the amino acid sequences of the complementarity determining regions HCCDR1, HCCDR2 and HCCDR3 of SEQ ID NOs 53, 54 and 55.

9. The antibody fusion protein of claim 6; wherein said light chain thereof has the amino acid sequences of the complementarity determining regions LCCDR1, LCCDR2 and LCCDR3 of SEQ ID NOs 56, 57 and 58.

10. The antibody fusion protein of claim 6; wherein the heavy and light chain pair thereof has an amino acid sequence selected from the group consisting of: SEQ ID NOS 34 and 36, SEQ ID NOS 38 and 40, SEQ ID NOS 42 and 44, SEQ ID NOS 46 and 48, SEQ ID NOS 78 and 80, SEQ ID NOS 82 and 84, SEQ ID NOS 86 and 88, SEQ ID NOS 90 and 92, SEQ ID NOS 94 and 96, and SEQ ID NOS 98 and 100.

11. The antibody fusion protein of claim 2, comprising an amino acid sequence selected from the group consisting of: SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 74 and SEQ ID NO. 76.

12. The antibody fusion protein of claim 2, comprising an amino acid sequence starting from amino acid 17 of an amino acid sequence selected from the group consisting of seq id nos: SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 74 and SEQ ID NO. 76.

13. The antibody fusion protein of any one of claims 1 to 12; wherein the antibody fusion protein has a dissociation constant K _d ≤10 ^-9 M binds to IL-6R and VEGF family members.

14. The antibody fusion protein of any one of claims 1 to 12; wherein the antibody fusion protein has a dissociation constant K _d ≤10 ^-10 M binds to IL-6R and VEGF family members.

15. An isolated nucleic acid molecule encoding the antibody fusion protein of any one of claims 1-12.

16. An isolated nucleic acid molecule having a sequence substantially as set forth in SEQ ID No. 17, 19, 21, 23, 25, 27, 29, 31, 59, 61, 63, 65, 75 or 77.

17. A vector comprising the nucleic acid molecule of claim 15 or 16.

18. The vector of claim 17, comprising the nucleic acid molecule operably linked to an expression control sequence.

19. A host-vector system comprising the expression vector of claim 18 in a host cell.

20. A host-vector system comprising an expression vector pair comprising a nucleic acid sequence pair selected from the group consisting of: SEQ ID NOS 17 and 19; SEQ ID NOS.21 and 23; SEQ ID NOS 25 and 27; SEQ ID NOS 29 and 31; SEQ ID NOS 79 and 81; SEQ ID NOS 83 and 85; SEQ ID NOS 87 and 89; SEQ ID NOS 91 and 93; SEQ ID NOS 95 and 97; and SEQ ID NOS 99 and 101.

21. A host-vector system comprising an expression vector comprising a nucleic acid sequence selected from the group consisting of: 59, 61, 63, 65, 75 and 77.

22. A method of producing a substantially purified antibody fusion protein, the method comprising: (a) Growing a cell of the host-vector system of claim 20 or 21 under conditions that allow production of the antibody fusion protein; and (b) recovering the antibody fusion protein to produce a recovered antibody fusion protein; and (c) purifying the recovered antibody fusion protein to produce the substantially purified antibody fusion protein.

23. A method of treating or controlling at least one disease, condition, or disorder, the etiology of which has abnormal angiogenesis or inflammation, in a subject in need thereof; wherein the method comprises administering to the subject a composition of an amount of an antibody fusion protein comprising an amino acid sequence substantially as set forth in seq id no: SEQ ID NOS 34 and 36; SEQ ID NOS 38 and 40; SEQ ID NOS 42 and 44; SEQ ID NOS 46 and 48; SEQ ID NOS 78 and 80; SEQ ID NOS 82 and 84; SEQ ID NOS 86 and 88; SEQ ID NOS 90 and 92; SEQ ID NOS 94 and 96; SEQ ID NOS 98 and 100; SEQ ID NO. 60; SEQ ID NO. 62; SEQ ID NO. 64; SEQ ID NO. 66; SEQ ID NO. 74; or SEQ ID NO. 76.

24. The method of claim 23, wherein the disease, condition, or disorder is selected from the group consisting of: choroidal neovascularization, neovascular age-related macular degeneration, polypoidal choroidal vasculopathy, myopic choroidal neovascularization, vascular leakage, macular edema, nonproliferative and proliferative diabetic retinopathy, corneal neovascularization, corneal inflammation, myopic neovascular and neovascular glaucoma.

25. The method of claim 24, wherein the subject is administered a dose of about 25-4000 micrograms of the antibody fusion protein.

26. The method of claim 25, wherein the composition is administered to the subject as: eye drops, punctal plugs, intracameral injections, retrobulbar injections, subconjunctival injections, peribulbar injections, subcapsular injections, scleral side injections, transscleral injections, intravitreal injections, subretinal injections, or suprachoroidal injections.

27. The method of claim 25, wherein the composition is administered to the subject for a period of at least one month if administered intra-ocularly.

28. The method of claim 25, wherein the composition is administered to the subject at a frequency of at least once a month if administered intra-ocular.

29. A method for treating or controlling at least one systemic disease, condition or disorder, the etiology of which is abnormal angiogenesis or inflammation, in a subject in need thereof; wherein the method comprises administering to the subject an amount of a composition of an antibody fusion protein or antigen-binding fragment thereof capable of substantially binding to IL-6R and one or more VEGF family members.

30. A method for treating or controlling at least one systemic disease, condition or disorder, the etiology of which is abnormal angiogenesis or inflammation, in a subject in need thereof; wherein the method comprises administering to the subject a composition of an amount of an antibody fusion protein comprising an amino acid sequence substantially as set forth in seq id no: SEQ ID NOS 34 and 36; SEQ ID NOS 38 and 40; SEQ ID NOS 42 and 44; SEQ ID NOS 46 and 48; SEQ ID NOS 78 and 80; SEQ ID NOS 82 and 84; SEQ ID NOS 86 and 88; SEQ ID NOS 90 and 92; SEQ ID NOS 94 and 96; SEQ ID NOS 98 and 100; SEQ ID NO. 60; SEQ ID NO. 62; SEQ ID NO. 64; SEQ ID NO. 66; SEQ ID NO. 74; and SEQ ID NO. 76.

31. The method of claim 30; wherein the systemic disease, condition or disorder involves tumor growth, tumor metastasis, or both.

32. The method of claim 30; wherein the systemic disease, condition or disorder is atherosclerosis.

33. The method of claim 30; wherein the systemic disease, condition or disorder is psoriasis.