TW202246359A - Antibody fusion proteins targeting il-6 receptor and angiogenic factors - Google Patents

Abstract

An antibody fusion protein comprises an antibody against IL-6 receptor or an antigen-binding fragment thereof linked to a VEGF binding unit comprising a plurality of Iglike domains of a first VEGF receptor, a second human VEGF receptor, and/or a third human VEGF receptor. The antibody fusion protein is useful in treating or controlling an ocular disease, condition, or disorder that has etiology in aberrant angiogenesis or inflammation.

Description

Antibody fusion protein targeting IL-6 receptor and angiogenesis factor

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

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

A family of secreted polypeptides has been shown to play an extremely important role in promoting endothelial cell proliferation and angiogenesis. The pathological hallmark of uncontrolled angiogenesis caused by VEGF overexpression is increased vascular permeability, which leads to 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 factors A-D ("VEGF-A", "VEGF-B", "VEGF- C" and "VEGF-D") and placental growth factor ("PlGF"). In this 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 stressors such as infection and injury. Under physiological conditions, IL-6 is barely detectable, but its amount can increase more than 100,000-fold during the early stages of inflammation. However, not all occurrences of IL-6 stimulation are beneficial. Dysregulated, persistent production of IL-6 is associated with the development of various autoimmune and chronic inflammatory diseases. There is evidence that unchecked production of IL-6 in inflamed tissues induces overproduction of VEGF-A and VEGF-C.

VEGF family growth factors stimulate blood vessel formation by acting through a family of cognate receptor tyrosine kinases found 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 "flk-1" in mice), VEGF receptor-3 ("VEGFR-3" , also known as "flt-4").

VEGF-A (sometimes shortened to VEGF) has become the most important member of this family of growth factors. Human VEGF-A is expressed in various tissues in multiple homodimeric forms (121, 145, 165, 183, 189 and 206 amino acids per monomer), each of which is formed by a single RNA transcript produced by alternative splicing.

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

Conversely, however, while vascular endothelial proliferation is desirable in certain circumstances, vascular endothelial proliferation and angiogenesis are also undesirable components of a variety of diseases and conditions, including tumor growth and metastasis, rheumatoid arthritis , psoriasis, atherosclerosis, diabetic retinopathy, retrolentic fibroplasia, neovascular glaucoma, neovascular age-related macular degeneration, hemangioma, immune rejection and chronic inflammation of transplanted corneal tissue and other tissues. In individuals suffering from any of these disorders, it is desirable to inhibit, or at least significantly reduce, the endothelial proliferative 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, one for anchoring the receptor A transmembrane domain localized on the surface of receptor-expressing cells 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 to VEGF-C and VEGF-D.

In view of the role of growth factors of the VEGF family in vascular endothelial proliferation and angiogenesis and the role these processes play in many different diseases and conditions, therapies targeting the control of these growth factors have been devised. However, anti-VEGF therapy alone does not completely block the progression of angiogenic disease.

Accordingly, it would be 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 result from abnormal angiogenesis. It would also be desirable to have a pharmacological approach for improved treatment or management of pathological conditions resulting from abnormal angiogenesis.

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

In general, the invention provides antibody fusion or chimeric proteins, methods of producing them and compositions comprising them, and methods for treating or managing at least one pathological condition in a subject, the etiology of which is Abnormal angiogenesis. In this 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 capable of binding IL-6R, including membrane-bound or soluble forms of IL-6R, and one or more VEGF The family members substantially bind; thereby simultaneously reducing or inhibiting IL-6 and VEGF family member signaling.

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

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

In yet another aspect, the antibody fusion protein or chimeric protein of the present invention comprises an antibody against IL-6R or an antigen-binding fragment or domain thereof; wherein at least one of the following is linked to a VEGF binding unit: (1) a light chain or an antigen-binding fragment or domain thereof; and (2) a heavy chain or an antigen-binding fragment or domain thereof, the 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 domain, an Ig-like domain of a second VEGF receptor, an Ig-like domain of a third VEGF receptor, and combinations thereof.

In yet 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) human Ig-like domain 3 or substantially Ig-like domain 3 of VEGFR-2 (or KDR); or (2) at least one Ig-like domain selected from the group consisting of human VEGFR- 3 (or flt-4) Ig-like domains 1, 2 and 3 or essentially Ig-like domains 1, 2 and 3.

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 against IL-6R or antigen-binding fragment thereof 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) human VEGFR-2 (or KDR) Ig-like domain 3 or essentially Ig-like domain 3.

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

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

In yet another aspect, the invention provides vectors comprising said nucleic acid molecules, said vectors comprising expression vectors comprising said nucleic acid molecules operably linked to expression control sequences. As used herein, the phrase "operably linked" refers to placing 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, the DNA of a presequence or secretory leader is "operably linked" to the DNA of a polypeptide if it appears to be a preprotein involved in the secretion of the polypeptide; if a promoter or enhancer affects the transcription of the sequence, the promoter Either an enhancer is operably linked to the coding sequence; or a ribosome binding site is operably linked to the coding sequence if it is positioned so as to facilitate translation.

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

In another aspect, the present invention provides a method of producing an antibody fusion protein or chimeric protein, the method comprising: (a) growing 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 thus produced.

In yet another aspect, the present invention provides a method for treating or managing at least one disease, condition or disorder in a subject, the etiology of which is selected from the group consisting of abnormal angiogenesis, Inflammation and combinations thereof.

In yet another aspect, the present invention provides a method for treating or managing at least one disease, condition or disorder in a subject the etiology of which is abnormal angiogenesis and/or inflammation. In certain embodiments, such disease, condition or disorder is an eye disease, condition or disorder. In certain other embodiments, such diseases, conditions or disorders are related to tumor growth and metastasis. In other embodiments, such disease, condition or disorder is rheumatoid arthritis, psoriasis or atherosclerosis.

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

In general, the invention provides antibody fusion proteins or chimeric proteins, or antigen-binding fragments or domains thereof, that are capable of substantially binding IL-6R and one or more VEGF family members; thereby reducing or inhibiting IL-6 and VEGF family members for both messaging. In this disclosure, the term "antibody fusion protein" is sometimes used instead of "antibody fusion protein or chimeric protein". In one aspect, the antibody fusion protein or antigen-binding fragment thereof is capable of substantially binding IL-6R and one or more VEGF family members; thereby reducing or inhibiting IL-6 and VEGF family member signaling.

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

An advantage of the antibody fusion proteins of the invention is that they can bind substantially both membrane-bound and soluble IL-6R and thereby inhibit their effects. 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 yet 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 protein or chimeric protein of the present invention comprises an antibody against IL-6R or an antigen-binding fragment or domain thereof; wherein one of the following is linked to a VEGF binding unit: (1) at least a light chain or an antigen-binding fragment or domain thereof; and (2) a heavy chain or an antigen-binding fragment or domain thereof, the 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 a third VEGF The Ig-like domain of the receptor. In one embodiment, the antibody fusion protein or chimeric protein of the present invention comprises an antibody against IL-6R or its antigen-binding fragment or domain; wherein the light chain or its antigen-binding fragment or domain and the heavy chain or its antigen-binding Fragments or domains 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 Ig-like domain of the third VEGF receptor.

In yet 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) human Ig-like domain 3 or substantially Ig-like domain 3 of VEGFR-2 (or KDR); or (2) at least one Ig-like domain selected from the group consisting of: VEGFR-3 (or flt4) Ig-like domain 1, 2, 3, and combinations thereof, or selected from the group consisting of substantially the same domain as the Ig-like domain of VEGFR-3. In one embodiment, the VEGF binding unit comprises: (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 of human VEGFR-3.

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 against IL-6R or antigen-binding fragment thereof 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) human VEGFR-2 (or KDR) Ig-like domain 3 or essentially Ig-like domain 3.

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

As disclosed herein, an "antigen-binding fragment or domain" of an antibody's light or heavy chain refers to a fragment or portion of such an antibody that comprises the complementarity determining regions ("CDRs") of the variable domains of such antibodies . In one embodiment, the antigen-binding fragment or domain of such an antibody comprises the variable domain of the light 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, triabodies, scFv-Fc antibodies, (Fab')2 and present Other antibodies known in the art. A non-limiting example of an sdAb is a Nanobody directed against human IL-6R disclosed in US Pat. No. 10,618,964; more specifically, vobarilizumab, the amino acid sequence of which is set forth below as SEQ ID NO: 73 .

In one aspect, the antibody fusion protein of the present invention comprises: (1) a heavy chain having a group selected from the group consisting of SEQ ID NO: 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 SEQ ID NO: 36, 40, 44, 48, 80, 84, 88, 92, 96 and 100 .

In Example 5, the antibody fusion protein of the present invention comprises a pair of IL-6R single chain variable fragments ("IL-6R scFv") or a dimer thereof, each of which is combined with an IgG1 The Fc domain and a VEGF binding unit are sequentially linked, the 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 listed in SEQ ID NO: 60. The nucleic acid sequence of this example is listed in SEQ ID NO: 59. In one aspect, the IgGl is human IgGl.

In embodiment 6, the antibody fusion protein of the present invention comprises an IL-6R scFv pair or a dimer thereof; wherein the carboxyl terminus (C terminus) of each IL-6R scFv is connected to a VEGF binding unit, and the VEGF binding unit comprises : (a) Ig-like domain 2 or essentially Ig-like domain 2 of human VEGFR-1 (or flt-1); and (b) Ig-like domain 3 or essential Ig-like domain 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 listed in SEQ ID NO: 62. The nucleic acid sequence of this example is listed in SEQ ID NO: 61. In one aspect, the IgGl is human IgGl.

In embodiment 7, the antibody fusion protein of the present invention comprises an IL-6R scFv pair or a dimer thereof; wherein the carboxyl terminus of each IL-6R scFv is connected to a first VEGF binding unit, and the first VEGF binding unit comprises : (a) Ig-like domain 2 or essentially Ig-like domain 2 of human VEGFR-1 (or flt-1); and (b) Ig-like domain 3 or essential Ig-like domain of human VEGFR-2 (or KDR) Ig-like domain 3 above; the carboxy-terminus of each first VEGF-binding unit is linked to the Fc domain of IgG1; and the carboxy-terminus of the Fc domain is linked to a second VEGF-binding unit comprising human Ig-like domains 1 and 2 or essentially Ig-like domains 1 and 2 of VEGFR-3 (or flt-4). The amino acid sequence of this example is listed in SEQ ID NO: 64. The nucleic acid sequence of this example is listed in SEQ ID NO: 63.

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

Example 9 is similar to Example 5, except that the Fc domain is connected to the VEGF binding unit through linkers with different lengths. The amino acid sequence of this example is listed in SEQ ID NO: 74. The nucleic acid sequence of this example is listed in SEQ ID NO: 75.

In Example 10, the antibody fusion protein of the present invention comprises an IL-6R scFv pair or a dimer thereof; wherein the amino terminus (N terminus) of each IL-6R scFv is connected to the carboxyl terminus (C terminus) of the Fc domain of IgG1 terminal) link, the amine terminus of which 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 listed in SEQ ID NO: 76. The nucleic acid sequence of this example is listed in SEQ ID NO: 77.

In any of the foregoing embodiments, the VEGF binding unit may be linked directly to the scFv, Fc domain or another VEGF binding unit or via a linker. Preferably, the VEGF binding unit is linked to the scFv, Fc domain or another VEGF binding unit via a linker.

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

In another embodiment, an antibody fusion protein of the invention comprises a minibody of an antibody directed against IL-6R, wherein each of the light chain and the heavy chain is linked to a VEGF binding unit. Such heavy chains may include an Fc region.

In one example, the antibody against human IL-6R ("hIL-6R") comprises the antibody known as tocilizumab, which is described in, for example, US Patents 10,323,095; 7,479,543; and 5,795,965 .

In one aspect, the heavy chain of an antibody fusion protein of the invention comprises the heavy chain complementarity determining regions CDR1, CDR2 and CDR3 set forth in SEQ ID NO: 53, 54 and 55 ("HCCDR1", "HCCDR2" and "HCCDR3") .

In another aspect, the light chain of the antibody fusion protein of the present invention comprises the light chain complementarity determining regions CDR1, CDR2 and CDR3 set forth in SEQ ID NO: 56, 57 and 58 ("LCCDR1", "LCCDR2" and "LCCDR3" ).

Other antibodies against hIL-6R can be used in the antibody fusion protein of the present invention; such as sarilumab as described in US Patent 7,582,298; or satralizumab as described in US Patent 8,562,991 . In some embodiments, the antibody fusion protein of the present invention can also pass through the heavy chain and light Chains are produced by ligation of VEGF binding units as described herein. For example, the heavy chain and light chain of sariluzumab or sartuzumab can be connected to a VEGF-binding unit through a flexible linker, each VEGF-binding unit comprising the polypeptides of SEQ ID NO: 6 and 8. In other embodiments, the heavy chain of Tocilizumab or Satuzumab is connected to a VEGF binding unit through a flexible linker, and the VEGF Binding unit comprises a polypeptide of SEQ ID NO: 10; and Thariluzumab or Satuzumab The light chain of tocilizumab is connected to the VEGF binding unit through a flexible linker, and the VEGF binding unit comprises the polypeptides of SEQ ID NO: 6 and 8.

The VEGF binding unit included in the antibody fusion protein of the invention is capable of binding at least one member of the VEGF family ("VEGF family member"); thereby rendering the at least one VEGF family member substantially non-binding to VEGF receptors on endothelial cells . Accordingly, the antibody fusion protein substantially inhibits the angiogenesis-promoting biological activity of the at least one VEGF family member; thereby controlling the pathological condition that is the result of abnormal angiogenesis.

In some embodiments, the present invention also provides a binding construct comprising or consisting of a plurality of antibody fusion proteins or chimeric proteins as described herein, the plurality of antibody fusion proteins or chimeric proteins The binding constructs are linked or associated with each other through covalent bonds or other forms of linkage; wherein the antibody moieties 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 part thereof and with high affinity.

The VEGF binding unit may be linked to the C-terminus (carboxy-terminus) or N-terminus (amine-terminus) of the light and heavy chains of the antibody moiety. Preferably, the VEGF binding unit is linked to the C-terminus of the light and heavy chains of the antibody moiety. More preferably, the VEGF-binding unit is connected to the C-termini of the light chain and the heavy chain of the antibody moiety through 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 chains of the antibody moiety 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. Antibody fusion proteins or binding constructs may further include heterologous peptides or other chemical moieties. Such additions may alter properties such as stability, solubility, toxicity, serum half-life, immunogenicity, detectability, or other properties.

The term "high affinity" is used in a physiological context to refer to the relative affinity of an antibody fusion protein for IL-6R and VEGF family members in mammals such as laboratory test animals, domesticated farm or pet animals, or humans . The antibody fusion proteins of the present invention that bind IL-6R and various VEGF members have characteristic affinities for their in vivo ligands, usually measured in sub-nanomolar dissociation constants (K _d ). For purposes of the present invention, antibody fusion proteins of the present invention may bind IL- _6R or its targeted VEGF family member with a K less than or equal to the K of the native IL-6/IL-6R or growth factor/receptor pair About 1, or about 5, or about 10, or about 50, or about 100, or about 500 or about 1000 times of _d .

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

In another aspect, targeting VEGF family members can be combined with one or more VEGF binding units of an antibody fusion protein or chimeric protein.

In yet another aspect, the VEGF binding unit essentially comprises 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 the Ig-like domains of human VEGFR-1, VEGFR-2 and VEGFR-3.

In still another aspect, each of the light chain and the heavy chain of the antibody fusion protein or chimeric protein of the present invention is linked to a VEGF binding unit comprising: (a) human VEGFR-1 (or flt- 1) Ig-like domain 2 or substantially Ig-like domain 2; 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 moiety.

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

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

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

In one aspect, the amino acid sequences of various parts or embodiments of the antibody fusion proteins of the present invention are listed in Table 1.

Table 1 Amino acid sequence Part of an antibody fusion protein SEQ ID NO: Antibody heavy chain 2 Light chains of antibody moieties 4 Ig-like domain 2 of human VEGFR-1 ("VEGFR-1-D2") 6 Ig-like domain 3 of human VEGFR-2 ("VEGFR-2-D3") ("VEGFR-2-D3") 8 Ig-like domains 1 and 2 of human VEGFR-3 ("VEGFR-3-D1D2") 10 Flexible joint 1 12 Flexible joint 2 14 Flexible joint 3 68 Flexible joint 4 70 Flexible joint 5 72 signal peptide 16 The complete heavy chain of Example 1 18 The complete light chain of Example 1 20 The complete heavy chain of Example 2 twenty two The complete light chain of Example 2 twenty four The complete heavy chain of Example 3 26 The complete light chain of Example 3 28 The complete heavy chain of Example 4 30 The complete light chain of Example 4 32 The functional heavy chain of Example 1 34 The functional light chain of Example 1 36 The functional heavy chain of Example 2 38 The functional light chain of Example 2 40 The functional heavy chain of Example 3 42 The functional light chain of Example 3 44 The functional heavy chain of Example 4 46 The functional light chain of Example 4 48 Tocilizumab heavy chain 49 Tocilizumab light chain 50 Satuzumab heavy chain 51 Satuzumab light chain 52 Thaliluumab HCCDR1 53 Thaliluumab HCCDR2 54 Thaliluumab HCCDR3 55 Tharilumab LCCDR1 56 Thaliluumab LCCDR2 57 Tharilumab LCCDR3 58 Example 5 comprising scFv (EB-DJ1) 60 Example 6 comprising scFv (EB-vvB) 62 Example 7 comprising scFv 64 Example 8 comprising scFv 66 Balinezumab 73 Example 9 comprising scFv (EB-vvA) 74 Example 10 comprising scFv (EB-vvC) 76 Heavy chain of B781401 78 Light chain of B781401 80 Heavy chain of B781402 82 Light chain of B781402 84 Heavy chain of B781403 86 Light chain of B781403 88 Heavy chain of B781404 90 Light chain of B781404 92 Heavy chain of B781405 94 Light chain of B781405 96 Heavy chain of B781406 98 Light chain of B781406 100 Ig-like domains 1, 2 and 3 of human VEGFR-3 ("VEGFR-3-D1D2D3") 102

On the other hand, the nucleic acid sequences encoding the amino acid sequences of various parts or embodiments of the antibody fusion proteins of the present invention are listed in Table 2.

Table 2 Nucleic acid sequence Part of an antibody fusion protein SEQ ID NO: Antibody heavy chain 1 Light chains of antibody moieties 3 Ig-like domain 2 of human VEGFR-1 ("VEGFR-1-D2") 5 Ig-like domain 3 of human VEGFR-2 ("VEGFR-2-D3") 7 Ig-like domains 1 and 2 of human VEGFR-3 ("VEGFR-3-D1D2") 9 Flexible joint 1 11 Flexible joint 2 13 Flexible joint 3 67 Flexible joint 4 69 Flexible joint 5 71 signal peptide 15 The complete heavy chain of Example 1 17 The complete light chain of Example 1 19 The complete heavy chain of Example 2 twenty one The complete light chain of Example 2 twenty three The complete heavy chain of Example 3 25 The complete light chain of Example 3 27 The complete heavy chain of Example 4 29 The complete light chain of Example 4 31 The functional heavy chain of Example 1 33 The functional light chain of Example 1 35 The functional heavy chain of Example 2 37 The functional light chain of Example 2 39 The functional heavy chain of Example 3 41 The functional light chain of Example 3 43 The functional heavy chain of Example 4 45 The functional light chain of Example 4 47 Example 5 comprising scFv (EB-DJ1) 59 Example 6 comprising scFv (EB-vvB) 61 Example 7 comprising scFv 63 Example 8 comprising scFv 65 Example 9 comprising scFv (EB-vvA) 75 Example 10 comprising scFv (EB-vvC) 77 Heavy chain of B781401 79 Light chain of B781401 81 Heavy chain of B781402 83 Light chain of B781402 85 Heavy chain of B781403 87 Light chain of B781403 89 Heavy chain of B781404 91 Light chain of B781404 93 Heavy chain of B781405 95 Light chain of B781405 97 Heavy chain of B781406 99 Light chain of B781406 101 Ig-like domains 1, 2 and 3 of human VEGFR-3 ("VEGFR-3-D1D2D3") 103

In yet another aspect, the antibody fusion protein or chimeric protein of the present invention comprises a combination with 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 at least 90% identical amino acid sequences.

In still another aspect, the antibody fusion protein or chimeric protein of the present invention comprises a combination with 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 at least 95% identical amino acid sequence.

In yet another aspect, one or more amino acid substitutions may be made in any of the aforementioned amino acid sequences. Preferably, such substitutions are conservative substitutions, wherein an amino acid from one of the following groups is replaced by another from 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 to substantially maintain the binding activity of the fusion polypeptide. In one embodiment, an antibody fusion protein of the invention having a conservative substitution has a Kd value for an IL- _6R or VEGF ligand that is less than about 120% of that prior to such substitution. Preferably, the _Kd value is less than about 110% of that prior to such substitution. More preferably, the _Kd value is less than about 105% of that prior to such substitution.

Most conservative substitutions are not expected to result in fundamental changes in the properties of the Ig-like domain or domains of the fusion polypeptide. However, when it is difficult to predict the exact effect of a substitution before doing so, one of ordinary skill in the art will understand that such effect will be assessed by conventional screening assays. For example, Ig-like domain variants are typically detected by site-specific mutagenesis of nucleic acid encoding the entire fusion polypeptide, expression of the variant nucleic acid in recombinant cell culture, purification of the variant fusion polypeptide from cell culture, and detection of the variant fusion The ability of the polypeptide to specifically bind IL-6R or VEGF ligands was tested. The article by Park et al., J. Biol. Chem., 269:25646-25654 (1994) describes a method that can be used to determine one or more specific Exemplary binding assays for whether substitutions affect the ability of fusion polypeptides to bind to and inhibit the activity of IL-6R or VEGF family members.

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., 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 (Stuttfeld et al., Life, 61(9):915 (2009)) . The VEGFR-3-D1D2 binding unit of the fusion protein can bind 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) encoding an antibody against human IL-6R ("hIL-6R antibody") (b) the nucleic acid sequence encoding the light chain of the hIL-6R antibody or its antigen-binding fragment or domain; and (c) the Ig encoding the VEGF receptor A nucleic acid sequence of a domain-like domain, which is operatively associated with the nucleic acid sequence encoding the heavy chain of the hIL-6R antibody or an antigen-binding fragment or domain thereof and the light chain encoding the hIL-6R antibody or Each of said nucleic acid sequences of antigen-binding fragments or domains thereof are linked.

In yet another aspect, the present invention provides an isolated nucleic acid molecule encoding the antibody fusion protein; wherein the isolated nucleic acid molecule comprises: (a) a heavy chain encoding a hIL-6R antibody or an antigen-binding fragment or domain thereof (b) the nucleic acid sequence encoding the light chain of the hIL-6R antibody or its antigen-binding fragment or domain; and (c) the nucleic acid sequence encoding VEGFR-1-D2 and VEGFR-2-D3, the The nucleic acid sequence is operatively related to the nucleic acid sequence encoding the heavy chain of the hIL-6R antibody or an antigen-binding fragment or domain thereof and the light chain encoding the hIL-6R antibody or an antigen-binding fragment or domain thereof Each of the nucleic acid sequences is linked.

In yet another aspect, the present invention provides an isolated nucleic acid molecule encoding the antibody fusion protein; wherein the isolated nucleic acid molecule comprises: (a) a heavy chain encoding a hIL-6R antibody or an antigen-binding fragment or domain thereof The nucleic acid sequence of the nucleic acid sequence has the sequence listed in SEQ ID NO: 1; (b) the nucleic acid sequence encoding the light chain of the hIL-6R antibody or its antigen-binding fragment or domain, the nucleic acid sequence has The sequence listed in SEQ ID NO: 3; and (c) the nucleic acid sequence encoding VEGFR-1-D2 and VEGFR-2-D3, the nucleic acid sequence has the sequence listed in SEQ ID NO: 5 and 7, the The nucleic acid sequence is operatively related to the nucleic acid sequence encoding the heavy chain of the hIL-6R antibody or an antigen-binding fragment or domain thereof and the light chain encoding the hIL-6R antibody or an antigen-binding fragment or domain thereof Each of the nucleic acid sequences is linked.

In yet another aspect, the present invention provides an isolated nucleic acid molecule encoding the antibody fusion protein; wherein the isolated nucleic acid molecule comprises: (a) a heavy chain encoding a hIL-6R antibody or an antigen-binding fragment or domain thereof (b) a nucleic acid sequence encoding the light chain of the hIL-6R antibody or its antigen-binding fragment or domain; (c) a nucleic acid sequence encoding VEGFR-3-D1D2, which is operatively compatible with The nucleic acid sequence encoding the heavy chain of the hIL-6R antibody or its antigen-binding fragment or domain is linked; and (d) the nucleic acid sequence encoding VEGFR-1-D2 and VEGFR-2-D3, the nucleic acid sequence manipulated is selectively 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 encoded by at least one nucleic acid sequence of a VEGFR-3 Ig-like domain selected from the group consisting of VEGFR-3-D1, VEGFR-3-D2 and VEGFR3-D3 substitute.

In yet another aspect, the present invention provides an isolated nucleic acid molecule encoding the antibody fusion protein; wherein the isolated nucleic acid molecule comprises: (a) a heavy chain encoding a hIL-6R antibody or an antigen-binding fragment or domain thereof The nucleic acid sequence of the nucleic acid sequence has the sequence listed in SEQ ID NO: 1; (b) the nucleic acid sequence encoding the light chain of the hIL-6R antibody or its antigen-binding fragment or domain, the nucleic acid sequence has The sequence listed in SEQ ID NO: 3; (c) the nucleic acid sequence encoding VEGFR-3-D1D2, the nucleic acid sequence has the sequence listed in SEQ ID NO: 9, the nucleic acid sequence is operatively with the encoding The nucleic acid sequence of the heavy chain of the hIL-6R antibody or its antigen-binding fragment or domain; and (d) the nucleic acid sequence encoding VEGFR-1-D2 and VEGFR-2-D3, the nucleic acid sequence has SEQ ID The sequence listed in NO: 5 and 7, the nucleic acid sequence is 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 encoded by at least one nucleic acid sequence of a VEGFR-3 Ig-like domain selected from the group consisting of VEGFR-3-D1, VEGFR-3-D2 and VEGFR3-D3 substitute.

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

In yet another aspect, the isolated nucleic acid molecule can further comprise a leader nucleic acid sequence encoding a signaling polypeptide. In certain embodiments, wherein the VEGF binding unit is linked to the C-terminus of the heavy or light chain of the antibody moiety, the leader nucleic acid sequence precedes SEQ ID NO: 1 and 3.

In another aspect, the present 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 that of the present disclosure due to the degeneracy of the genetic code. The nucleic acid sequences listed in the content differ in one or more codons. Such different nucleic acid sequences are within the scope of the present invention.

In yet another aspect, the invention provides vectors comprising any of the nucleic acid molecules, including expression vectors comprising any of the nucleic acid molecules operably linked to expression control sequences. The embodiment of vector comprises the nucleotide sequence selected from the following group: 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: 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 yet another aspect, the invention provides a host-vector system for producing the antibody fusion or chimeric protein comprising an expression vector in a suitable host cell.

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 Expression of the antibody fusion protein. 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 DNA fragments into vectors can be used to construct expression vectors encoding chimeric polypeptide molecules under the control of transcriptional/translational control signals. These methods can include in vitro recombinant DNA and synthetic techniques as well as in vivo recombination (genetic recombination) (see Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Press); Current Protocols in Molecular Biology, eds., Ausubel et al., Greene Publishing Association (Greene Publ. Assoc., Wiley-Interscience, New York) .

Expression of a nucleic acid molecule encoding an antibody fusion protein of the present invention can 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, plastid vectors containing replicon and control sequences derived from species compatible with the host cell are used in conjunction with these hosts. The vector usually carries a replication site and a marker sequence capable of providing phenotypic selection in the transformed cell. For example, E. coli is commonly transformed with pBR322, a plastid derived from the E. coli species (see, eg, Bolivar et al., Gene, 2:95 (1977)). Plastid 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 a promoter that the microbial organism can use to express the protein.

Those most commonly used in recombinant DNA constructs include the β-lactamase (penicillinase) and lactose promoter systems or the tryptophan (trp) promoter system (Goeddel et al., Nucleic Acids Res. ", 8:4057 (1980)). Although these are the most commonly used, other microbial promoters have been discovered and utilized. For example, the tac promoter is a synthetically produced DNA promoter that results from a combination of promoters from the trp and lac operators (de Boer et al., 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 can be combined with Methods for producing antibody fusion proteins of the invention are used in combination.

In addition to prokaryotes, eukaryotic microorganisms such as yeast cultures can also be used. Saccharomyces cerevisiae, or common baker's yeast, is the most commonly used eukaryotic microorganism, even though many other strains are commonly available. For expression in Saccharomyces, for example the plastid YRp7 is commonly used (Stinchcomb et al., Nature, 282:39 (1979)). Other exemplary plasmids are disclosed in US Patent 4,615,974; Struhl et al., PNAS, 76(3):1035 (1979). Plastid YRp7 contains the trp1 gene that provides a selection marker for mutant strains of yeast lacking the ability to grow in the absence of tryptophan, such as ATCC number 44,076 or RH218 (Jones, Genetics, 85 :23 (1977)). The presence of trp1 lesions characteristic of the yeast host cell genome then provides an efficient 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 glycerol Aldehyde-3-phosphate dehydrogenase, hexokinase, pyruvate decarboxylase, and glucokinase (Romanos et al., Yeast, 8:423 (1992); Weinhandl et al., Microbial Cell Factory factories), 13:5 (2014)). Upon construction of suitable expression plastids, termination sequences associated with these genes are also ligated into the expression vector 3' of the desired expressed sequence to provide for polyadenylation and termination of the mRNA. Other promoters have the added advantage of growth-condition-controlled transcription, such as the promoter region for alcohol dehydrogenase 2 and the enzymes responsible for maltose and galactose utilization (Romanos et al., Weinhandl et al., supra). Any plastid vector containing a yeast-compatible promoter, origin of replication, and termination sequences is suitable.

In addition to microorganisms, cell cultures derived from multicellular organisms can also be used as hosts. In principle, any such cell culture is feasible, whether from vertebrate or invertebrate cultures. However, more attention has been paid to vertebrate cells, and the propagation of vertebrate cells in culture (tissue culture) has become routine in recent years (Tissue Culture, Academic Press, Kruse and Patterson, eds. (1973)). Examples of such useful host cell lines are VERO and HeLa cells, the Chinese Hamster Ovary (CHO) cell line, and the W138, BHK, COS-7, 293 and MDCK cell lines. Expression vectors for such cells typically include (if necessary) an origin of replication, a promoter preceding the gene to be expressed, and any necessary ribosome binding sites, RNA splicing sites, polyadenylation sites, and transcription terminators sequence.

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

Thus, according to the present invention, an expression vector capable of replicating in a bacterial, yeast cell, insect cell or mammalian cell host comprising a nucleic acid encoding an antibody fusion protein as described herein is used to transfect the host and thereby direct this The quasi-nucleic acid is expressed to produce a fusion polypeptide, which can then be recovered in a biologically active form. As used herein, biologically active forms include forms capable of binding at least one VEGF family member.

In some embodiments, the host cell may be Escherichia coli, COS cells, HEK 293 cells (also referred to simply as 293 cells), or Chinese Hamster Ovary ("CHO") cells. Preferably, the host cells are HEK 293 or CHO cells.

Carrier construction

Construction of suitable vectors containing the desired coding and control sequences employs standard ligation techniques. The isolated plastids or DNA fragments are cleaved, tailored and ligated into the desired form to form the desired plastids. The methods employed are independent of the DNA source or intended host. Cleavage is performed by treatment with one or more restriction enzymes in a suitable buffer.

A nucleic acid sequence substantially encoding one or more Ig-like domains of VEGFR-1, VEGFR-2 or VEGR-3 can be generated according to the methods disclosed in US Patent No. 6,897,294.

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

The entire chimeric nucleic acid sequence is then positioned in a vector containing a promoter that uses the same reading frame as the gene and is compatible with the proposed host cell. A number of plastids, such as those described in US Pat. Nos. 4,456,748; 5,460,811; 5,888,808; and 6,333,147, can be used to generate antibody fusion proteins of the invention.

In one embodiment, the chimeric heavy and light chains of the antibody fusion proteins of the invention are produced according to the methods described in US Patent No. 7,070,959. 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, The chimeric nucleic acid sequence of 99 or 101 was inserted into expression vector pEE14.1 (Lonza Biologics) with a CMV promoter.

In one example, CHO K1 cells were transfected with the pEE14.1/SEQ ID NO: 17 and pEE14.1/SEQ ID NO: 19 constructs and then grown. 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, build and grow. Antibody fusion proteins obtained from these CHO or HEK293 cells can be similarly purified and characterized.

In one embodiment, the antibody fusion protein of the present invention can bind to hIL-6R and VEGF family members with K _d ≤ 10 ^-9 M. In another embodiment, the antibody fusion protein of the present invention can bind to VEGF family members with K _d ≤ 5 × 10 ^-10 M. In yet another embodiment, the antibody fusion protein of the present invention can bind to VEGF family members with K _d ≤ 10 ⁻¹⁰ M.

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

In another aspect, the present invention provides a method for treating or managing at least one ocular disease, condition or disorder in a subject, wherein the etiology of the ocular disease, condition or disorder is abnormal angiogenesis. The methods include administering to a subject in need of such treatment or management a composition comprising an antibody fusion protein disclosed herein. Such antibody fusion proteins comprise a pair of heavy and light chains having the following: SEQ ID NO: 18 and 20; or SEQ ID NO: 22 and 24; or SEQ ID NO: 26 and 28; or SEQ ID NO: 30 and 32; or SEQ ID NO: 78 and 80; or SEQ ID NO: 82 and 84; or SEQ ID NO: 86 and 88; or SEQ ID NO: 90 and 100. In one embodiment, an antibody fusion protein for use in such methods may comprise a protein pair having a sequence as set forth in SEQ ID NO: 60, 62, 64, 66, 74 or 76 or a dimer thereof. In another embodiment, an antibody fusion protein for use in such methods may comprise a protein pair or dimerization thereof having a sequence starting from amino acid 17 of SEQ ID NO: 60, 62, 64, 66, 74 or 76 body.

In yet another aspect, the eye disease, condition or condition 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 leak, macular edema due to 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, a dose of about 25-4000 micrograms of the fusion polypeptide is administered to the subject. In another embodiment, the dose administered to the subject is 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 fusion polypeptide.

In yet another aspect, the composition comprising the fusion polypeptide is in the form of eye drops or ocular injections (such as intravitreal injections, intracameral injections, periorbital injections, subcapsular injections, subretinal injections, or choroidal injections). in the form of injection). Such compositions include ophthalmic compositions. Antibody fusion proteins of the invention can also be incorporated into medical devices that can be implanted in or near diseased tissue.

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

In yet another aspect, the eye drops are administered to the subject at least once a day, at least once a week, or at least once a month until the disease, condition or disorder is substantially treated or controlled.

In yet another aspect, the composition is administered to the subject via 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, the intravitreal injection is administered to the subject or the injection is administered into or near the diseased tissue according to the protocol recommended by the healthcare practitioner for the particular patient. For example, the injection can be administered at least monthly, at least every two months, at least every three months, or at least every six months until the disease, condition or disorder is substantially treated or controlled. In one embodiment, treatment may be administered more frequently initially, and then less frequently over time. Such time periods may be determined by a medical practitioner.

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

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

In one embodiment, such a physiologically acceptable carrier may be 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, such a carrier comprises an emulsion of a hydrophobic material and water. In yet another embodiment, antibody fusion proteins of the invention can be associated or linked to high molecular weight materials to provide long circulation times.

Physiologically acceptable buffers include, but are not limited to, phosphate buffer or Tris-HCl buffer (including tris(hydroxymethyl)aminomethane and HCl). For example, a Tris-HCl buffer at pH 7.4 contains 3 g/l tris(hydroxymethyl)aminomethane and 0.76 g/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 biologicals include phosphate, citric acid, acetic acid, tromethamine, histidine, arginine, gluconic acid, lactic acid, tartaric acid, asparagine acid and glutamic acid.

In some cases, other buffers may also be found suitable or desirable, such as HEPES (N-{2-hydroxyethyl}piperazine- N'-{2-ethanesulfonic acid}); BES (N,N-bis{2-hydroxyethyl}2-amino) with a pKa of 7.1 at 25°C and a pH in the range of about 6.4-7.8 ethanesulfonic acid); MOPS (3-{N-morpholino}propanesulfonic acid) with a pKa of 7.2 at 25°C and a pH in the range of about 6.5-7.9; a pKa of 7.4 at 25°C and a pH of about 6.8 - TES (N-tris{hydroxymethyl}-methyl-2-aminoethanesulfonic acid) in the range of -8.2; MOBS (4-{ N-morpholino}butanesulfonic acid); DIPSO (3-(N,N-bis{2-hydroxyethyl}amino)-2 with a pKa of 7.52 at 25°C and a pH in the range of about 7-8.2 -hydroxypropane); TAPSO (2-hydroxy-3{tris(hydroxymethyl)methylamino}-1-propanesulfonic acid) with a pKa of 7.61 at 25°C and a pH in the range of about 7-8.2.

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

In addition to buffers, the compositions of the present invention may comprise materials selected from the group consisting of surfactants, stabilizers, preservatives, co-solvents, humectants, emollients, chelating agents, osmo-regulators and antioxidants .

In one aspect, any of these materials that may be used in the compositions of the 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 can be used include quaternary ammonium compounds such as benzalkonium chloride and various polyquaternium compounds. These agents may be present in individual amounts of from about 0.001% to about 2% by weight (preferably, from about 0.01% to about 0.05% by weight).

Non-limiting examples of surfactants include, but are not limited to, nonionic surfactants such as polysorbates (e.g., polysorbate 20, polysorbate 80), 4-(1,1,3,3-tetra Methylbutyl)phenol/poly(oxyethylene) polymers such as those sold under the trademark Tyloxapol, poly(oxyethylene)-poly(oxypropylene) block copolymers, glycolic acid esters of fatty acids, etc., 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 8, or about 6.5 to about 7.5.

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

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

In yet another aspect, the composition can also comprise a viscosity-modifying compound designed to facilitate administration of the composition to a subject or to facilitate bioavailability in a subject. In yet another aspect, the viscosity modifying compound can be selected such that the composition does not readily disperse after application in the ocular environment. Such compounds can increase the viscosity of the composition and include, but are not limited to: monomeric polyols such as glycerin, propylene glycol, ethylene glycol; polymeric polyols such as polyethylene glycol; various polymers of the cellulose family such as hydroxy Propylmethylcellulose (“HPMC”), sodium carboxymethylcellulose (“CMC”), hydroxypropylcellulose (“HPC”); polysaccharides such as hyaluronic acid and its salts, chondroitin sulfate and its Salt, dextran, such as dextran 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 acrylic polymers. In general, desirable viscosities may range from about 1 to about 400 centipoise ("cps") or mPa.s.

Non-limiting examples of chelating agents include ethylenediaminetetraacetic acid ("EDTA"), diethylenetriaminepenta(methylphosphonic acid), hydroxyethylenediphosphonic acid, tetrakis of hydroxyethylenediphosphonic acid, Sodium salt (also known as "HAP").

While the buffer itself is an "osmotic regulator" and "pH regulator" that broadly maintains the ophthalmic solution at a specific ionic concentration and pH, additional "osmotic regulators" can be added to adjust the solution's final osmotic pressure. Such osmo-adjusting agents are well known to those of ordinary skill in the art and include, but are not limited to, mannitol, sorbitol, dextrose, sucrose, urea, propylene glycol, and glycerin. In addition, various salts can be used, including halide salts of monovalent cations (eg, NaCl or KCl). Typically, the osmolarity of the formulations of the invention is in the range of about 200 to 400 mOsm/kg. Alternatively, the osmolality of the formulations of the invention is in the range of about 220 to 400 mOsm/kg, or about 220 to 350 mOsm/kg, or about 220 to 300 mOsm/kg, or about 250 to 350 mOsm/kg .

Non-limiting examples of antioxidants include: ascorbic acid (vitamin C) and its salts and esters; tocopherols (such as alpha-tocopherol) and tocotrienols (vitamin E) and their salts and esters (such as vitamin E TGPS (D - Alpha-tocopherol macrogol 1000 succinate)); glutathione; lipoic acid; uric acid; butylated hydroxyanisole ("BHA"); butylated hydroxytoluene ("BHT"); tert-butyl Hydroquinone (“TBHQ”); and polyphenolic antioxidants (such as gallic acid, cinnamic acid, flavonoids and their salts, esters and derivatives).

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

It should be understood that the proportions of various components or mixtures in the following examples can be adjusted as appropriate.

In another aspect, the antibody fusion protein of the present invention and appropriate amount of one or more desired excipients are incorporated into a formulation for topical administration or injection into a part of the eye, such as the anterior or posterior segment or the vitreous humor. Injectable formulations may desirably include a carrier that provides sustained release of the active ingredient, such as a period of greater than about 1 week (or greater than about 1, 2, 3, 4, 5 or 6 months). In certain embodiments, antibody fusion proteins of the invention are included in a delivery device for sustained release of the active ingredient over an extended period of time, such as 4, 5, 6 months or longer. Examples of such delivery devices are described in US Patents 8,399,006 and 9,417,238.

In yet another aspect, compositions comprising antibody fusion proteins of the invention and desired excipients are lyophilized and reconstituted with a physiologically acceptable liquid carrier substantially immediately prior to administration to a subject.

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

In still another aspect, the antibody fusion protein of the present invention is incorporated into an ophthalmic device comprising a biodegradable material, and the device is implanted into the posterior segment tissue of a subject to provide protection against angiogenic diseases, conditions or long-term (eg, longer than about 1 week or longer than about 1, 2, 3, 4, 5, or 6 months) treatment or management of a disorder. Such devices may be implanted in the eye or periocular tissue 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 US Patent Nos. 5,378,475; 5,773,019; 5,902,598; 6,001,386;

In yet another aspect, a method for treating or managing 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 yet another aspect, the antibody fusion protein used in the method comprises an antibody to IL-6R or an antigen-binding fragment or domain thereof; wherein at least one of the following is linked to a VEGF binding unit: (1) a light chain or an antigen-binding fragment or domain thereof; and (2) a heavy chain or an antigen-binding fragment or domain thereof, said VEGF-binding unit comprising: (1) (a) the Ig-like domain 2 of human VEGFR-1 or substantially Ig-like domain 2; 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 From the lower group: 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: (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 of human VEGFR-3 substantially Ig-like domains 1, 2 and 3.

In yet another aspect, a method for treating or managing an ocular angiogenic disease, condition or disorder comprises administering to a subject in need thereof an antibody comprising an antibody having heavy and light chain amino acid sequences as listed below Compositions of fusion proteins: SEQ ID NO: 18 and 20; or SEQ ID NO: 22 and 24; or SEQ ID NO: 26 and 28; SEQ ID NO: 30 and 32; SEQ ID NO: 78 and 80; SEQ ID NO: 82 and 84; SEQ ID NO: 86 and 88; SEQ ID NO: 90 and 92; SEQ ID NO: 94 and 96; Or SEQ ID NO: 98 and 100; Or have such as SEQ ID NO: 60, SEQ ID An antibody fusion protein of the amino acid sequence listed in 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 used in such methods may comprise a protein pair having a sequence beginning at amino acid 17 of the sequence set forth in SEQ ID NO: 60, 62, 64, 66, 74 or 76 or its dimers.

In yet another aspect, a method for treating or controlling an ocular neovascular disease, condition or disorder in the posterior segment of the eye due to abnormal angiogenesis comprises intravitreal injection into a subject in need thereof comprising The composition of the antibody fusion protein of heavy chain and light chain amino acid sequence: SEQ ID NO: 18 and 20; Or SEQ ID NO: 22 and 24; Or SEQ ID NO: 26 and 28; Or SEQ ID NO: 30 and 32; SEQ ID NO: 78 and 80; SEQ ID NO: 82 and 84; SEQ ID NO: 86 and 88; SEQ ID NO: 90 and 92; SEQ ID NO: 94 and 96; or SEQ ID NO: 98 and 100; or an antibody fusion 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 protein. In yet another aspect, the antibody fusion protein used in such methods may comprise a protein pair having a sequence beginning at amino acid 17 of the sequence set forth in SEQ ID NO: 60, 62, 64, 66, 74 or 76 or its dimers.

In another embodiment, such disease, condition or condition is selected from the group consisting of neovascular age-related macular degeneration (wet age-related macular degeneration), polypoidal choroidal vasculopathy (PCV) and myopic choroidal neogenesis Vascular degeneration of choroidal neovascularization, vascular leak, macular edema due to 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 once a week, once a month, once a year, twice a year, four times a year, or at a frequency determined to be suitable for the treatment or management of an anterior segment inflammatory disease, condition or disorder .

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

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

Six antibody fusion proteins of the present invention were produced according to the methods disclosed herein and are denoted as 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 tocilizumab, a mAb against IL-6R. The heavy chain of B781401 has an amino acid sequence of SEQ ID NO: 78 and a nucleic acid sequence of SEQ ID NO: 79. The light chain of B781401 has an amino acid sequence of SEQ ID NO: 80 and a nucleic acid sequence of SEQ ID NO: 81.

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

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 tocilizumab. The heavy chain of B781405 has an amino acid sequence of SEQ ID NO: 94 and a nucleic acid sequence of SEQ ID NO: 95. The light chain of B781405 has an amino acid sequence of SEQ ID NO: 96 and a nucleic acid sequence of SEQ ID NO: 97.

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

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

Figures 7A-D show schematics of antibody fusion proteins B781401-781406.

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

The four antibody fusion proteins of the present invention are prepared according to the methods disclosed herein, and are denoted as EB-DJ1, EB-vvA, EB-vvB, and EB-vvC. Each of these fusion proteins comprises a pair of constructs, each comprising IL-6R scFv, the Fc domain of IgG1, and human VEGFR-1-D2 and human VEGFR-2, or dimers thereof. - VEGF binding unit of D3. Specifically, each of EB-DJ1 and EB-vvA consisted of dimers of constructs each consisting of IL-6R scFv linked to the Fc domain of IgG1. The carboxyl terminus of the IgG1-Fc domain is linked to a VEGF binding unit consisting of VEGFR-1-D2-VEGFR-2-D3 through a flexible linker. The construct of EB-DJ1 has an amino acid sequence of SEQ ID NO: 60 and a nucleic acid sequence of SEQ ID NO: 59. The construct of EB-vvA has an amino acid sequence of SEQ ID NO: 74 and a nucleic acid sequence of SEQ ID NO: 75.

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

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

Example 2: Comparison of ELISA binding affinities of EB-DJ1, EB- _vvA , EB-vvB and EB-vvC with aflibercept, B781403 and B781405 for recombinant human VEGF-A165.

Figure 8 shows a schematic diagram of antibody fusion proteins EB-DJ1, EB-vvA, EB-vvB and EB-vvC.

Example 3: Transient expression and purification of B781401-781406.

Genes encoding the amino acid sequences of B781401-781406 shown in SEQ ID NO: 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99 and 101 were synthesized, and constructed based on The expression vector of the vector pcDNA3.4 for expressing proteins. Expression vectors were used to transiently transfect HEK293 cells with chemically defined media. The resulting protein was purified by a protein A affinity column, ultrafiltered and then subjected to 0.2 μm sterile filtration to obtain large amounts of highly pure protein. Expression of B781401-781406 in HEK293 cells yielded a protein with a MW of ~200 KDa (non-reduced form on SDS-PAGE) with ~100% purity when analyzed by SEC-HPLC. The SEC-HPLC chromatogram of B781401 is shown in FIG. 9 . Table 3 shows the performance and purification results of B781401-781406.

Table 3 Expression and purification of B781401-781406 produced in HEK293 cells Molecular ID Total protein yield (mg/100 ml) Purity measured by SEC at 280 nm Purity measured by SDS-PAGE Endotoxin (EU/mg) Theoretical molecular weight (reduced, KDa) Theoretical molecular weight (non-reduced, KDa) B781401 4.56 100% >95% <1 72/23 190 B781402 5.25 100% >95% <1 73/23 192 B781403 4.80 100% >95% <1 74/23 194 B781404 5.08 100% >95% <1 73/23 192 B781405 13.29 100% >95% <1 49/47 192 B781406 13.74 100% >95% <1 49/48 194

Genes encoding the amino acid sequences of B781401-781406 shown in SEQ ID NO: 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99 and 101 were synthesized, and constructed based on The expression vector of the vector pcDNA3.4 for expressing proteins. Expression vectors are used to transiently transfect CHO cells with chemically defined media. The resulting protein was purified by a protein A affinity column, ultrafiltered and then subjected to 0.2 μm sterile filtration to obtain large amounts of highly pure protein. Expression of B781401-781406 in CHO cells yielded a protein with a MW of ~200 KDa (non-reduced form on SDS-PAGE) with ~93% purity when analyzed by SEC-HPLC. The SEC-HPLC chromatogram of B781401 is shown in FIG. 10 . Table 4 shows the performance and purification results of B781401-781406.

Table 4 Expression and purification of B781401-781406 produced in CHO cells Molecular ID Total protein yield (mg/100 ml) Purity measured by SEC at 280 nm Purity measured by SDS-PAGE Endotoxin (EU/mg) Theoretical molecular weight (reduced, KDa) Theoretical molecular weight (non-reduced, KDa) B781401 30.22 90.3% >95% <1 72/23 190 B781402 24.62 93.0% >95% <1 73/23 192 B781403 26.68 94.8% >95% <1 74/23 194 B781404 22.68 95.2% >95% <1 73/23 192 B781405 33.47 94.2% >95% <1 49/47 192 B781406 26.63 90.3% >95% <1 49/48 194

Example 4: Comparison of the binding affinity of B781401-781406 and aflibercept (Eylea ^® ) for recombinant human VEGF-A ₁₆₅ using enzyme-linked immunosorbent assay (ELISA).

ELISA assays were performed using 96-well plates coated with recombinant human VEGF-A ₁₆₅ (2 μg/ml, 100 μl/well) at +4°C for 16 hours. After nonspecific blocking with 1% BSA for 1 hour at 25°C, serial dilutions of the test antibodies were added to the coated wells and incubated for 1 hour at 25°C. Bound Ab was detected using a secondary Ab conjugated to HRP (goat anti-human IgG1-Fc), followed by _OD450 reading. The binding affinities of B781401-781406 to recombinant human VEGF-A ₁₆₅ were in the subnanomole range and comparable to aflibercept. Figure 11 shows the results.

Example 5: Comparison of ELISA binding affinities of B781401-781406 and aflibercept to recombinant human VEGF- _B167 .

ELISA assays were performed using 96-well plates coated with recombinant human VEGF-B ₁₆₇ (2 μg/ml, 100 μl/well) for 16 hours at +4°C. After nonspecific blocking with 1% BSA for 1 hour at 25°C, serial dilutions of the test antibodies were added to the coated wells and incubated for 1 hour at 25°C. Bound Ab was detected using a secondary Ab conjugated to HRP (goat anti-human IgG1-Fc), followed by _OD450 reading. The binding affinities of B781401-781406 to recombinant human VEGF-B ₁₆₇ were in the subnanomore range and comparable to aflibercept. The results are shown in FIG. 12 .

Example 6: Comparison of ELISA binding affinities of B781401-781406 and aflibercept to recombinant human PlGF.

ELISA assays were performed using 96-well plates coated with recombinant human PlGF (2 μg/ml, 100 μl/well) for 16 hours at +4°C. After nonspecific blocking with 1% BSA for 1 hour at 25°C, serial dilutions of the test antibodies were added to the coated wells and incubated for 1 hour at 25°C. Bound Ab was detected using a secondary Ab conjugated to HRP (goat anti-human IgG1-Fc), followed by _OD450 reading. The binding affinities of B781401-781406 to recombinant human PlGF were in the sub-nanomole range and comparable to aflibercept. The results are shown in FIG. 13 .

Example 7: Comparison of ELISA binding affinity of B781401-781406 and tocilizumab to recombinant human IL-6R.

ELISA assays were performed using 96-well plates coated with recombinant human IL-6R (2 μg/ml, 100 μl/well) for 16 hours at +4°C. After nonspecific blocking with 1% BSA for 1 hour at 25°C, serial dilutions of the test antibodies were added to IL-6R-coated wells and incubated for 1 hour at 25°C. Bound Ab was detected using a secondary Ab conjugated to HRP (goat anti-human IgG1-Fc), followed by _OD450 reading. The binding affinity of B781401-781406 to recombinant human IL-6R was in the sub-nanomore range and comparable to tocilizumab. The results are shown in FIG. 17 .

Example 8: Comparison of the effect of B781401-781406 and aflibercept on inhibiting VEGF-A ₁₆₅ mediated VEGFR2 signaling in VEGFR2-NFAT-RE luciferase reporter cells.

Recombinant human VEGF-A ₁₆₅ was mixed with serially diluted test Abs, incubated for 30 min at room temperature, and then added to a culture medium containing ⁴ × 104 VEGFR2(KDR)-NFAT-RE luciferase reporter cells/well wells and incubated at 37°C for 6 hours. After adding 50 μl Bright-Lite, the luciferase signal was detected by a microplate reader. The VEGFR2 signaling luciferase assay was validated using Bevacizumab (Avastin) as a positive control (see Figure 15A). B781401-781406 were as effective as aflibercept in inhibiting VEGF-A ₁₆₅ -mediated VEGFR2 signaling (see Figure 15B).

Example 9: Comparison of the effect of B781401-781406 and tocilizumab on inhibiting IL-6R signaling.

Signal transducer and activator of transcription 3 (Signal transducer and activator of transcription 3 ( STAT3)) phosphorylation. The detection of phosphorylated STAT3 relates to a sandwich immunoassay comprising an anti-phospho-STAT3 antibody conjugated to an anti-total antibody fluorescently labeled with a donor or acceptor. Activation of IL-6/IL-6R signaling in TF-1 cells results in increased homogeneous time-resolved fluorescence (HTRF) signaling, whereas inhibition will exhibit the opposite effect. B781401, B781402, B781404 and B781405 showed comparable effects to tocilizumab in inhibiting STAT3 phosphorylation in TF-1 cells stimulated by recombinant human IL-6 ligand. The results are shown in FIG. 16 .

Example 10: Comparison of the effect of B781401-781406 on inhibition of IL-6R signaling with stuximab and tocilizumab.

Measurement of IL-6-mediated proliferation of TF-1 cells was performed using the CellTiter- ^Glo® Luminescent Cell Viability Assay with a kit obtained from Promega according to the manufacturer's instructions. Activation of IL-6R signaling in TF-1 cells leads to proliferation of TF-1 cells, which is reflected by increased luminescent signaling, whereas inhibition of IL-6R signaling will exhibit the opposite effect. B781404, B781405 and B781406 showed comparable efficacy in inhibiting the proliferation of TF-1 cells stimulated by recombinant human IL-6 ligand. Stuximab is a mAb directed against IL-6. The results are shown in FIG. 17 .

Table 5 shows the transient expression of B781401-781406 in HEK293 and CHO cells, ELISA binding affinities to human VEGF-A ₁₆₅ , VEGF-B ₁₆₇ , PlGF and IL-6R and in three cell-based functional assays. Summary summary of suppressions.

Table 5 Summary of B781401-781406 Profiles molecular Performance level (mg/100 ml) Ligand binding affinity (EC ₅₀ , nM) In vitro functional assessment (IC ₅₀ , nM) HEK293 CHO VEGF-A ₁₆₅ VEGF-B ₁₆₇ PlGF IL-6R VEGFR2 luciferase P-STAT3 TF-1 proliferation B781401 4.56 30.22 0.077 0.124 0.116 1.787 0.198 7.705 2.381 B781402 5.25 24.62 0.085 0.115 0.108 1.035 0.183 3.398 1.623 B781403 4.80 26.68 0.049 0.060 0.288 0.639 0.213 23.990 1.302 B781404 5.08 22.68 0.142 0.157 0.448 1.709 0.172 4.908 0.874 B781405 13.29 33.47 0.033 0.059 0.026 0.505 0.160 0.938 0.417 B781406 13.74 26.63 0.050 0.061 0.131 2.121 0.187 11.515 0.904 Aflibercept N/A N/A 0.034 0.865 0.281 N/A 0.113 N/A N/A Tocilizumab N/A N/A N/A N/A N/A 0.476 N/A 3.87/3.84 0.215

Example 11: Comparison of ELISA binding affinities of EB-DJ1, EB- _vvA , EB-vvB and EB-vvC with aflibercept, B781403 and B781405 for recombinant human VEGF-A165.

ELISA assays were performed using 96-well plates coated with recombinant human VEGF-A ₁₆₅ (2 μg/ml, 100 μl/well) at +4°C for 16 hours. After nonspecific blocking with 1% BSA for 1 hour at 25°C, serial dilutions of the test antibodies were added to the coated wells and incubated for 1 hour at 25°C. Bound Ab was detected using a secondary Ab conjugated to HRP (goat anti-human IgG1-Fc), followed by _OD450 reading. The binding affinities of EB-DJ1, EB-vvA, EB-vvB, and EB-vvC to recombinant human VEGF-A ₁₆₅ were in the subnanomole range and comparable to aflibercept, B781403, and B781405. The results are shown in FIG. 18 .

Example 12: Comparison of ELISA binding affinities of EB-DJ1, EB-vvA, EB-vvB and EB-vvC with aflibercept, B781402, B781403 and B781405 for recombinant human VEGF-B ₁₆₇ .

ELISA assays were performed using 96-well plates coated with recombinant human VEGF-B ₁₆₇ (2 μg/ml, 100 μl/well) for 16 hours at +4°C. After nonspecific blocking with 1% BSA for 1 hour at 25°C, serial dilutions of the test antibodies were added to VEGF-B ₁₆₇ -coated wells and incubated for 1 hour at 25°C. Bound Ab was detected using a secondary Ab conjugated to HRP (goat anti-human IgG1-Fc), followed by _OD450 reading. The binding affinities of EB-DJ1, EB-vvA, EB-vvB and EB-vvC to recombinant human VEGF-B ₁₆₇ were in the subnanomole range and comparable to aflibercept, B781402, B781403 and B781405. The results are shown in FIG. 19 .

Example 13: Comparison of ELISA binding affinities of EB-DJ1, EB-vvA, EB-vvB and EB-vvC with aflibercept, B781403 and B781405 for recombinant human PlGF.

ELISA assays were performed using 96-well plates coated with recombinant human PlGF (2 μg/ml, 100 μl/well) for 16 hours at +4°C. After nonspecific blocking with 1% BSA for 1 hour at 25°C, serially diluted test antibodies were added to the coated wells and incubated for 1 hour at 25°C. Bound Ab was detected using a secondary Ab conjugated to HRP (goat anti-human IgG1-Fc), followed by _OD450 reading. The binding affinities of EB-DJ1, EB-vvA, EB-vvB and EB-vvC to recombinant human PlGF were in the sub-nanomole range and comparable to aflibercept, B781403 and B781405. The results are shown in FIG. 20 .

Example 14: Comparison of ELISA binding affinities of EB-DJ1, EB-vvA, EB-vvB and EB-vvC with tocilizumab, B781402, B781403 and B781405 for recombinant human IL-6R.

ELISA assays were performed using 96-well plates coated with recombinant human IL-6R (2 μg/ml, 100 μl/well) for 16 hours at +4°C. After nonspecific blocking with 1% BSA for 1 hour at 25°C, serial dilutions of the test antibody were added to the Il-6R-coated wells and incubated for 1 hour at 25°C. Bound Ab was detected using a secondary Ab conjugated to HRP (goat anti-human IgG1-Fc), followed by _OD450 reading. The binding affinities of EB-DJ1, EB-vvA, EB-vvB, and EB-vvC to recombinant human IL-6R were in the sub-nanomore range and comparable to tocilizumab, B781402, B781403, and B781405. The results are shown in FIG. 21 .

A summary of the binding affinities of EB-DJ1 , EB-vvA, EB-vvB and EB-vvC to human VEGF-A ₁₆₅ , VEGF-B ₁₆₇ , PlGF and IL-6R is shown in Table 6.

Table 6 Summary of EB-DJ1, EB-vvA, EB-vvB and EB-vvC molecular Productivity of HEK293 cells (mg/L) Ligand binding affinity (EC ₅₀ , nM) VEGF-A ₁₆₅ VEGF-B ₁₆₇ PlGF IL-6R EB-DJ1 13.2 0.1722 2.6950 0.6845 0.0654 EB-vvA 17.9 0.2793 0.9110 0.9250 0.0504 EB-vvB 24.0 0.2046 0.3643 0.7140 0.0416 EB-vvC 13.2 0.2516 2.1875 0.3049 0.3847 B781402 52.5 undone 0.3130 undone 0.1862 B781403 48.0 0.3071 0.1379 0.9747 0.0432 B781405 132.9 0.1940 0.0766 0.3071 0.1707 Aflibercept N/A 0.2407 0.0697 3.4649 N/A Tocilizumab N/A N/A N/A N/A 0.0547

List of Nucleic Acid and Amino Acid Sequences

CAG GTG CAG CTG CAG GAA TCA GGG CCT GGT TTG GTG CGG CCG AGT CAG ACG CTC AGC TTG ACT TGT ACG GTG TCA GGT TAC TCT ATC ACT AGC GAT CAT GCC TGG AGC TGG GTA CGA CAA CCA CCG GGT CGG GGT CTC GAA TGG ATA GGT TAC ATA AGC TAC TCA GGA ATC ACG ACA TAC AAT CCC TCC CTT AAA AGT CGG GTC ACC ATG CTC CGA GAC ACT AGT AAA AAT CAG TTC TCC CTG CGG TTG TCC AGC GTG ACT GCT GCC GAC ACG GCG GTC TAT TAT TGC GCA AGA AGT CTG GCG CGG ACA ACG GCA ATG GAC TAC TGG GGA CAA GGT TCA CTG GTA ACC GTT AGT TCA GCA AGC ACC AAG GGT CCG TCT GTC TTT CCA CTC GCG CCT TCT AGC AAG TCA ACC TCA GGG GGG ACT GCC GCG CTT GGA TGT CTG GTC AAA GAT TAT TTT CCT GAG CCG GTA ACA GTT AGC TGG AAT TCA GGT GCC CTC ACA TCT GGG GTA CAC ACG TTT CCC GCC GTG CTT CAG AGC TCT GGC CTC TAC AGT CTT TCT AGC GTG GTC ACC GTC CCA TCT TCA TCA TTG GGT ACA CAA ACT TAC ATT TGT AAC GTT AAT CAC AAA CCT AGC AAC ACT AAG GTG GAT AAA AAA GTA GAG CCA AAG TCC TGC GAC AAG ACT CAC ACC TGT CCT CCC TGT CCA GCA CCC GAA CTT TTG GGC GGT CCT TCT GTT TTC CTG TTT CCT CCT AAA CCC AAAGAT ACA CTC ATG ATC TCC AGA ACC CCG GAA GTA ACC TGC GTA GTC GTG GAC GTA TCC CAT GAG GAT CCC GAG GTA AAA TTC AAC TGG TAC GTA GAC GGG GTC GAG GTG CAC AAT GCC AAG ACT AAA CCT AGG GAA GAG CAA TAC AAT AGT ACG TAC AGG GTG GTT TCC GTG CTG ACC GTC CTG CAT CAG GAT TGG CTC AAC GGG AAA GAG TAT AAA TGT AAG GTG TCA AAC AAA GCT TTG CCG GCA CCA ATA GAG AAA ACC ATT AGT AAG GCG AAA GGA CAA CCC CGA GAG CCA CAA GTG TAT ACG TTG CCT CCC AGC CGC GAG GAA ATG ACG AAG AAT CAA GTC TCT CTG ACT TGT CTG GTG AAG GGT TTT TAC CCG TCT GAT ATA GCT GTC GAA TGG GAG TCT AAC GGC CAG CCA GAG AAT AAT AAT TAC AAA ACC ACT CCT CCG GTC TTG GAT TCT GAT GGG AGC TTT TTC CTG TAT TCC AAA TTG ACA GTT GAT AAA AGT CGG TGG CAG CAG GGG AAC GTC TTC TCC TGT AGC GTC ATG CAT GAA GCA CTG CAT AAT CAT TAT ACC CAA AAA AGT TTG TCC TTG AGC CCT GGT (SEQ ID NO: 1)

QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG        (SEQ ID NO: 2)

GAC ATT CAA ATG ACT CAG TCT CCA TCC AGT CTC TCC GCT TCT GTG GGG GAC CGA GTA ACC ATA ACA TGT CGG GCA TCT CAG GAC ATA AGC TCA TAC TTG AAT TGG TAT CAG CAG AAA CCA GGG AAG GCG CCC AAG CTT CTT ATC TAC TAT ACA TCA AGA CTT CAT AGC GGG GTG CCA AGC CGA TTC AGT GGC AGC GGT TCA GGA ACA GAC TTT ACG TTC ACC ATT TCA TCT TTG CAG CCA GAA GAT ATA GCT ACG TAC TAC TGT CAG CAA GGA AAT ACG TTG CCG TAC ACC TTT GGC CAG GGC ACA AAA GTC GAA ATT AAG CGA ACC GTA GCA GCC CCG AGT GTC TTT ATC TTT CCT CCC TCA GAT GAG CAA CTT AAA AGC GGG ACA GCC TCA GTA GTT TGC CTC CTG AAC AAT TTC TAC CCA CGG GAA GCC AAG GTG CAG TGG AAG GTG GAC AAT GCT CTT CAG TCC GGC AAC TCT CAG GAA AGT GTT ACC GAG CAA GAC TCT AAA GAC TCA ACT TAC AGC CTC AGC TCC ACC CTC ACT TTG TCC AAG GCT GAT TAC GAA AAA CAT AAG GTA TAT GCC TGC GAA GTT ACG CAC CAA GGA CTT TCA TCC CCG GTG ACA AAG AGC TTC AAC AGA GGC GAA TGT (SEQ ID NO: 3)

DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC        (SEQ ID NO: 4)

TCC GAC ACA GGA CGC CCC TTC GTA GAA ATG TAC TCT GAG ATT CCG GAA ATC ATC CAT ATG ACT GAG GGC AGA GAG TTG GTC ATA CCA TGC AGA GTC ACT TCA CCA AAT ATA ACC GTG ACG TTG AAG AAA TTT CCC TTG GAC ACG TTG ATT CCC GAT GGT AAG CGG ATT ATA TGG GAC AGC CGC AAG GGC TTT ATA ATA AGT AAT GCA ACA TAT AAG GAA ATA GGT CTC CTC ACA TGC GAA GCT ACA GTC AAC GGC CAT CTC TAC AAG ACA AAT TAT CTT ACC CAC AGG CAG ACG AAC ACA ATA ATT (SEQ ID NO: 5)

SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTII (SEQ ID NO: 6)

GAC GTG GTT CTT TCA CCC TCA CAC GGT ATT GAG TTG TCA GTC GGT GAG AAG CTG GTC TTG AAC TGC ACG GCC AGA ACG GAA TTG AAC GTC GGC ATT GAT TTT AAC TGG GAA TAC CCG TCC TCT AAA CAC CAA CAC AAG AAG TTG GTC AAC CGC GAT CTG AAG ACC CAA TCC GGA AGT GAA ATG AAG AAA TTC TTG TCT ACT TTG ACC ATT GAT GGC GTC ACG AGA TCT GAT CAA GGG CTT TAC ACC TGC GCC GCG AGC TCT GGT CTT ATG ACC AAG AAG AAC AGT ACA TTT GTG CGG GTA CAT GAA AAA (SEQ ID NO: 7)

DVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEK (SEQ ID NO: 8)

TAT TCT ATG ACA CCG CCG ACC TTG AAC ATA ACC GAG GAA TCA CAT GTA ATA GAC ACA GGG GAC TCA CTT TCA ATC AGC TGT CGA GGC CAG CAC CCC CTG GAA TGG GCT TGG CCG GGG GCA CAA GAA GCA CCT GCT ACT GGT GAC AAG GAC AGC GAA GAT ACG GGA GTA GTT AGA GAC TGT GAG GGC ACA GAC GCT AGA CCT TAC TGC AAG GTC CTG CTT TTG CAT GAA GTG CAC GCT AAC GAC ACT GGG AGC TAT GTC TGC TAC TAC AAG TATA ATC AAA GCG CGG ATA GAG GGA ACG ACA GCT GCG TCA AGT TAT GTG TTC GTC AGA GAT TTT GAG CAA CCG TTT ATT AAT AAG CCT GAC ACG CTG CTT GTA AAT AGA AAA GAC GCC ATG TGG GTA CCA TGT CTG GTC AGT ATA CCT GGT CTC AAT GTG ACT CTT CGC TCT CAA AGC AGC GTG CTG TGG CCG GAC GGC CAG GAA GTG GTT TGG GAT GAC AGG CGG GGG ATG CTT GTT TCC ACT CCG CTT CTC CAT GAC GCC CTC TAC CTG CAA TGT GAA ACC ACG TGG GGT GAT CAA GAT TTC CTG TCT AAT CCC TTC TTG GTA CAT ATC ACC GGG AAC GAA CTC (SEQ ID NO: 9)

YSMTPPTLNITEESHVIDTGDSLSISCRGQHPLEWAWPGAQEAPATGDKDSEDTGVVRDCEGTDARPYCKVLLLHEVHANDTGSYVCYYKYIKARIEGTTAASSYVFVRDFEQPFINKPDTLLVNRKDAMWVPCLVSIPGLNVTLRSQSSVLWPDGQEVVWDDRRGMLVSTPLLHDALYLQCETTWGDQDFLSNPFLVHITGNEL        (SEQ ID NO:10)

GGA GAA GGT TCC GGT GAT GGA GGT GAG GGG AGC GGG GAT GGG GAA GGT (SEQ ID NO: 11)

GEGSGDGGE GSGDGEG (SEQ ID NO: 12)

GGA GGC TCA GGT GGC GGT GGT TCT GGC GGA GGA (SEQ ID NO: 13)

GGSGGG GSGGG (SEQ ID NO: 14)

ATG CCG TTG CTG CTG CTT TTG CCA CTC CTT TGG GCC GGG GCT TTG GCA (SEQ ID NO: 15)

MPLLLLLPLLWAGALA (SEQ ID NO: 16)

ATG CCT CTC CTC CTC CTC TTG CCC CTC CTT TGG GCC GGA GCC CTG GCT CAG GTG CAG CTG CAG GAA TCA GGG CCT GGT TTG GTG CGG CCG AGT CAG ACG CTC AGC TTG ACT TGT ACG GTG TCA GGT TAC TCT ATC ACT AGC GAT CAT GCC TGG AGC TGG GTA CGA CAA CCA CCG GGT CGG GGT CTC GAA TGG ATA GGT TAC ATA AGC TAC TCA GGA ATC ACG ACA TAC AAT CCC TCC CTT AAA AGT CGG GTC ACC ATG CTC CGA GAC ACT AGT AAA AAT CAG TTC TCC CTG CGG TTG TCC AGC GTG ACT GCT GCC GAC ACG GCG GTC TAT TAT TGC GCA AGA AGT CTG GCG CGG ACA ACG GCA ATG GAC TAC TGG GGA CAA GGT TCA CTG GTA ACC GTT AGT TCA GCA AGC ACC AAG GGT CCG TCT GTC TTT CCA CTC GCG CCT TCT AGC AAG TCA ACC TCA GGG GGG ACT GCC GCG CTT GGA TGT CTG GTC AAA GAT TAT TTT CCT GAG CCG GTA ACA GTT AGC TGG AAT TCA GGT GCC CTC ACA TCT GGG GTA CAC ACG TTT CCC GCC GTG CTT CAG AGC TCT GGC CTC TAC AGT CTT TCT AGC GTG GTC ACC GTC CCA TCT TCA TCA TTG GGT ACA CAA ACT TAC ATT TGT AAC GTT AAT CAC AAA CCT AGC AAC ACT AAG GTG GAT AAA AAA GTA GAG CCA AAG TCC TGC GAC AAG ACT CAC ACC TGT CCT CCC TGT CCA GCA CCCGAA CTT TTG GGC GGT CCT TCT GTT TTC CTG TTT CCT CCT AAA CCC AAA GAT ACA CTC ATG ATC TCC AGA ACC CCG GAA GTA ACC TGC GTA GTC GTG GAC GTA TCC CAT GAG GAT CCC GAG GTA AAA TTC AAC TGG TAC GTA GAC GGG GTC GAG GTG CAC AAT GCC AAG ACT AAA CCT AGG GAA GAG CAA TAC AAT AGT ACG TAC AGG GTG GTT TCC GTG CTG ACC GTC CTG CAT CAG GAT TGG CTC AAC GGG AAA GAG TAT AAA TGT AAG GTG TCA AAC AAA GCT TTG CCG GCA CCA ATA GAG AAA ACC ATT AGT AAG GCG AAA GGA CAA CCC CGA GAG CCA CAA GTG TAT ACG TTG CCT CCC AGC CGC GAG GAA ATG ACG AAG AAT CAA GTC TCT CTG ACT TGT CTG GTG AAG GGT TTT TAC CCG TCT GAT ATA GCT GTC GAA TGG GAG TCT AAC GGC CAG CCA GAG AAT AAT TAC AAA ACC ACT CCT CCG GTC TTG GAT TCT GAT GGG AGC TTT TTC CTG TAT TCC AAA TTG ACA GTT GAT AAA AGT CGG TGG CAG CAG GGG AAC GTC TTC TCC TGT AGC GTC ATG CAT GAA GCA CTG CAT AAT CAT TAT ACC CAA AAA AGT TTG TCC TTG AGC CCT GGT GGC GAG GGT TCA GGG GAT GGA GGC GAG GGG TCC GGG GAC GGC GAA GGC TCA GAT ACC GGA AGA CCA TTT GTG GAG ATG TAT TCC GAA ATA CCG GAG ATA ATA CAT ATGACG GAA GGT CGA GAA CTC GTC ATC CCA TGT CGC GTA ACC TCT CCA AAT ATC ACC GTA ACA CTC AAA AAA TTC CCT CTT GAC ACG TTG ATA CCG GAC GGC AAA AGA ATA ATA TGG GAT TCA AGG AAA GGA TTT ATA ATA AGC AAC GCC ACA TAC AAA GAG ATT GGG CTG CTC ACT TGT GAA GCC ACT GTT AAT GGG CAC TTG TAT AAG ACT AAT TAT CTC ACC CAC CGC CAG ACG AAT ACT ATA ATA GAT GTC GTT CTG AGC CCA AGT CAT GGG ATT GAA CTT TCT GTT GGC GAA AAG CTC GTG TTG AAT TGC ACT GCT AGG ACG GAG CTG AAT GTT GGT ATA GAT TTC AAT TGG GAA TAT CCT AGC TCT AAA CAC CAG CAC AAA AAA CTC GTT AAT CGC GAC TTG AAG ACG CAG TCA GGA TCA GAG ATG AAA AAG TTC CTC TCA ACG CTG ACT ATA GAT GGA GTA ACG AGA TCC GAC CAG GGA TTG TAC ACC TGC GCC GCG TCT TCC GGG CTC ATG ACA AAA AAA AAC AGC ACT TTC GTA CGC GTC CAT GAA AAA TAG (SEQ ID NO: 17)

MPLLLLLPLLWAGALAQVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGEGSGDGGEGSGDGEGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEK        (SEQ ID NO: 18)

ATG CCC TTG CTG CTG TTG CTG CCC CTT CTC TGG GCA GGG GCG CTG GCT GAC ATT CAA ATG ACT CAG TCT CCA TCC AGT CTC TCC GCT TCT GTG GGG GAC CGA GTA ACC ATA ACA TGT CGG GCA TCT CAG GAC ATA AGC TCA TAC TTG AAT TGG TAT CAG CAG AAA CCA GGG AAG GCG CCC AAG CTT CTT ATC TAC TAT ACA TCA AGA CTT CAT AGC GGG GTG CCA AGC CGA TTC AGT GGC AGC GGT TCA GGA ACA GAC TTT ACG TTC ACC ATT TCA TCT TTG CAG CCA GAA GAT ATA GCT ACG TAC TAC TGT CAG CAA GGA AAT ACG TTG CCG TAC ACC TTT GGC CAG GGC ACA AAA GTC GAA ATT AAG CGA ACC GTA GCA GCC CCG AGT GTC TTT ATC TTT CCT CCC TCA GAT GAG CAA CTT AAA AGC GGG ACA GCC TCA GTA GTT TGC CTC CTG AAC AAT TTC TAC CCA CGG GAA GCC AAG GTG CAG TGG AAG GTG GAC AAT GCT CTT CAG TCC GGC AAC TCT CAG GAA AGT GTT ACC GAG CAA GAC TCT AAA GAC TCA ACT TAC AGC CTC AGC TCC ACC CTC ACT TTG TCC AAG GCT GAT TAC GAA AAA CAT AAG GTA TAT GCC TGC GAA GTT ACG CAC CAA GGA CTT TCA TCC CCG GTG ACA AAG AGC TTC AAC AGA GGC GAA TGT GGA GAG GGG TCC GGC GAC GGC GGT GAA GGG TCT GGT GAT GGG GAA GGT TCC GAT ACC GGTCGA CCC TTC GTC GAG ATG TAT TCT GAG ATT CCG GAA ATC ATC CAC ATG ACC GAA GGA CGA GAG CTT GTA ATT CCT TGC CGA GTT ACA TCA CCC AAC ATA ACG GTG ACA CTC AAG AAG TTT CCT TTG GAT ACA TTG ATT CCG GAC GGG AAG CGC ATA ATT TGG GAT AGT AGA AAG GGT TTT ATT ATC AGC AAC GCT ACG TAT AAG GAG ATA GGT CTG CTC ACT TGT GAA GCC ACT GTG AAT GGG CAC CTG TAC AAA ACA AAT TAT CTC ACC CAC CGA CAG ACT AAC ACC ATT ATC GAT GTT GTT TTG TCT CCA TCT CAT GGA ATC GAA CTT AGT GTC GGA GAA AAG CTC GTA CTG AAT TGC ACA GCC CGA ACG GAA CTT AAT GTT GGG ATT GAC TTT AAT TGG GAG TAT CCG TCT TCT AAG CAT CAA CAC AAG AAG CTT GTT AAC AGG GATA CTC AAG ACG CAA TCC GGA TCA GAA ATG AAA AAA TTT CTC TCC ACT CTT ACT ATA GAT GGA GTC ACA CGC TCC GAC CAA GGT CTC TAC ACG TGC GCA GCT AGT AGT GGT CTG ATG ACC AAA AAG AAG AAC TCT ACG TTC GTG AGA GTA CAT GAG AAG TAG (SEQ ID NO: 19)

MPLLLLLPLLWAGALADIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGEGSGDGGEGSGDGEGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEK        (SEQ. ID. NO. 20)

ATG CCC CTG CTT CTC CTC TTG CCG TTG CTC TGG GCT GGT GCT TTG GCG CAA GTA CAA CTT CAA GAA TCA GGT CCC GGG CTC GTG CGG CCT TCA CAA ACA CTT AGC CTC ACC TGC ACT GTG TCC GGG TAT AGC ATA ACA AGT GAC CAC GCG TGG AGC TGG GTG CGG CAG CCT CCT GGT CGC GGC CTC GAG TGG ATT GGA TAC ATA TCC TAC TCA GGA ATC ACT ACA TAT AAT CCA AGT TTG AAA TCC CGA GTT ACC ATG TTG AGG GAC ACG AGT AAA AAT CAG TTC AGT CTG AGG TTG TCA AGC GTA ACG GCG GCT GAT ACG GCT GTT GTT TAT TAC TGT GCA AGA AGT TTG GCA CGA ACA ACC GCG ATG GAC TAC TGG GGT CAA GGC TCA TTG GTA ACT GTG AGC TCT GCG TCT ACC AAG GGC CCT AGC GTT TTT CCT CTG GCC CCT TCC TCC AAG TCC ACG TCC GGT GGA ACA GCT GCT CTC GGC TGT TTG GTA AAA GAT TAT TTC CCA GAA CCC GTT ACT GTG TCA TGG AAC TCT GGT GCT TTG ACA AGT GGA GTC CAT ACT TTT CCT GCC GTT CTG CAA TCA AGT GGG CTC TAT AGC TTG TCC TCA GTT GTC ACA GTA CCA TCA TCA AGC CTG GGT ACA CAG ACT TAT ATA TGC AAT GTG AAC CAC AAG CCT TCC AAT ACG AAA GTC GAC AAG AAG GTC GAG CCC AAG TCA TGC GAC AAG ACC CATA ACC TGC CCC CCA TGT CCA GCC CCCGAA CTG CTG GGC GGA CCC TCA GTC TTC CTC TTT CCA CCA AAG CCG AAA GAT ACC CTT ATG ATC TCT AGG ACC CCC GAG GTA ACG TGC GTT GTC GTC GAT GTG TCT CAC GAG GAC CCG GAG GTC AAG TTC AAT TGG TAC GTC GAT GGC GTC GAG GTT CAT AAC GCG AAG ACT AAA CCG AGG GAG GAA CAA TAC AAC TCT ACG TAC CGA GTA GTG TCC GTG TTG ACA GTA CTG CAT CAA GAT TGG CTC AAT GGT AAA GAA TAT AAA TGC AAG GTC TCT AAC AAA GCG TTG CCT GCG CCA ATC GAA AAA ACT ATT AGC AAA GCT AAG GGT CAA CCG CGA GAG CCT CAG GTA TAC ACG CTT CCT CCG TCC CGA GAA GAG ATG ACG AAA AAT CAA GTC TCC CTG ACA TGT CTT GTT AAG GGT TTT TAC CCT TCT GAC ATT GCT GTC GAA TGG GAG TCC AAT GGC CAG CCC GAG AAC AAC TAT AAG ACG ACG CCT CCC GTC TTG GAT AGT GAC GGA AGC TTT TTC CTG TAT TCT AAA TTG ACC GTG GAC AAG AGC CGG TGG CAA CAG GGT AAC GTC TTT TCA TGC TCC GTA ATG CAC GAG GCG CTT CAT AAC CAC TAC ACC CAA AAG AGT CTC TCA TTG TCT CCC GGT GGC GGT TCA GGT GGG GGG GGA AGC GGT GGT GGA TCT GAC ACT GGA CGG CCT TTC GTT GAG ATG TAC TCA GAA ATT CCG GAG ATC ATT CAC ATG ACA GAA GGG AGG GAGTTG GTG ATA CCT TGC CGG GTT ACA TCA CCA AAC ATA ACT GTA ACA CTC AAA AAA TTC CCC CTG GAT ACA CTT ATC CCT GAT GGA AAG CGA ATA ATA TGG GAC AGT AGA AAA GGA TTT ATC ATT AGC AAC GCA ACG TAT AAA GAA ATC GGA TTG CTT ACC TGC GAA GCG ACG GTG AAT GGC CAT CTG TAC AAA ACG AAC TAC CTC ACG CAC CGA CAA ACG AAC ACT ATC ATA GAT GTA GTT TTG AGT CCT AGT CAC GGT ATT GAG CTC AGC GTC GGG GAG AAA CTG GTC CTT AAC TGT ACT GCT AGA ACG GAA CTC AAC GTG GGT ATA GAT TTC AAC TGG GAG TAC CCG TCA TCC AAA CAT CAA CAC AAG AAA CTT GTC AAC CGA GAC CTG AAG ACA CAA TCT GGA TCA GAG ATG AAG AAG TTT TTG TCT ACT CTT ACA ATT GAT GGG GTC ACT CGG TCT GAT CAA GGA CTG TAT ACC TGC GCA GCC AGT TCA GGG TTG ATG ACT AAA AAA AAT TCC ACC TTC GTA CGA GTC CAC GAG AAG TAG (SEQ ID NO: 21)

MPLLLLLPLLWAGALAQVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSGGGGSGGGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEK        (SEQ ID NO: 22)

ATG CCT CTG CTC CTT CTC CTG CCA TTG TTG TGG GCT GGT GCG CTC GCA GAT ATT CAA ATG ACT CAG TCT CCT TCA AGC CTT TCC GCC TCA GTC GGC GAC AGA GTA ACA ATA ACT TGT CGG GCG TCT CAA GAT ATC TCC TCA TAT TTG AAT TGG TAC CAG CAA AAA CCC GGT AAA GCA CCA AAG CTT CTC ATC TAC TAT ACC TCA AGA CTG CAT TCC GGG GTG CCG AGC CGG TTT AGC GGA TCT GGA TCT GGA ACA GAC TTT ACA TTC ACG ATT TCC AGC CTG CAG CCG GAG GAT ATT GCC ACC TAT TAT TGT CAG CAG GGA AAC ACG TTG CCT TAC ACT TTC GGA CAG GGA ACC AAA GTG GAG ATA AAG AGG ACT GTT GCC GCA CCG AGC GTG TTT ATC TTT CCT CCT TCA GAT GAG CAG CTT AAG TCT GGT ACA GCC TCA GTT GTA TGT TTG CTG AAC AAC TTC TAC CCA AGG GAA GCT AAA GTA CAG TGG AAG GTT GAT AAT GCC CTT CAA TCC GGG AAC TCT CAA GAG TCT GTA ACA GAA CAA GAT AGT AAG GAC TCA ACG TAT AGC CTT TCC AGC ACG TTG ACG CTG AGT AAG GCA GAC TAT GAA AAG CAC AAG GTC TAC GCG TGC GAG GTG ACA CAC CAA GGC CTG TCT TCC CCT GTA ACC AAA AGC TTT AAC AGG GGT GAG TGC GGT GGA AGC GGC GGC GGC GGT TCT GGA GGC GGG TCA GAC ACT GGT CGA CCG TTT GTC GAGATG TAT TCT GAG ATA CCT GAG ATT ATC CAC ATG ACA GAA GGA CGG GAA CTG GTG ATC CCT TGC CGG GTA ACC TCA CCC AAT ATC ACC GTG ACA TTG AAA AAG TTT CCC CTT GAC ACA CTT ATA CCT GAC GGA AAG AGG ATC ATT TGG GAC AGT CGC AAG GGT TTC ATC ATT TCC AAC GCA ACA TAT AAA GAG ATA GGA CTT TTG ACG TGC GAA GCG ACG GTC AAT GGT CAC TTG TAC AAG ACG AAC TAT TTG ACC CAT AGA CAA ACG AAC ACT ATA ATA GAT GTT GTG CTT AGT CCA AGT CAC GGG ATA GAA TTG AGT GTA GGC GAG AAG CTT GTA CTC AAT TGT ACG GCC CGA ACC GAG CTC AAC GTT GGA ATA GAC TTC AAC TGG GAG TAC CCT AGC AGC AAG CAC CAA CAT AAG AAG CTT GTA AAC CGC GAT TTG AAG ACG CAG TCA GGC AGT GAA ATG AAA AAG TTC TTG TCC ACT TTG ACG ATT GAT GGT GTT ACG AGA TCA GAC CAG GGC TTG TAT ACC TGC GCA GCG TCA AGC GGG CTG ATG ACG AAG AAG AAC TCA ACT TTT GTC AGA GTT CAC GAA AAG TAG (SEQ ID NO: 23)

MPLLLLLPLLWAGALADIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGSGGGGSGGGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEK        (SEQ ID NO: 24)

ATG CCG CTT CTT TTG TTG CTC CCC CTG CTG TGG GCG GGG GCC CTC GCG CAA GTT CAA CTG CAG GAG AGC GGC CCG GGT TTG GTA CGA CCA AGC CAA ACA CTC TCA CTT ACA TGC ACC GTG TCA GGG TAT AGC ATT ACC TCA GAC CAC GCG TGG AGC TGG GTA CGG CAG CCG CCG GGT CGA GGC CTC GAG TGG ATA GGG TAT ATC TCT TAC TCA GGT ATT ACA ACA TAC AAC CCG TCT CTT AAG TCT CGC GTG ACC ATG CTG CGG GAT ACA AGC AAA AAC CAG TTC TCC CTC AGA CTG AGC TCT GTC ACT GCG GCC GAT ACT GCT GTC TAC TAT TGT GCT CGA AGT TTG GCG AGG ACA ACG GCT ATG GAC TAT TGG GGC CAA GGA TCC CTG GTA ACA GTT TCT TCT GCA AGT ACG AAA GGC CCA AGT GTG TTT CCA CTG GCT CCC TCC TCT AAG AGC ACT TCT GGG GGA ACG GCA GCT CTG GGC TGC CTT GTG AAG GAC TTT CCT GAG CCA GTA ACA GTC TCC TGG AAT TCA GGA GCC CTT ACT AGC GGT GTT CAT ACG TTC CCG GCC GTT CTG CAG AGT AGC GGG CTT TAC TCT CTG TCA TCT GTT GTG ACG GTT CCA TCC AGC AGC TTG GGC ACA CAG ACC TAC ATA TGC AAT GTC AAT CAC AAA CCT TCT AAT ACA AAG GTG GAT AAA AAA GTC GAG CCT AAG AGT TGC GAT AAG ACC CAT ACC TGT CCT CCA TGT CCC GCA CCAGAA CTT TTG GGC GGG CCA TCA GTG TTT CTG TTC CCC CCC AAG CCT AAA GAT ACC CTT ATG ATT AGT AGA ACA CCC GAA GTG ACC TGT GTA GTA GTG GAT GTT AGC CAT GAG GAC CCT GAA GTT AAA TTC AAT TGG TAT GTC GAT GGG GTT GAA GTT CAC AAT GCC AAA ACT AAG CCC CGC GAA GAA CAG TAT AAC AGT ACA TAT AGG GTC GTT TCA GTA CTG ACA GTA TTG CAC CAG GAC TGG TTG AAC GGA AAG GAG TAT AAG TGC AAA GTC AGC AAC AAA GCC CTG CCT GCA CCT ATC GAA AAA ACC ATC AGT AAG GCA AAG GGA CAG CCG AGG GAA CCG CAG GTG TAC ACG CTC CCC CCG TCC AGA GAA GAG ATG ACA AAG AAC CAG GTC AGC CTG ACA TGT TTG GTC AAG GGA TTC TAT CCG TCA GAC ATT GCC GTC GAG TGG GAG AGT AAT GGC CAG CCC GAG AAT AAT TAT AAA ACT ACT CCG CCC GTG CTT GAC TCC GAC GGG TCA TTT TTC CTC TAT AGC AAA CTG ACC GTG GAT AAG TCA AGA TGG CAA CAA GGT AAC GTC TTT AGT TGT AGT GTT ATG CAT GAG GCG CTT CAT AAC CAC TAT ACA CAG AAG AGT TTG AGT TTG TCA CCT GGT GGG GGG AGC GGT GGT GGA GGT TCT GGT GGT GGT TAT AGC ATG ACT CCA CCC ACC CTG AAC ATC ACT GAA GAA TCA CAT GTC ATC GAC ACT GGT GAC TCC TTG TCC ATAAGT TGC CGG GGG CAA CAC CCT CTG GAA TGG GCC TGG CCC GGT GCA CAG GAG GCC CCA GCG ACT GGC GAC AAG GAC TCA GAG GAC ACG GGG GTT GTC AGA GAT TGT GAG GGG ACT GAC GCG AGG CCG TAT TGC AAA GTT CTG CTG CTT CAT GAA GTG CAC GCA AAC GAT ACG GGA TCT TAC GTG TGC TAC TAC AAA TAT ATA AAG GCC CGG ATT GAA GGT ACG ACA GCG GCT TCA AGC TAC GTA TTC GTT AGG GAT TTC GAG CAA CCA TTC ATC AAC AAG CCT GAT ACA TTG TTG GTT AAC CGA AAA GAC GCC ATG TGG GTC CCT TGC CTC GTC TCC ATT CCG GGA CTT AAT GTA ACA CTC AGG AGC CAA AGT TCC GTC TTG TGG CCC GAC GGC CAA GAA GTA GTT TGG GAC GAC AGG CGA GGC ATG CTC GTG AGT ACG CCG CTG CTT CAT GAT GCG CTG TAC CTT CAA TGC GAG ACG ACT TGG GGT GAC CAA GAC TTT CTC TCT AAC CCT TTT CTG GTC CAT ATC ACA GGG AAC GAG CTC TAG (SEQ ID NO: 25)

MPLLLLLPLLWAGALAQVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSGGGGSGGGYSMTPPTLNITEESHVIDTGDSLSISCRGQHPLEWAWPGAQEAPATGDKDSEDTGVVRDCEGTDARPYCKVLLLHEVHANDTGSYVCYYKYIKARIEGTTAASSYVFVRDFEQPFINKPDTLLVNRKDAMWVPCLVSIPGLNVTLRSQSSVLWPDGQEVVWDDRRGMLVSTPLLHDALYLQCETTWGDQDFLSNPFLVHITGNEL        (SEQ ID NO: 26)

ATG CCC TTG CTC CTG TTG CTC CCC CTG CTC TGG GCA GGA GCT CTT GCT GAC ATA CAA ATG ACT CAA TCT CCT AGC TCA CTC TCC GCT AGT GTG GGC GAT CGG GTA ACC ATC ACA TGT CGG GCC AGC CAG GAC ATA TCT TCA TAT CTG AAT TGG TAT CAG CAG AAG CCA GGG AAG GCC CCT AAG CTG CTT ATC TAC TAC ACG TCA AGG TTG CAC TCA GGT GTC CCG TCT CGG TTC TCT GGT AGT GGG TCC GGG ACT GAC TTT ACA TTC ACA ATT AGT AGC CTC CAG CCC GAG GAC ATA GCG ACT TAC TAC TGC CAA CAG GGT AAT ACC TTG CCC TAC ACT TTC GGA CAA GGG ACC AAG GTT GAG ATT AAG CGA ACG GTC GCT GCT CCC AGT GTG TTC ATT TTT CCT CCG TCT GAT GAA CAG TTG AAA TCC GGG ACC GCT AGC GTT GTG TGT CTC CTG AAT AAC TTT TAC CCA AGG GAG GCC AAA GTT CAA TGG AAA GTA GAT AAC GCC TTG CAG AGT GGA AAC AGC CAG GAG AGT GTT ACT GAG CAA GAC TCA AAA GAT TCA ACC TAT AGC CTC AGC TCC ACT CTC ACG CTG AGC AAA GCT GAC TAC GAA AAG CAC AAG GTA TAT GCC TGC GAA GTT ACT CAT CAA GGA CTG AGC TCT CCA GTG ACG AAG AGT TTC AAC CGG GGG GAA TGC GGC GAA GGC TCC GGA GAC GGC GGT GAG GGA AGC GGC GAT GGA GAG GGG TCC GAT ACT GGCCGC CCC TTT GTG GAG ATG TAT TCT GAG ATC CCG GAG ATT ATA CAC ATG ACT GAG GGA CGA GAG CTC GTT ATC CCA TGT CGA GTA ACG AGT CCG AAT ATA ACG GTC ACG CTC AAA AAA TTT CCC TTG GAT ACC TTG ATA CCA GAT GGT AAG CGA ATA ATC TGG GAT TCT CGG AAA GGG TTT ATT ATC TCA AAC GCT ACG TAC AAA GAA ATA GGG CTT TTG ACT TGT GAG GCT ACA GTT AAT GGA CAT CTT TAT AAA ACG AAT TAT CTT ACG CAC CGA CAG ACA AAC ACC ATA ATA GAT GTT GTC CTT TCT CCC TCT CAT GGA ATT GAG TTG AGC GTG GGT GAA AAG TTG GTG CTG AAC TGC ACC GCT CGC ACT GAG CTT AAT GTC GGA ATT GAT TTT AAT TGG GAG TAC CCT TCA AGC AAA CAT CAG CAT AAG AAA CTG GTA AAT AGA GATA CTT AAA ACA CAG TCA GGT AGC GAA ATG AAA AAG TTC CTG AGT ACG TTG ACA ATC GAC GGT GTG ACT AGA TCC GAT CAA GGT CTC TAT ACA TGT GCC GCC AGT TCT GGT CTG ATG ACC AAA AAG AAT AGT ACA TTT GTT CGA GTT CAC GAG AAA TAG (SEQ ID NO: 27)

MPLLLLLPLLWAGALADIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGEGSGDGGEGSGDGEGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEK        (SEQ ID NO: 28)

ATG CCC CTC CTC CTT TTG CTT CCT CTG CTG TGG GCG GGC GCG CTG GCA CAA GTA CAA TTG CAA GAG AGC GGC CCA GGT CTC GTA AGG CCG TCC CAG ACT TTG TCT CTG ACA TGC ACA GTA TCA GGG TAT TCC ATC ACT AGT GAT CAC GCT TGG TCC TGG GTC CGA CAG CCG CCT GGG AGA GGC CTG GAG TGG ATA GGG TAC ATC TCC TAC TCC GGA ATA ACG ACG TAC AAC CCG AGT CTG AAG TCT CGA GTA ACC ATG CTG AGG GAT ACA AGC AAG AAT CAG TTT TCA TTG AGG CTC TCA TCC GTT ACA GCC GCC GAC ACA GCT GTC TAT TAT TGC GCT CGC AGT TTG GCC AGA ACC ACT GCA ATG GAT TAC TGG GGC CAA GGA TCC CTG GTT ACC GTC AGC TCA GCT AGC ACG AAA GGT CCA TCT GTT TTC CCA CTT GCA CCG TCC AGT AAG TCC ACC TCA GGC GGA ACC GCT GCC CTT GGA TGC CTG GTC AAG GAT TAT TTC CCC GAG CCA GTC ACA GTC AGC TGG AAC TCT GGA GCC CTC ACC AGC GGA GTT CAC ACG TTT CCC GCT GTC TTG CAA AGT TCC GGG CTC TAC AGT CTG AGC TCT GTA GTA ACC GTG CCC AGT TCA AGC CTT GGG ACC CAA ACT TAC ATA TGT AAT GTA AAT CAC AAG CCA AGC AAC ACT AAG GTG GAT AAA AAA GTC GAG CCG AAA TCC TGC GAC AAA ACA CAC ACG TGT CCT CCG TGT CCG GCT CCCGAA TTG CTT GGC GGC CCC TCC GTG TTT CTG TTC CCA CCG AAG CCA AAG GAC ACT CTG ATG ATC TCT CGC ACG CCA GAA GTG ACA TGC GTC GTT GTA GAC GTA TCA CAC GAA GAC CCC GAA GTT AAG TTT AAC TGG TAT GTG GAT GGA GTC GAA GTA CAT AAT GCC AAG ACG AAA CCA AGG GAA GAA CAA TAC AAT TCT ACA TAT CGG GTC GTG AGT GTT CTG ACG GTA TTG CAT CAA GAT TGG CTC AAC GGT AAA GAA TAC AAA TGT AAG GTG AGT AAT AAA GCG CTT CCC GCT CCA ATA GAG AAG ACA ATA TCC AAA GCT AAA GGT CAG CCA CGG GAG CCG CAA GTT TAT ACC TTG CCG CCT TCA AGA GAA GAG ATG ACA AAA AAC CAG GTT TCC CTT ACG TGC CTG GTG AAG GGA TTT TAC CCA AGT GAT ATA GCA GTT GAA TGG GAG AGC AAC GGT CAA CCA GAA AAC AAC TAC AAG ACT ACT CCC CCA GTT CTC GAC TCT GAT GGG TCT TTC TTT TTG TAC TCA AAA CTC ACC GTT GAC AAA TCA AGA TGG CAG CAA GGC AAC GTT TTT TCA TGT AGC GTC ATG CAT GAG GCC TTG CAC AAC CAC TAC ACG CAA AAA AGC CTC AGT TTG AGT CCC GGG GGT GGT AGT GGC GGT GGC GGT TCC GGC GGT GGG TAT TCT ATG ACA CCA CCC ACG CTC AAT ATT ACA GAG GAG AGC CAC GTA ATT GATA ACA GGT GAT TCT CTG TCC ATTAGT TGC AGG GGT CAA CAT CCG CTG GAA TGG GCC TGG CCG GGT GCG CAA GAA GCA CCC GCA ACA GGA GAT AAA GAC TCC GAA GAT ACG GGG GTG GTC AGA GAT TGT GAA GGG ACA GAT GCA AGG CCT TAT TGT AAG GTT TTG CTT CTC CAC GAG GTA CAT GCG AAC GAT ACT GGG TCT TAC GTG TGT TAC TAC AAG TAT ATC AAA GCT AGG ATC GAG GGG ACT ACC GCC GCG AGT TCT TAT GTT TTT GTC CGA GAC TTC GAG CAG CCG TTC ATC AAT AAA CCT GAC ACA CTG TTG GTA AAC CGG AAA GAC GCC ATG TGG GTG CCT TGT CTT GTT TCT ATC CCG GGT CTG AAC GTC ACT CTT AGG AGT CAG TCC AGC GTC CTC TGG CCC GAT GGC CAG GAG GTC GTC TGG GAT GAC AGA AGG GGC ATG TTG GTA TCC ACT CCG CTT TTG CAC GAT GCG CTG TAC CTT CAG TGT GAG ACC ACT TGG GGT GAC CAA GAT TTT CTC TCA AAT CCC TTT CTG GTC CAC ATA ACC GGC AAC GAG CTC TAG (SEQ ID NO: 29)

MPLLLLLPLLWAGALAQVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSGGGGSGGGYSMTPPTLNITEESHVIDTGDSLSISCRGQHPLEWAWPGAQEAPATGDKDSEDTGVVRDCEGTDARPYCKVLLLHEVHANDTGSYVCYYKYIKARIEGTTAASSYVFVRDFEQPFINKPDTLLVNRKDAMWVPCLVSIPGLNVTLRSQSSVLWPDGQEVVWDDRRGMLVSTPLLHDALYLQCETTWGDQDFLSNPFLVHITGNEL        (SEQ ID NO: 30)

ATG CCG CTC CTG CTT CTT CTC CCA CTC CTC TGG GCC GGA GCG CTT GCC GAC ATA CAG ATG ACC CAG TCC CCT AGT AGC CTC AGC GCA AGC GTT GGA GAT CGG GTG ACT ATA ACG TGC CGA GCG TCC CAA GAC ATT TCT TCT TAT TTG AAT TGG TAT CAA CAA AAA CCA GGG AAA GCC CCG AAA CTG CTG ATT TAT ACC AGT CGA CTG CAC TCC GGA GTC CCT AGT CGG TTC AGC GGG TCT GGA TCA GGT ACT GAT TTT ACC TTT ACT ATA AGC TCA CTC CAG CCA GAG GAC ATT GCG ACC TAT TAT TGC CAG CAG GGA AAC ACA CTT CCG TAC ACG TTT GGC CAG GGG ACC AAA GTT GAA ATC AAG AGG ACC GTG GCA GCC CCC TCA GTT TTC ATA TTC CCT CCG TCT GAC GAG CAG TTG AAG TCA GGG ACT GCA TCC GTG GTG TGT CTG CTG AAT AAT TTC TAC CCA CGC GAG GCC AAG GTG CAG TGG AAG GTA GAT AAT GCT CTC CAA TCC GGG AAC AGC CAA GAG TCT GTT ACT GAA CAA GAT TCC AAA GAC TCT ACC TAT AGC CTC TCA AGC ACC CTT ACA CTT AGT AAG GCG GAT TAC GAA AAA CAC AAA GTC TAC GCA TGT GAA GTG ACC CAT CAG GGT CTC AGC AGC CCG GTC ACT AAA AGC TTT AAC AGG GGG GAA TGT GGG GGG AGT GGT GGT GGA GGT AGC GGC GGT GGC TCC GAC ACC GGA AGG CCT TTC GTA GAGATG TAT TCA GAA ATT CCC GAA ATT ATA CAT ATG ACG GAA GGC AGA GAG CTG GTC ATA CCG TGT AGA GTA ACA TCA CCC AAC ATA ACT GTT ACG CTT AAA AAG TTC CCA CTT GAC ACA CTT ATA CCC GAC GGC AAG AGA ATA ATC TGG GAC AGC AGA AAA GGT TTC ATC ATC TCC AAT GCT ACT TAT AAA GAG ATC GGG CTC CTG ACG TGC GAG GCG ACC GTA AAC GGG CAT TTG TAC AAA ACC AAC TAT CTC ACT CAT AGA CAA ACA AAC ACT ATT ATT GAT GTG GTG CTC AGC CCC TCT CAT GGG ATC GAG CTT TCC GTA GGT GAA AAG CTG GTC CTG AAC TGC ACA GCA CGG ACT GAG TTG AAT GTA GGG ATA GAT TTC AAC TGG GAA TAC CCG TCT TCA AAA CAT CAG CAC AAA AAG CTT GTG AAT CGC GAC CTC AAG ACA CAA TCA GGG TCA GAA ATG AAA AAG TTT CTC TCA ACG CTG ACT ATC GAC GGC GTC ACG CGG TCC GAT CAG GGC CTT TAC ACT TGT GCG GCC TCT TCT GGG TTG ATG ACG AAG AAA AAC AGT ACG TTT GTA CGC GTA CAT GAG AAG TAG (SEQ ID NO: 31)

MPLLLLLPLLWAGALADIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGSGGGGSGGGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEK        (SEQ ID NO: 32)

CAG GTG CAG CTG CAG GAATCA GGG CCT GGT TTG GTG CGG CCG AGT CAG ACG CTC AGC TTG ACT TGT ACG GTG TCA GGT TAC TCTATC ACT AGC GAT CAT GCC TGG AGC TGG GTA CGA CAA CCA CCG GGT CGG GGT CTC GAA TGG ATA GGT TAC ATA AGC TAC TCA GGA ATC ACG ACA TAC AAT CCC TCC CTT AAA AGT CGG GTC ACC ATG CTC CGA GAC ACT AGT AAA AAT CAG TTC TCC CTG CGG TTG TCC AGC GTG ACT GCT GCC GAC ACG GCG GTC TAT TAT TGC GCA AGA AGT CTG GCG CGG ACA ACG GCA ATG GAC TAC TGG GGA CAA GGT TCA CTG GTA ACC GTT AGT TCA GCA AGC ACC AAG GGT CCG TCT GTC TTT CCA CTC GCG CCT TCT AGC AAG TCA ACC TCA GGG GGG ACT GCC GCG CTT GGA TGT CTG GTC AAA GAT TAT TTT CCT GAG CCG GTA ACA GTT AGC TGG AAT TCA GGT GCC CTC ACA TCT GGG GTA CAC ACG TTT CCC GCC GTG CTT CAG AGC TCT GGC CTC TAC AGT CTT TCT AGC GTG GTC ACC GTC CCA TCT TCA TCA TTG GGT ACA CAA ACT TAC ATT TGT AAC GTT AAT CAC AAA CCT AGC AAC ACT AAG GTG GAT AAA AAA GTA GAG CCA AAG TCC TGC GAC AAG ACT CAC ACC TGT CCT CCC TGT CCA GCA CCC GAA CTT TTG GGC GGT CCT TCT GTT TTC CTG TTT CCT CCT AAA CCC AAA GA T ACA CTC ATG ATC TCC AGA ACC CCG GAA GTA ACC TGC GTA GTC GTG GAC GTA TCC CAT GAG GAT CCC GAG GTA AAA TTC AAC TGG TAC GTA GAC GGG GTC GAG GTG CAC AAT GCC AAG ACT AAA CCT AGG GAA GAG CAA TAC AAT AGT ACG TAC AGG GTG GTT TCC GTG CTG ACC GTC CTG CAT CAG GAT TGG CTC AAC GGG AAA GAG TAT AAA TGT AAG GTG TCA AAC AAA GCT TTG CCG GCA CCA ATA GAG AAA ACC ATT AGT AAG GCG AAA GGA CAA CCC CGA GAG CCA CAA GTG TAT ACG TTG CCT CCC AGC CGC GAG GAA ATG ACG AAG AAT CAA GTC TCT CTG ACT TGT CTG GTG AAG GGT TTT TAC CCG TCT GAT ATA GCT GTC GAA TGG GAG TCT AAC GGC CAG CCA GAG AAT AAT AAT TAC AAA ACC ACT CCT CCG GTC TTG GAT TCT GAT GGG AGC TTT TTC CTG TAT TCC AAA TTG ACA GTT GAT AAA AGT CGG TGG CAG CAG GGG AAC GTC TTC TCC TGT AGC GTC ATG CAT GAA GCA CTG CAT AAT CAT TAT ACC CAA AAA AGT TTG TCC TTG AGC CCT GGT GGC GAG GGT TCA GGG GAT GGA GGC GAG GGG TCC GGG GAC GGC GAA GGC TCA GAT ACC GGA AGA CCA TTT GTG GAG ATG TAT TCC GAA ATA CCG GAG ATA ATA CAT ATG ACG GAA GGT CGA GAA CTC GTC ATC CCA TGT CGC GTA ACC TCT CCA AAT AT C ACC GTA ACA CTC AAA AAA TTC CCT CTT GAC ACG TTG ATA CCG GAC GGC AAA AGA ATA ATA TGG GAT TCA AGG AAA GGA TTT ATA ATA AGC AAC GCC ACA TAC AAA GAG ATT GGG CTG CTC ACT TGT GAA GCC ACT GTT AAT GGG CAC TTG TAT AAG ACT AAT TAT CTC ACC CAC CGC CAG ACG AAT ACT ATA ATA GAT GTT CTG AGC CCA AGT CAT GGG ATT GAA CTT TCT GTT GGC GAA AAG CTC GTG TTG AAT TGC ACT GCT AGG ACG GAG CTG AAT GTT GGT ATA GAT TTC AAT TGG GAA TAT CCT AGC TCT AAA CAC CAG CAC AAA AAA CTC GTT AAT CGC GAC TTG AAG ACG CAG TCA GGA TCA GAG ATG AAA AAG TTC CTC TCA ACG CTG ACT ATA GAT GGA GTA ACG AGA TCC GAC CAG GGA TTG TAC ACC TGC GCC GCG TCT TCC GGG CTC ATG ACA AAA AAA AAC AGC ACT TTC GTA CGC GTC CAT GAA AAA TAG (SEQ ID NO: 33)

QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGEGSGDGGEGSGDGEGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEK                (SEQ ID NO: 34)

GAC ATT CAA ATG ACT CAG TCT CCA TCC AGT CTC TCC GCT TCT GTG GGG GAC CGA GTA ACC ATA ACA TGT CGG GCA TCT CAG GAC ATA AGC TCA TAC TTG AAT TGG TAT CAG CAG AAA CCA GGG AAG GCG CCC AAG CTT CTT ATC TAC TAT ACA TCA AGA CTT CAT AGC GGG GTG CCA AGC CGA TTC AGT GGC AGC GGT TCA GGA ACA GAC TTT ACG TTC ACC ATT TCA TCT TTG CAG CCA GAA GAT ATA GCT ACG TAC TAC TGT CAG CAA GGA AAT ACG TTG CCG TAC ACC TTT GGC CAG GGC ACA AAA GTC GAA ATT AAG CGA ACC GTA GCA GCC CCG AGT GTC TTT ATC TTT CCT CCC TCA GAT GAG CAA CTT AAA AGC GGG ACA GCC TCA GTA GTT TGC CTC CTG AAC AAT TTC TAC CCA CGG GAA GCC AAG GTG CAG TGG AAG GTG GAC AAT GCT CTT CAG TCC GGC AAC TCT CAG GAA AGT GTT ACC GAG CAA GAC TCT AAA GAC TCA ACT TAC AGC CTC AGC TCC ACC CTC ACT TTG TCC AAG GCT GAT TAC GAA AAA CAT AAG GTA TAT GCC TGC GAA GTT ACG CAC CAA GGA CTT TCA TCC CCG GTG ACA AAG AGC TTC AAC AGA GGC GAA TGT GGA GAG GGG TCC GGC GAC GGC GGT GAA GGG TCT GGT GAT GGG GAA GGT TCC GAT ACC GGT CGA CCC TTC GTC GAG ATG TAT TCT GAG ATT CCG GAA ATC ATC CAC ATGACC GAA GGA CGA GAG CTT GTA ATT CCT TGC CGA GTT ACA TCA CCC AAC ATA ACG GTG ACA CTC AAG AAG TTT CCT TTG GAT ACA TTG ATT CCG GAC GGG AAG CGC ATA ATT TGG GAT AGT AGA AAG GGT TTT ATT ATC AGC AAC GCT ACG TAT AAG GAG ATA GGT CTG CTC ACT TGT GAA GCC ACT GTG AAT GGG CAC CTG TAC AAA ACA AAT TAT CTC ACC CAC CGA CAG ACT AAC ACC ATT ATC GAT GTT GTT TTG TCT CCA TCT CAT GGA ATC GAA CTT AGT GTC GGA GAA AAG CTC GTA CTG AAT TGC ACA GCC CGA ACG GAA CTT AAT GTT GGG ATT GAC TTT AAT TGG GAG TAT CCG TCT TCT AAG CAT CAA CAC AAG AAG CTT GTT AAC AGG GAT CTC AAG ACG CAA TCC GGA TCA GAA ATG AAA AAA TTT CTC TCC ACT CTT ACT ATA GAT GGA GTC ACA CGC TCC GAC CAA GGT CTC TAC ACG TGC GCA GCT AGT AGT GGT CTG ATG ACC AAA AAG AAC TCT ACG TTC GTG AGA GTA CAT GAG AAG TAG (SEQ ID NO: 35)

DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGEGSGDGGEGSGDGEGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEK        (SEQ. ID. NO. 36)

CAA GTA CAA CTT CAA GAA TCA GGT CCC GGG CTC GTG CGG CCT TCA CAA ACA CTT AGC CTC ACC TGC ACT GTG TCC GGG TAT AGC ATA ACA AGT GAC CAC GCG TGG AGC TGG GTG CGG CAG CCT CCT GGT CGC GGC CTC GAG TGG ATT GGA TAC ATA TCC TAC TCA GGA ATC ACT ACA TAT AAT CCA AGT TTG AAA TCC CGA GTT ACC ATG TTG AGG GAC ACG AGT AAA AAT CAG TTC AGT CTG AGG TTG TCA AGC GTA ACG GCG GCT GAT ACG GCT GTT TAT TAC TGT GCA AGA AGT TTG GCA CGA ACA ACC GCG ATG GAC TAC TGG GGT CAA GGC TCA TTG GTA ACT GTG AGC TCT GCG TCT ACC AAG GGC CCT AGC GTT TTT CCT CTG GCC CCT TCC TCC AAG TCC ACG TCC GGT GGA ACA GCT GCT CTC GGC TGT TTG GTA AAA GAT TAT TTC CCA GAA CCC GTT ACT GTG TCA TGG AAC TCT GGT GCT TTG ACA AGT GGA GTC CAT ACT TTT CCT GCC GTT CTG CAA TCA AGT GGG CTC TAT AGC TTG TCC TCA GTT GTC ACA GTA CCA TCA TCA AGC CTG GGT ACA CAG ACT TAT ATA TGC AAT GTG AAC CAC AAG CCT TCC AAT ACG AAA GTC GAC AAG AAG AAG GTC GAG CCC AAG TCA TGC GAC AAG ACC CAT ACC TGC CCC CCA TGT CCA GCC CCC GAA CTG CTG GGC GGA CCC TCA GTC TTC CTC TTT CCA CCA AAG CCG AAAGAT ACC CTT ATG ATC TCT AGG ACC CCC GAG GTA ACG TGC GTT GTC GTC GAT GTG TCT CAC GAG GAC CCG GAG GTC AAG TTC AAT TGG TAC GTC GAT GGC GTC GAG GTT CAT AAC GCG AAG ACT AAA CCG AGG GAG GAA CAA TAC AAC TCT ACG TAC CGA GTA GTG TCC GTG TTG ACA GTA CTG CAT CAA GAT TGG CTC AAT GGT AAA GAA TAT AAA TGC AAG GTC TCT AAC AAA GCG TTG CCT GCG CCA ATC GAA AAA ACT ATT AGC AAA GCT AAG GGT CAA CCG CGA GAG CCT CAG GTA TAC ACG CTT CCT CCG TCC CGA GAA GAG ATG ACG AAA AAT CAA GTC TCC CTG ACA TGT CTT GTT AAG GGT TTT TAC CCT TCT GAC ATT GCT GTC GAA TGG GAG TCC AAT GGC CAG CCC GAG AAC AAC TAT AAG ACG ACG CCT CCC GTC TTG GAT AGT GAC GGA AGC TTT TTC CTG TAT TCT AAA TTG ACC GTG GAC AAG AGC CGG TGG CAA CAG GGT AAC GTC TTT TCA TGC TCC GTA ATG CAC GAG GCG CTT CAT AAC CAC TAC ACC CAA AAG AGT CTC TCA TTG TCT CCC GGT GGC GGT TCA GGT GGG GGG GGA AGC GGT GGT GGA TCT GAC ACT GGA CGG CCT TTC GTT GAG ATG TAC TCA GAA ATT CCG GAG ATC ATT CAC ATG ACA GAA GGG AGG GAG TTG GTG ATA CCT TGC CGG GTT ACA TCA CCA AAC ATA ACT GTA ACA CTCAAA AAA TTC CCC CTG GAT ACA CTT ATC CCT GAT GGA AAG CGA ATA ATA TGG GAC AGT AGA AAA GGA TTT ATC ATT AGC AAC GCA ACG TAT AAA GAA ATC GGA TTG CTT ACC TGC GAA GCG ACG GTG AAT GGC CAT CTG TAC AAA ACG AAC TAC CTC ACG CAC CGA CAA ACG AAC ACT ATC ATA GAT GTA GTT TTG AGT CCT AGT CAC GGT ATT GAG CTC AGC GTC GGG GAG AAA CTG GTC CTT AAC TGT ACT GCT AGA ACG GAA CTC AAC GTG GGT ATA GAT TTC AAC TGG GAG TAC CCG TCA TCC AAA CAT CAA CAC AAG AAA CTT GTC AAC CGA GAC CTG AAG ACA CAA TCT GGA TCA GAG ATG AAG AAG TTT TTG TCT ACT CTT ACA ATT GAT GGG GTC ACT CGG TCT GAT CAA GGA CTG TAT ACC TGC GCA GCC AGT TCA GGG TTG ATG ACT AAA AAA AAT TCC ACC TTC GTA CGA GTC CAC GAG AAG TAG (SEQ ID NO: 37)

QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSGGGGSGGGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEK        (SEQ ID NO: 38)

GAT ATT CAA ATG ACT CAG TCT CCT TCA AGC CTT TCC GCC TCA GTC GGC GAC AGA GTA ACA ATA ACT TGT CGG GCG TCT CAA GAT ATC TCC TAT TTG AAT TGG TAC CAG CAA AAA CCC GGT AAA GCA CCA AAG CTT CTC ATC TAC TAT ACC TCA AGA CTG CAT TCC GGG GTG CCG AGC CGG TTT AGC GGA TCT GGA TCT GGA ACA GAC TTT ACA TTC ACG ATT TCC AGC CTG CAG CCG GAG GAT ATT GCC ACC TAT TAT TGT CAG CAG GGA AAC ACG TTG CCT TAC ACT TTC GGA CAG GGA ACC AAA GTG GAG ATA AAG AGG ACT GTT GCC GCA CCG AGC GTG TTT ATC TTT CCT CCT TCA GAT GAG CAG CTT AAG TCT GGT ACA GCC TCA GTT GTA TGT TTG CTG AAC AAC TTC TAC CCA AGG GAA GCT AAA GTA CAG TGG AAG GTT GAT AAT GCC CTT CAA TCC GGG AAC TCT CAA GAG TCT GTA ACA GAA CAA GAT AGT AAG GAC TCA ACG TAT AGC CTT TCC AGC ACG TTG ACG CTG AGT AAG GCA GAC TAT GAA AAG CAC AAG GTC TAC GCG TGC GAG GTG ACA CAC CAA GGC CTG TCT TCC CCT GTA ACC AAA AGC TTT AAC AGG GGT GAG TGC GGT GGA AGC GGC GGC GGC GGT TCT GGA GGC GGG TCA GAC ACT GGT CGA CCG TTT GTC GAG ATG TAT TCT GAG ATA CCT GAG ATT ATC CAC ATG ACA GAA GGA CGG GAACTG GTG ATC CCT TGC CGG GTA ACC TCA CCC AAT ATC ACC GTG ACA TTG AAA AAG TTT CCC CTT GAC ACA CTT ATA CCT GAC GGA AAG AGG ATC ATT TGG GAC AGT CGC AAG GGT TTC ATC ATT TCC AAC GCA ACA TAT AAA GAG ATA GGA CTT TTG ACG TGC GAA GCG ACG GTC AAT GGT CAC TTG TAC AAG ACG AAC TAT TTG ACC CAT AGA CAA ACG AAC ACT ATA ATA GAT GTT GTG CTT AGT CCA AGT CAC GGG ATA GAA TTG AGT GTA GGC GAG AAG CTT GTA CTC AAT TGT ACG GCC CGA ACC GAG CTC AAC GTT GGA ATA GAC TTC AAC TGG GAG TAC CCT AGC AGC AAG CAC CAA CAT AAG AAG CTT GTA AAC CGC GAT TTG AAG ACG CAG TCA GGC AGT GAA ATG AAA AAG TTC TTG TCC ACT TTG ACG ATT GAT GGT GTT ACG AGA TCA GAC CAG GGC TTG TAT ACC TGC GCA GCG TCA AGC GGG CTG ATG ACG AAG AAG AAC TCA ACT TTT GTC AGA GTT CAC GAA AAG TAG (SEQ ID NO: 39)

DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGSGGGGSGGGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEK                (SEQ ID NO: 40)

CAA GTT CAA CTG CAG GAG AGC GGC CCG GGT TTG GTA CGA CCA AGC CAA ACA CTC TCA CTT ACA TGC ACC GTG TCA GGG TAT AGC ATT ACC TCA GAC CAC GCG TGG AGC TGG GTA CGG CAG CCG CCG GGT CGA GGC CTC GAG TGG ATA GGG TAT ATC TCT TAC TCA GGT ATT ACA ACA TAC AAC CCG TCT CTT AAG TCT CGC GTG ACC ATG CTG CGG GAT ACA AGC AAA AAC CAG TTC TCC CTC AGA CTG AGC TCT GTC ACT GCG GCC GAT ACT GCT GTC TAC TAT TGT GCT CGA AGT TTG GCG AGG ACA ACG GCT ATG GAC TAT TGG GGC CAA GGA TCC CTG GTA ACA GTT TCT TCT GCA AGT ACG AAA GGC CCA AGT GTG TTT CCA CTG GCT CCC TCC TCT AAG AGC ACT TCT GGG GGA ACG GCA GCT CTG GGC TGC CTT GTG AAG GAC TAC TTT CCT GAG CCA GTA ACA GTC TCC TGG AAT TCA GGA GCC CTT ACT AGC GGT GTT CAT ACG TTC CCG GCC GTT CTG CAG AGT AGC GGG CTT TAC TCT CTG TCA TCT GTT GTG ACG GTT CCA TCC AGC AGC TTG GGC ACA CAG ACC TAC ATA TGC AAT GTC AAT CAC AAA CCT TCT AAT ACA AAG GTG GAT AAA AAA GTC GAG CCT AAG AGT TGC GAT AAG AAG ACC CAT ACC TGT CCT CCA TGT CCC GCA CCA GAA CTT TTG GGC GGG CCA TCA GTG TTT CTG TTC CCC CCC AAG CCT AAAGAT ACC CTT ATG ATT AGT AGA ACA CCC GAA GTG ACC TGT GTA GTA GTG GAT GTT AGC CAT GAG GAC CCT GAA GTT AAA TTC AAT TGG TAT GTC GAT GGG GTT GAA GTT CAC AAT GCC AAA ACT AAG CCC CGC GAA GAA CAG TAT AAC AGT ACA TAT AGG GTC GTT TCA GTA CTG ACA GTA TTG CAC CAG GAC TGG TTG AAC GGA AAG GAG TAT AAG TGC AAA GTC AGC AAC AAA GCC CTG CCT GCA CCT ATC GAA AAA ACC ATC AGT AAG GCA AAG GGA CAG CCG AGG GAA CCG CAG GTG TAC ACG CTC CCC CCG TCC AGA GAA GAG ATG ACA AAG AAC CAG GTC AGC CTG ACA TGT TTG GTC AAG GGA TTC TAT CCG TCA GAC ATT GCC GTC GAG TGG GAG AGT AAT GGC CAG CCC GAG AAT AAT TAT AAA ACT ACT CCG CCC GTG CTT GAC TCC GAC GGG TCA TTT TTC CTC TAT AGC AAA CTG ACC GTG GAT AAG TCA AGA TGG CAA CAA GGT AAC GTC TTT AGT TGT AGT GTT ATG CAT GAG GCG CTT CAT AAC CAC TAT ACA CAG AAG AGT TTG AGT TTG TCA CCT GGT GGG GGG AGC GGT GGT GGA GGT TCT GGT GGT GGT TAT AGC ATG ACT CCA CCC ACC CTG AAC ATC ACT GAA GAA TCA CAT GTC ATC GAC ACT GGT GAC TCC TTG TCC ATA AGT TGC CGG GGG CAA CAC CCT CTG GAA TGG GCC TGG CCC GGT GCA CAGGAG GCC CCA GCG ACT GGC GAC AAG GAC TCA GAG GAC ACG GGG GTT GTC AGA GAT TGT GAG GGG ACT GAC GCG AGG CCG TAT TGC AAA GTT CTG CTG CTT CAT GAA GTG CAC GCA AAC GAT ACG GGA TCT TAC GTG TGC TAC TAC AAA TAT ATA AAG GCC CGG ATT GAA GGT ACG ACA GCG GCT TCA AGC TAC GTA TTC GTT AGG GAT TTC GAG CAA CCA TTC ATC AAC AAG CCT GAT ACA TTG TTG GTT AAC CGA AAA GAC GCC ATG TGG GTC CCT TGC CTC GTC TCC ATT CCG GGA CTT AAT GTA ACA CTC AGG AGC CAA AGT TCC GTC TTG TGG CCC GAC GGC CAA GAA GTA GTT TGG GAC GAC AGG CGA GGC ATG CTC GTG AGT ACG CCG CTG CTT CAT GAT GCG CTG TAC CTT CAA TGC GAG ACG ACT TGG GGT GAC CAA GAC TTT CTC TCT AAC CCT TTT CTG GTC CAT ATC ACA GGG AAC GAG CTC TAG (SEQ ID NO: 41)

QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSGGGGSGGGYSMTPPTLNITEESHVIDTGDSLSISCRGQHPLEWAWPGAQEAPATGDKDSEDTGVVRDCEGTDARPYCKVLLLHEVHANDTGSYVCYYKYIKARIEGTTAASSYVFVRDFEQPFINKPDTLLVNRKDAMWVPCLVSIPGLNVTLRSQSSVLWPDGQEVVWDDRRGMLVSTPLLHDALYLQCETTWGDQDFLSNPFLVHITGNEL        (SEQ ID NO: 42)

GAC ATA CAA ATG ACT CAA TCT CCT AGC TCA CTC TCC GCT AGT GTG GGC GAT CGG GTA ACC ATC ACA TGT CGG GCC AGC CAG GAC ATA TCT TCA TAT CTG AAT TGG TAT CAG CAG AAG CCA GGG AAG GCC CCT AAG CTG CTT ATC TAC TAC ACG TCA AGG TTG CAC TCA GGT GTC CCG TCT CGG TTC TCT GGT AGT GGG TCC GGG ACT GAC TTT ACA TTC ACA ATT AGT AGC CTC CAG CCC GAG GAC ATA GCG ACT TAC TAC TGC CAA CAG GGT AAT ACC TTG CCC TAC ACT TTC GGA CAA GGG ACC AAG GTT GAG ATT AAG CGA ACG GTC GCT GCT CCC AGT GTG TTC ATT TTT CCT CCG TCT GAT GAA CAG TTG AAA TCC GGG ACC GCT AGC GTT GTG TGT CTC CTG AAT AAC TTT TAC CCA AGG GAG GCC AAA GTT CAA TGG AAA GTA GAT AAC GCC TTG CAG AGT GGA AAC AGC CAG GAG AGT GTT ACT GAG CAA GAC TCA AAA GAT TCA ACC TAT AGC CTC AGC TCC ACT CTC ACG CTG AGC AAA GCT GAC TAC GAA AAG CAC AAG GTA TAT GCC TGC GAA GTT ACT CAT CAA GGA CTG AGC TCT CCA GTG ACG AAG AGT TTC AAC CGG GGG GAA TGC GGC GAA GGC TCC GGA GAC GGC GGT GAG GGA AGC GGC GAT GGA GAG GGG TCC GAT ACT GGC CGC CCC TTT GTG GAG ATG TAT TCT GAG ATC CCG GAG ATT ATA CAC ATG ACT GAG GGA CGA GAG CTC GTT ATC CCA TGT CGA GTA ACG AGT CCG AAT ATA ACG GTC ACG CTC AAA AAA TTT CCC TTG GAT ACC TTG ATA CCA GAT GGT AAG CGA ATA ATC TGG GAT TCT CGG AAA GGG TTT ATT ATC TCA AAC GCT ACG TAC AAA GAA ATA GGG CTT TTG ACT TGT GAG GCT ACA GTT AAT GGA CAT CTT TAT AAA ACG AAT TAT CTT ACG CAC CGA CAG ACA AAC ACC ATA ATA GAT GTT GTC CTT TCT CCC TCT CAT GGA ATT GAG TTG AGC GTG GGT GAA AAG TTG GTG CTG AAC TGC ACC GCT CGC ACT GAG CTT AAT GTC GGA ATT GAT TTT AAT TGG GAG TAC CCT TCA AGC AAA CAT CAG CAT AAG AAA CTG GTA AAT AGA GAT CTT AAA ACA CAG TCA GGT AGC GAA ATG AAA AAG TTC CTG AGT ACG TTG ACA ATC GAC GGT GTG ACT AGA TCC GAT CAA GGT CTC TAT ACA TGT GCC GCC AGT TCT GGT CTG ATG ACC AAA AAG AAT AGT ACA TTT GTT CGA GTT CAC GAG AAA TAG (SEQ ID NO: 43)

DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGEGSGDGGEGSGDGEGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEK        (SEQ ID NO: 44)

CAA GTA CAA TTG CAA GAG AGC GGC CCA GGT CTC GTA AGG CCG TCC CAG ACT TTG TCT CTG ACA TGC ACA GTA TCA GGG TAT TCC ATC ACT AGT GAT CAC GCT TGG TCC TGG GTC CGA CAG CCG CCT GGG AGA GGC CTG GAG TGG ATA GGG TAC ATC TCC TAC TCC GGA ATA ACG ACG TAC AAC CCG AGT CTG AAG TCT CGA GTA ACC ATG CTG AGG GAT ACA AGC AAG AAT CAG TTT TCA TTG AGG CTC TCA TCC GTT ACA GCC GCC GAC ACA GCT GTC TAT TAT TGC GCT CGC AGT TTG GCC AGA ACC ACT GCA ATG GAT TAC TGG GGC CAA GGA TCC CTG GTT ACC GTC AGC TCA GCT AGC ACG AAA GGT CCA TCT GTT TTC CCA CTT GCA CCG TCC AGT AAG TCC ACC TCA GGC GGA ACC GCT GCC CTT GGA TGC CTG GTC AAG GAT TAT TTC CCC GAG CCA GTC ACA GTC AGC TGG AAC TCT GGA GCC CTC ACC AGC GGA GTT CAC ACG TTT CCC GCT GTC TTG CAA AGT TCC GGG CTC TAC AGT CTG AGC TCT GTA GTA ACC GTG CCC AGT TCA AGC CTT GGG ACC CAA ACT TAC ATA TGT AAT GTA AAT CAC AAG CCA AGC AAC ACT AAG GTG GAT AAA AAA GTC GAG CCG AAA TCC TGC GAC AAA ACA CAC ACG TGT CCT CCG TGT CCG GCT CCC GAA TTG CTT GGC GGC CCC TCC GTG TTT CTG TTC CCA CCG AAG CCA AAGGAC ACT CTG ATG ATC TCT CGC ACG CCA GAA GTG ACA TGC GTC GTT GTA GAC GTA TCA CAC GAA GAC CCC GAA GTT AAG TTT AAC TGG TAT GTG GAT GGA GTC GAA GTA CAT AAT GCC AAG ACG AAA CCA AGG GAA GAA CAA TAC AAT TCT ACA TAT CGG GTC GTG AGT GTT CTG ACG GTA TTG CAT CAA GAT TGG CTC AAC GGT AAA GAA TAC AAA TGT AAG GTG AGT AAT AAA GCG CTT CCC GCT CCA ATA GAG AAG ACA ATA TCC AAA GCT AAA GGT CAG CCA CGG GAG CCG CAA GTT TAT ACC TTG CCG CCT TCA AGA GAA GAG ATG ACA AAA AAC CAG GTT TCC CTT ACG TGC CTG GTG AAG GGA TTT TAC CCA AGT GAT ATA GCA GTT GAA TGG GAG AGC AAC GGT CAA CCA GAA AAC AAC TAC AAG ACT ACT CCC CCA GTT CTC GAC TCT GAT GGG TCT TTC TTT TTG TAC TCA AAA CTC ACC GTT GAC AAA TCA AGA TGG CAG CAA GGC AAC GTT TTT TCA TGT AGC GTC ATG CAT GAG GCC TTG CAC AAC CAC TAC ACG CAA AAA AGC CTC AGT TTG AGT CCC GGG GGT GGT AGT GGC GGT GGC GGT TCC GGC GGT GGG TAT TCT ATG ACA CCA CCC ACG CTC AAT ATT ACA GAG GAG AGC CAC GTA ATT GAT ACA GGT GAT TCT CTG TCC ATT AGT TGC AGG GGT CAA CAT CCG CTG GAA TGG GCC TGG CCG GGT GCG CAAGAA GCA CCC GCA ACA GGA GAT AAA GAC TCC GAA GAT ACG GGG GTG GTC AGA GAT TGT GAA GGG ACA GAT GCA AGG CCT TAT TGT AAG GTT TTG CTT CTC CAC GAG GTA CAT GCG AAC GAT ACT GGG TCT TAC GTG TGT TAC TAC AAG TAT ATC AAA GCT AGG ATC GAG GGG ACT ACC GCC GCG AGT TCT TAT GTT TTT GTC CGA GAC TTC GAG CAG CCG TTC ATC AAT AAA CCT GAC ACA CTG TTG GTA AAC CGG AAA GAC GCC ATG TGG GTG CCT TGT CTT GTT TCT ATC CCG GGT CTG AAC GTC ACT CTT AGG AGT CAG TCC AGC GTC CTC TGG CCC GAT GGC CAG GAG GTC GTC TGG GAT GAC AGA AGG GGC ATG TTG GTA TCC ACT CCG CTT TTG CAC GAT GCG CTG TAC CTT CAG TGT GAG ACC ACT TGG GGT GAC CAA GAT TTT CTC TCA AAT CCC TTT CTG GTC CAC ATA ACC GGC AAC GAG CTC TAG (SEQ ID NO: 45)

QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSGGGGSGGGYSMTPPTLNITEESHVIDTGDSLSISCRGQHPLEWAWPGAQEAPATGDKDSEDTGVVRDCEGTDARPYCKVLLLHEVHANDTGSYVCYYKYIKARIEGTTAASSYVFVRDFEQPFINKPDTLLVNRKDAMWVPCLVSIPGLNVTLRSQSSVLWPDGQEVVWDDRRGMLVSTPLLHDALYLQCETTWGDQDFLSNPFLVHITGNEL        (SEQ ID NO: 46)

GAC ATA CAG ATG ACC CAG TCC CCT AGT AGC CTC AGC GCA AGC GTT GGA GAT CGG GTG ACT ATA ACG TGC CGA GCG TCC CAA GAC ATT TCT TCT TAT TTG AAT TGG TAT CAA CAA AAA CCA GGG AAA GCC CCG AAA CTG CTG ATT TAT TAC ACC AGT CGA CTG CAC TCC GGA GTC CCT AGT CGG TTC AGC GGG TCT GGA TCA GGT ACT GAT TTT ACC TTT ACT ATA AGC TCA CTC CAG CCA GAG GAC ATT GCG ACC TAT TAT TGC CAG CAG GGA AAC ACA CTT CCG TAC ACG TTT GGC CAG GGG ACC AAA GTT GAA ATC AAG AGG ACC GTG GCA GCCCC TCA GTT TTC ATA TTC CCT CCG TCT GAC GAG CAG TTG AAG TCA GGG ACT GCA TCC GTG GTG TGT CTG CTG AAT AAT TTC TAC CCA CGC GAG GCC AAG GTG CAG TGG AAG GTA GAT AAT GCT CTC CAA TCC GGG AAC AGC CAA GAG TCT GTT ACT GAA CAA GAT TCC AAA GAC TCT ACC TAT AGC CTC TCA AGC ACC CTT ACA CTT AGT AAG GCG GAT TAC GAA AAA CAC AAA GTC TAC GCA TGT GAA GTG ACC CAT CAG GGT CTC AGC AGC CCG GTC ACT AAA AGC TTT AAC AGG GGG GAA TGT GGG GGG AGT GGT GGT GGA GGT AGC GGC GGT GGC TCC GAC ACC GGA AGG CCT TTC GTA GAG ATG TAT TCA GAA ATT CCC GAA ATT ATA CAT ATG ACG GAA GGC AGA GAG CT G GTC ATA CCG TGT AGA GTA ACA TCA CCC AAC ATA ACT GTT ACG CTT AAA AAG TTC CCA CTT GAC ACA CTT ATA CCC GAC GGC AAG AGA ATA ATC TGG GAC AGC AGA AAA GGT TTC ATC ATC TCC AAT GCT ACT TAT AAA GAG ATC GGG CTC CTG ACG TGC GAG GCG ACC GTA AAC GGG CAT TTG TAC AAA ACC AAC TAT CTC ACT CAT AGA CAA ACA AAC ACT ATT ATT GAT GTG GTG CTC AGC CCC TCT CAT GGG ATC GAG CTT TCC GTA GGT GAA AAG CTG GTC CTG AAC TGC ACA GCA CGG ACT GAG TTG AAT GTA GGG ATA GAT TTC AAC TGG GAA TAC CCG TCT TCA AAA CAT CAG CAC AAA AAG CTT GTG AAT CGC GAC CTC AAG ACA CAA TCA GGG TCA GAA ATG AAA AAG TTT CTC TCA ACG CTG ACT ATC GAC GGC GTC ACG CGG TCC GAT CAG GGC CTT TAC ACT TGT GCG GCC TCT TCT GGG TTG ATG ACG AAG AAA AAC AGT ACG TTT GTA CGC GTA CAT GAG AAG TAG (SEQ ID NO: 47)

DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGSGGGGSGGGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEK                (SEQ ID NO: 48)

EVQLVESGGGLVQPGRSLRLSCAASRFTFDDYAMHWVRQAPGKGLEWVSGISWNSGRIGYADSVKGRFTISRDNAENSLFLQMNGLRAEDTALYYCAKGRDSFDIWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK        (SEQ ID NO: 49)

DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYGASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFASYYCQQANSFPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC        (SEQ ID NO: 50)

QVQLQESGPGLVKPSETLSLTCAVSGHSISHDHAWSWVRQPPGEGLEWIGFISYSGITNYNPSLQGRVTISRDNSKNTLYLQMNSLRAEDTAVYYCARSLARTTAMDYWGEGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQEGNVFSCSVMHEALHAHYTQKSLSLSP        (SEQ ID NO: 51)

DIQMTQSPSSLSASVGDSVTITCQASTDISSHLNWYQQKPGKAPELLIYYGSHLLSGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCGQGNRLPYTFGQGTKVEIERTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC        (SEQ ID NO: 52)

SDHAWS (SEQ ID NO: 53)

YISYSGITTYNPSLKS (SEQ ID NO: 54)

SLARTTAMDY (SEQ ID NO: 55)

RASQDISSYLN (SEQ ID NO: 56)

YTSRLHS (SEQ ID NO: 57)

QQGNTLPYT (SEQ ID NO: 58)

ATG CCG CTC TTG CTC CTT CTT CCA TTG CTC TGG GCG GGC GCA CTG GCC GAT ATC CAA ATG ACG CAA AGT CCA AGT TCT CTT TCA GCC AGC GTC GGA GAT AGA GTC ACT ATA ACA TGC CGC GCG AGC CAG GAT ATA TCA AGC TAC CTT AAT TGG TAT CAA CAA AAA CCG GGT AAA GCG CCG AAA CTC TTG ATT TAT TAT ACC AGT AGG CTC CAC TCC GGT GTA CCA AGT CGG TTC AGT GGC TCC GGG AGT GGA ACC GAC TTC ACA

TTT ACA ATA AGC TCT TTG CAA CCA GAG GAT ATT GCA ACT TAC TAT TGC CAG CAA GGC AAC ACG TTG CCT TAC ACG TTT GGA CAG GGA ACA AAG GTT GAG ATA AAG CGA GGG GGC GGT GGC AGT GGT GGA GGG GGT AGC GGA GGC GGG GGG AGT CAA GTC CAG CTC CAA GAG TCC GGA CCA GGC TTG GTC AGA CCT AGC CAG ACG CTT AGC TTG ACA TGT ACG GTG AGT GGC TAT TCA ATT ACA TCC GAT CAT GCT TGG AGC TGG GTC CGG CAA CCT CCA GGC AGA GGA TTG GAG TGG ATT GGT TAT ATC TCT TAT TCT GGT ATT ACC ACA TAT AAC CCA TCA CTC AAA AGT CGG GTT ACT ATG CTG CGG GAC ACC TCC AAA AAC CAA TTT TCC CTT CGG CTG TCA TCA GTG ACC GCG GCG GAT ACA GCG GTG TAT TAT TGT GCG CGC AGC TTG GCC CGC ACA ACT GCA ATG GAT TAC TGG GGT CAA GGT TCT CTT GTT ACT GTT AGT TCA GAT AAA ACT CAT ACG TGT CCC CCT TGT CCA GCA CCA GAA TTG CTG GGA GGC CCC TCT GTG TTT TTG TTT CCT CCC AAG CCA AAA GAC ACC CTT ATG ATC AGT CGG ACT CCA GAA GTC ACG TGC GTT GTG GTT GAT GTG TCA CAC GAG GAT CCA GAA GTG AAA TTC AAC TGG TAC GTT GAT GGC GTT GAG GTC CAT AAT GCA AAA ACC AAA CCA AGA GAA GAA CAA TAT AAC AGC ACA TACCGG GTG GTC TCC GTT CTG ACT GTG TTG CAC CAG GAC TGG TTG AAT GGT AAG GAA TAT AAG TGC AAG GTG TCA AAC AAA GCG TTG CCT GCT CCG ATC GAA AAA ACA ATA TCC AAG GCA AAA GGT CAA CCC CGC GAG CCT CAA GTA TAT ACT CTC CCT CCT AGC CGC GAC GAG TTG ACA AAG AAC CAG GTT TCC TTG ACA TGT CTT GTC AAA GGG TTC TAC CCG TCC GAT ATA GCT GTT GAA TGG GAA AGT AAT GGC CAG CCG GAA AAT AAT TAT AAA ACT ACT CCA CCG GTA CTT GAC TCA GAT GGT TCA TTC TTC CTT TAC TCC AAA CTT ACA GTT GAC AAA TCC AGG TGG CAA CAG GGA AAT GTA TTT TCT TGT AGT GTT ATG CAC GAG GCG CTG CAC AAT CAC TAT ACA CAA AAA AGC CTT TCT CTT AGC CCA GGA GGG GGC TCT GGA GGG GGT GGG AGT GGC GGT GGC AGC GAC ACC GGA CGA CCG TTC GTA GAG ATG TAC TCT GAA ATA CCA GAG ATA ATC CAC ATG ACT GAA GGA CGG GAG CTG GTG ATA CCC TGC AGG GTA ACA TCT CCC AAC ATT ACG GTG ACT CTC AAG AAG TTC CCT CTT GAT ACA CTG ATT CCG GAT GGT AAA CGG ATC ATA TGG GAT AGT CGA AAA GGT TTT ATA ATC AGC AAT GCA ACC TAT AAG GAG ATT GGG CTC TTG ACC TGC GAA GCC ACT GTT AAT GGG CAT CTT TAT AAG ACG AAC TAT CTTACC CAT CGC CAG ACA AAC ACC ATT ATA GAT GTG GTT TTG TCC CCT AGT CAC GGG ATA GAA CTC TCA GTG GGC GAG AAG CTG GTC CTC AAT TGT ACT GCC AGG ACC GAA CTT AAT GTG GGT ATC GAT TTC AAT TGG GAA TAT CCA TCT TCA AAA CAC CAA CAC AAA AAG CTC GTT AAC AGG GAC TTG AAG ACC CAA TCT GGA TCT GAG ATG AAG AAG TTC CTT TCT ACA TTG ACA ATT GAC GGC GTT ACG CGA AGC GAC CAA GGC TTG TAT ACT TGC GCA GCG TCA TCC GGT CTG ATG ACC AAA AAA AAC AGC ACT TTT GTA AGA GTT CAC GAA AAG TAG (SEQ ID NO: 59)

MPLLLLLPLLWAGALADIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRGGGGSGGGGSGGGGSQVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSGGGGSGGGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEK        (SEQ ID NO: 60)

ATG CCG CTG CTT TTG CTG CTC CCC CTG TTG TGG GCG GGT GCA CTT GCC GAC ATA CAG ATG ACA CAG TCC CCG TCA TCA CTG AGC GCA TCC GTA GGG GAC CGC GTC ACT ATC ACC TGC CGG GCC TCT CAA GAC ATA TCC TCT TAC CTT AAC TGG TAC CAA CAA AAG CCA GGG AAG GCC CCG AAA CTC CTC ATA TAT TAT ACA AGC CGG CTC CAT AGC GGG GTA CCC AGT CGG TTT AGT GGG TCC GGC TCC GGA ACG GAT TTT ACG TTT ACT ATC AGT AGC CTG CAG CCG GAG GAC ATT GCC ACG TAC TAT TGT CAG CAG GGA AAT ACT CTC CCC TAT ACA TTT GGA CAA GGC ACG AAA GTC GAA ATT AAA CGC GGC GGC GGT GGA TCT GGC GGG GGA GGC TCA GGG GGT GGA GGG AGC CAG GTG CAG CTC CAG GAA TCT GGG CCA GGG TTG GTA AGG CCC TCC CAG ACT TTG AGT CTC ACA TGC ACC GTC TCT GGG TAT TCT ATA ACG TCT GAC CAC GCG TGG AGC TGG GTG CGG CAG CCG CCT GGA CGC GGT CTG GAG TGG ATA GGA TAC ATC TCT TAC AGT GGC ATC ACT ACG TAC AATA CCG TCA CTT AAG AGC CGC GTC ACT ATG CTC CGG GAC ACT TCA AAA AAC CAG TTT TCC CTC CGC TTG TCT AGT GTC ACG GCG GCG GAT ACG GCC GTC TAC TAT TGT GCA CGG TCT TTG GCA CGA ACA ACT GCG ATG GAC TAT TGG GGC CAAGGT TCC CTC GTG ACG GTC TCC AGT GGT GGA TCA GGG GGC GGA GGA TCC GGC GGC GGT AGC GGG GGT GGT GGT TCC GAC ACG GGG AGG CCC TTT GTG GAA ATG TAC AGT GAA ATA CCA GAG ATT ATT CAT ATG ACG GAG GGA CGG GAA CTC GTA ATA CCC TGC CGG GTA ACA TCA CCG AAT ATT ACG GTT ACT CTC AAA AAA TTC CCC CTC GAC ACA CTC ATC CCA GAT GGC AAG AGA ATA ATA TGG GAT AGC CGG AAA GGC TTT ATC ATC TCT AAC GCG ACC TAT AAA GAG ATA GGC CTG CTT ACG TGC GAG GCG ACA GTT AAT GGA CAT CTT TAT AAA ACG AAT TAC CTT ACT CAC CGG CAG ACG AAC ACG ATA ATC GAC GTC GTC CTG AGT CCT TCC CAT GGC ATA GAG CTT AGC GTG GGA GAG AAG TTG GTC TTG AAT TGC ACC GCG CGC ACA GAA TTG AAT GTA GGG ATT GAC TTT AAC TGG GAG TAC CCA TCC TCA AAA CAT CAA CAT AAA AAG CTG GTG AAC CGG GAT TTG AAG ACT CAG AGC GGA TCT GAG ATG AAA AAG TTC CTG TCA ACT CTC ACC ATC GAT GGA GTA ACC CGA AGT GAC CAG GGT CTT TAT ACA TGT GCA GCT AGT TCA GGT CTT ATG ACC AAG AAA AAC TCA ACG TTC GTT CGC GTG CAC GAA AAG GGT GGC AGC GGT GGG GGA GGG AGC GGT GGA GGG GAC AAG ACC CAT ACT TGC CCC CCA TGT CCTGCC CCG GAA TTG CTC GGT GGG CCA TCT GTA TTC CTT TTC CCA CCT AAG CCC AAG GAC ACC CTC ATG ATT AGC CGA ACA CCG GAA GTA ACT TGC GTT GTC GTA GAT GTG TCT CAC GAG GAT CCC GAA GTC AAA TTC AAC TGG TAC GTC GAC GGC GTA GAG GTC CAT AAT GCT AAA ACT AAG CCC CGC GAA GAA CAA TAT AAT TCC ACG TAC CGA GTA GTG AGT GTG CTT ACC GTG CTT CAC CAG GAC TGG TTG AAC GGA AAG GAG TAC AAG TGT AAG GTT AGC AAC AAG GCG CTC CCG GCT CCG ATA GAA AAG ACT ATC TCA AAG GCC AAA GGG CAG CCA AGG GAG CCG CAG GTG TAC ACA TTG CCT CCC TCA AGG GAT GAG CTT ACT AAA AAC CAA GTC TCT CTC ACC TGT CTC GTA AAG GGG TTT TAT CCC TCT GAT ATC GCT GTG GAA TGG GAA AGT AAC GGG CAA CCA GAA AAT AAT TAC AAA ACG ACT CCG CCG GTA CTG GAT AGT GAC GGT AGC TTC TTT TTG TAC AGC AAG TTG ACA GTA GAT AAA TCT AGG TGG CAA CAA GGT AAC GTA TTT TCC TGC TCA GTA ATG CAC GAA GCG CTG CAC AAC CAT TAC ACT CAA AAA AGT CTG TCA TTG TCC CCT GGC TAG (SEQ ID NO: 61)

MPLLLLLPLLWAGALADIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRGGGGSGGGGSGGGGSQVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSGGSGGGGSGGGSGGGGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKGGSGGGGSGGGDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG        (SEQ ID NO: 62)

ATG CCA TTG CTT CTC TTG CTG CCA CTC CTT TGG GCT GGA GCC CTC GCT GAC ATT CAA ATG ACC CAG AGT CCG TCT TCA CTT TCT GCC TCC GTT GGG GAT AGA GTG ACG ATC ACG TGC CGC GCG TCA CAA GAC ATC TCT AGT TAC CTC AAC TGG TAT CAG CAA AAG CCC GGT AAA GCT CCA AAA CTT CTC ATC TAC TAT ACT TCT AGA TTG CAC TCC GGC GTA CCG TCT AGG TTT TCA GGT AGT GGT AGC GGC ACC GAC TTC ACT TTT ACG ATA TCC TCT TTG CAG CCC GAG GAT ATC GCT ACT TAC TAT TGT CAA CAA GGA AAC ACG CTT CCG TAC ACC TTC GGT CAA GGG ACC AAG GTA GAA ATC AAA AGG GGT GGC GGT GGA TCA GGT GGC GGG GGA TCC GGA GGG GGT GGA TCC CAG GTA CAA TTG CAA GAG TCT GGC CCC GGT CTC GTC AGG CCA TCC CAA ACT TTG TCA CTG ACT TGT ACG GTT AGC GGT TAC AGT ATA ACC AGC GAT CAC GCG TGG AGC TGG GTC CGA CAG CCC CCC GGG CGG GGA TTG GAA TGG ATC GGG TAT ATC TCC TAC TCA GGA ATA ACC ACT TAC AAT CCA TCC CTG AAA TCC CGA GTT ACG ATG CTT AGG GAT ACA AGT AAA AAC CAG TTC TCT CTG AGG CTT AGC TCT GTG ACT GCC GCC GAC ACA GCG GTT TAT TAC TGT GCA CGG TCA CTG GCG AGG ACC ACG GCG ATG GAC TAT TGG GGC CAGGGA TCA CTC GTG ACT GTA AGC TCA GGG GGG TCA GGA GGT GGT GGC TCA GGT GGT GGA AGT GGT GGG GGC GGG TCA GAC ACG GGA AGG CCG TTT GTA GAA ATG TAT AGT GAG ATA CCG GAA ATT ATA CAC ATG ACC GAA GGC CGA GAA CTC GTC ATA CCC TGC AGA GTT ACT TCA CCT AAC ATA ACG GTC ACG CTT AAA AAA TTT CCC CTG GAC ACC CTG ATA CCT GAC GGG AAA CGG ATC ATA TGG GAC TCA AGG AAA GGG TTT ATC ATC TCC AAT GCT ACT TAT AAA GAG ATC GGG CTC CTG ACT TGT GAA GCC ACC GTA AAC GGT CAT CTT TAT AAG ACC AAC TAC CTC ACT CAT CGA CAG ACG AAT ACG ATA ATT GAT GTC GTG CTT AGT CCA AGC CAC GGT ATT GAG TTG TCA GTG GGC GAG AAA CTG GTG CTC AAT TGC ACA GCA AGA ACG GAG CTT AAC GTG GGT ATA GAC TTC AAC TGG GAG TAT CCC TCC AGT AAA CAC CAA CAC AAA AAA CTC GTT AAT AGA GAT TTG AAG ACC CAA AGC GGA TCA GAG ATG AAG AAA TTT TTG AGC ACT CTC ACG ATA GAT GGC GTG ACG CGG TCA GAT CAG GGG CTC TAT ACC TGC GCT GCC TCC TCC GGT CTC ATG ACA AAA AAG AAT AGC ACT TTT GTT AGG GTG CAC GAA AAA GGC GGC AGC GGA GGG GGG GGA TCA GGT GGT GGA GAC AAG ACA CAT ACT TGC CCA CCG TGT CCCGCT CCG GAA CTG CTT GGC GGG CCT AGC GTC TTC CTC TTC CCG CCT AAG CCG AAA GAC ACC CTT ATG ATC TCA CGA ACG CCC GAG GTG ACG TGC GTC GTT GTT GAT GTG AGC CAC GAA GAT CCA GAA GTT AAG TTC AAT TGG TAC GTC GAC GGG GTG GAA GTA CAC AAT GCG AAG ACC AAA CCG AGG GAG GAG CAG TAT AAT TCA ACA TAC AGA GTC GTT TCT GTC CTC ACG GTT CTC CAC CAG GAT TGG TTG AAC GGC AAA GAA TAT AAA TGC AAA GTG AGC AAT AAG GCT CTC CCC GCT CCC ATC GAA AAG ACA ATC TCT AAG GCT AAA GGC CAG CCG AGA GAA CCG CAG GTT TAT ACC CTC CCA CCC TCA CGC GAC GAG TTG ACT AAG AAC CAG GTC AGC CTT ACG TGT TTG GTG AAG GGG TTC TAT CCG TCT GAC ATC GCG GTC GAA TGG GAA TCT AAC GGT CAA CCC GAG AAT AAC TAT AAA ACT ACC CCA CCA GTT TTG GAC TCA GAC GGG TCC TTT TTC CTG TAC AGC AAG CTC ACG GTC GAC AAA TCC CGG TGG CAG CAG GGA AAT GTT TTC AGT TGC AGT GTC ATG CAC GAA GCA TTG CAT AAT CAT TAC ACA CAA AAA TCA CTC AGC CTG AGC CCT GGG GGG GGT AGT GGC GGG GGA GGA AGC GGT GGA GGA TAC TCT ATG ACT CCG CCA ACA CTT AAC ATT ACT GAG GAG AGC CAC GTC ATT GAT ACG GGG GAC TCT TTGTCC ATT TCC TGC AGA GGC CAG CAT CCG CTC GAA TGG GCC TGG CCC GGA GCT CAA GAG GCC CCG GCG ACT GGT GAT AAA GAC AGC GAG GAT ACG GGA GTA GTA AGA GAC TGC GAG GGC ACT GAC GCC CGA CCG TAC TGC AAG GTA CTC CTC CTC CAT GAA GTC CAT GCT AAT GAT ACA GGG AGT TAC GTC TGT TAC TAC AAA TAC ATC AAA GCG AGG ATA GAA GGT ACG ACC GCG GCT TCA TCT TAC GTT TTT GTT AGA GAT TTT GAG CAA CCC TTT ATA AAT AAA CCC GAT ACC CTC CTG GTC AAT CGC AAG GAC GCC ATG TGG GTC CCG TGC CTG GTG TCA ATC CCA GGA CTT AAC GTC ACT CTC AGA TCT CAA AGC TCT GTG CTT TGG CCT GAC GGA CAG GAG GTT GTT TGG GAC GAC AGA CGG GGC ATG CTC GTG TCA ACC CCT CTG CTT CAT GAT GCC CTC TAT TTG CAG TGT GAG ACG ACG TGG GGT GAC CAG GAT TTT CTG TCA AAC CCT TTT CTG GTG CAC ATC ACG GGC AAT GAG CTC TAG (SEQ ID NO: 63)

MPLLLLLPLLWAGALADIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRGGGGSGGGGSGGGGSQVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSGGSGGGGSGGGSGGGGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKGGSGGGGSGGGDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSGGGGSGGGYSMTPPTLNITEESHVIDTGDSLSISCRGQHPLEWAWPGAQEAPATGDKDSEDTGVVRDCEGTDARPYCKVLLLHEVHANDTGSYVCYYKYIKARIEGTTAASSYVFVRDFEQPFINKPDTLLVNRKDAMWVPCLVSIPGLNVTLRSQSSVLWPDGQEVVWDDRRGMLVSTPLLHDALYLQCETTWGDQDFLSNPFLVHITGNEL        (SEQ ID NO: 64)

ATG CCG CTG CTG TTG CTT CTT CCC CTG CTC TGG GCT GGG GCA CTG GCC GAC ATA CAA ATG ACC CAG TCA CCA AGT AGT CTC TCT GCA AGC GTC GGA GAC CGG GTC ACG ATA ACC TGT CGA GCA AGT CAG GAC ATT AGT AGC TAC CTG AAC TGG TAT CAG CAG AAG CCT GGC AAA GCC CCG AAG CTC CTC ATA TAC TAT ACC AGC AGA CTG CAC AGT GGT GTA CCA TCC CGA TTC TCC GGC TCA GGA TCC GGA ACC GAC TTC ACG TTC ACC ATA AGC AGT CTT CAA CCC GAG GAC ATC GCA ACT TAT TAC TGT CAA CAA GGT AAC ACA CTT CCA TAT ACA TTC GGC CAG GGT ACC AAA GTT GAG ATC AAA AGA GGA GGC GGT GGT TCC GGG GGT GGA GGC TCT GGA GGT GGC GGA TCC CAG GTC CAG CTC CAG GAA AGC GGT CCG GGT TTG GTG AGA CCA TCT CAG ACA CTG AGC TTG ACG TGT ACG GTA AGT GGT TAC TCT ATA ACT TCC GAT CAT GCG TGG

TCC TGG GTA CGG CAA CCC CCT GGC AGA GGT CTC GAA TGG ATA GGC TAT ATT AGC TAT TCT GGA ATT ACC ACA TAC AAC CCA AGC CTG AAA TCT CGC GTC ACC ATG CTG CGC GAT ACT TCC AAG AAT CAA TTT TCT CTG CGG TTG TCA AGT GTT ACG GCG GCT GAC ACT GCC GTC TAC TAC TGT GCT CGA TCC CTC GCG CGG ACA ACA GCC ATG GAT TAC TGG GGC CAA GGG TCC CTT GTG ACG GTA TCC TCC GGC GGG AGT GGT GGC GGG GGT TCC GGG GGA GGT AGT GGT GGG GGG GGT TCA GAC ACA GGA CGC CCA TTT GTC GAG ATG TAC AGT GAG ATA CCT GAA ATA ATT CAC ATG ACG GAA GGA CGC GAG CTT GTC ATA CCA TGC CGC GTG ACT AGC CCT AAT ATT ACG GTA ACA CTG AAA AAA TTC CCA CTT GAT ACT CTG ATT CCG GAC GGC AAG CGA ATC ATT TGG GAC TCA AGG AAA GGT TTC ATA ATA TCC AAC GCA ACA TAT AAG GAA ATC GGA CTC CTG ACG TGC GAG GCG ACG GTA AAC GGC CAC CTT TAT AAG ACA AAC TAT CTT ACG CAC CGG CAA ACT AAT ACT ATT ATA GAC GTT GTC CTT TCT CCC TCT CAC GGC ATA GAG TTG AGT GTC GGT GAA AAA TTG GTA CTT AAT TGC ACC GCG AGA ACG GAA CTT AAT GTC GGA ATT GAT TTC AAT TGG GAA TAC CCA AGT AGT AAA CAC CAG CAT AAG AAG CTTGTA AAC CGC GAT TTG AAA ACG CAA TCT GGA TCA GAA ATG AAA AAA TTT CTC AGT ACG CTT ACA ATA GAT GGG GTA ACC CGA AGC GAT CAA GGA CTG TAT ACC TGC GCA GCG TCT AGT GGC CTC ATG ACA AAG AAG AAT TCA ACA TTC GTA AGA GTT CAC GAG AAG GGT GGC GGT GGT TCA GGT GGG GGA TCA GGC GGG GGC GGT TAT AGC ATG ACG CCC CCG ACA TTG AAC ATT ACA GAA GAG TCT CAC GTA ATA GAT ACG GGG GAT TCC CTC AGT ATT TCC TGC CGC GGG CAA CAC CCA CTT GAA TGG GCG TGG CCC GGG GCT CAA GAA GCA CCA GCA ACC GGA GAC AAA GAT AGC GAG GAT ACT GGT GTC GTT CGA GAC TGT GAA GGG ACC GAT GCC CGG CCG TAC TGT AAG GTT CTC CTG TTG CAT GAG GTT CAT GCT AAT GAT ACG GGC AGC TAT GTG TGC TAC TAT AAG TAC ATC AAA GCG CGG ATC GAA GGC

ACT ACC GCC GCG TCT TCT TAT GTT TTC GTG CGA GAT TTT GAA CAA CCA TTT ATA AAC AAG CCG GAC ACT TTG CTC GTC AAT AGG AAA GAC GCC ATG TGG GTT CCC TGC TTG GTG TCC ATA CCC GGC CTG AAT GTT ACA CTT AGG TCA CAG AGC TCT GTT TTG TGG CCT GAC GGA CAG GAG GTT GTT TGG GAT GAT AGA CGA GGC ATG CTC GTG TCA ACT CCA CTT CTT CAC GAT GCG CTG TAT CTC CAA TGC GAG ACT ACG TGG GGA GAT CAA GAC TTT CTT AGC AAT CCC TTC CTG GTC CAC ATT ACT GGA AAT GAG CTT GGT GGG AGC GGA GGT GGG GGC TCA GGA GGT GGG GAT AAG ACC CAT ACT TGC CCA CCC TGC CCG GCA CCT GAA CTT CTC GGA GGT CCG TCA GTG TTT TTG TTT CCG CCA AAG CCT AAA GAC ACA CTG ATG ATT TCT CGG ACG CCC GAG GTA ACT TGT GTA GTC GTA GAC GTG TCC CAT GAG GAC CCT GAA GTT AAA TTC AAC TGG TACGTG GAC GGG GTT GAA GTA CAT AAT GCA AAG ACA AAA CCC CGG GAG GAG CAG TAT AAC AGT ACT TAC AGA GTA GTC TCC GTG CTC ACC GTA CTC CAC CAA GAT TGG CTC AAC GGC AAG GAG TAC AAA TGC AAA GTG TCA AAT AAA GCG TTG CCT GCT CCA ATT GAA AAA ACA ATA TCC AAG GCG AAG GGG CAA CCC CGA GAG CCT CAG GTT TAC ACA TTG CCG C CA AGT CGA GAC GAA TTG ACA AAG AAC CAA GTT AGC TTG ACC TGC CTC GTG AAG GGT TTT TAT CCG AGC GAT ATA GCC GTT GAA TGG GAG TCT AAC GGG CAA CCG GAA AAT AAC TAT AAA ACC ACT CCG CCG GTG CTT GAC AGC GAC GGT TCT TTT TTC CTG TAC AGT AAA CTC ACC GTT GAT AAA TCT AGG TGG CAG CAG GGT AAC GTC TTT AGT TGC AGC GTT ATG CAT GAG GCT CTT CAT AAT CAT TAT ACT CAA AAA TCT TTG AGT CTG TCT CCC GGA TAG (SEQ ID NO: 65)

MPLLLLLPLLWAGALADIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRGGGGSGGGGSGGGGSQVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSGGSGGGGSGGGSGGGGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKGGGGSGGGSGGGGYSMTPPTLNITEESHVIDTGDSLSISCRGQHPLEWAWPGAQEAPATGDKDSEDTGVVRDCEGTDARPYCKVLLLHEVHANDTGSYVCYYKYIKARIEGTTAASSYVFVRDFEQPFINKPDTLLVNRKDAMWVPCLVSIPGLNVTLRSQSSVLWPDGQEVVWDDRRGMLVSTPLLHDALYLQCETTWGDQDFLSNPFLVHITGNELGGSGGGGSGGGDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG        (SEQ ID NO: 66)

GGG GGC GGT GGC AGT GGT GGA GGG GGT AGC GGA GGC GGG GGG AGT (SEQ ID NO: 67)

GGGGSGGGGSGGGGS (SEQ ID NO: 68)

GGT GGA TCA GGG GGC GGA GGA TCC GGC GGC GGT AGC GGG GGT GGT GGT (SEQ ID NO: 69)

GGSGGGGSGGGSGGGG (SEQ ID NO: 70)

GGT GGC GGT GGT TCA GGT GGG GGA TCA GGC GGG GGC GGT (SEQ ID NO: 71)

GGGGSGGGSGGGG (SEQ ID NO: 72)

EVQLVESGGGLVQPGGSLRLSCAASGSVFKINVMAWYRQAPGKGRELVAGIISGGSTSYADSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAFITTESDYDLGRRYWGQGTLVTVSS (SEQ ID NO: 73)

MPLLLLLPLLWAGALADIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRGGGGSGGGGSGGGGSQVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSGGGSGGGGSGGGGGSGGGGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEK                (SEQ ID NO: 74)

ATGCCGCTCTTGCTCCTTCTTCCATTGCTCTGGGCGGGCGCACTGGCCGATATCCAAATGACGCAAAGTCCAAGTTCTCTTTCAGCCAGCGTCGGAGATAGAGTCACTATAACATGCCGCGCGAGCCAGGATATATCAAGCTACCTTAATTGGTATCAACAAAAACCGGGTAAAGCGCCGAAACTCTTGATTTATTATACCAGTAGGCTCCACTCCGGTGTACCAAGTCGGTTCAGTGGCTCCGGGAGTGGAACCGACTTCACATTTACAATAAGCTCTTTGCAACCAGAGGATATTGCAACTTACTATTGCCAGCAAGGCAACACGTTGCCTTACACGTTTGGACAGGGAACAAAGGTTGAGATAAAGCGAGGGGGCGGTGGCAGTGGTGGAGGGGGTAGCGGAGGCGGGGGGAGTCAAGTCCAGCTCCAAGAGTCCGGACCAGGCTTGGTCAGACCTAGCCAGACGCTTAGCTTGACATGTACGGTGAGTGGCTATTCAATTACATCCGATCATGCTTGGAGCTGGGTCCGGCAACCTCCAGGCAGAGGATTGGAGTGGATTGGTTATATCTCTTATTCTGGTATTACCACATATAACCCATCACTCAAAAGTCGGGTTACTATGCTGCGGGACACCTCCAAAAACCAATTTTCCCTTCGGCTGTCATCAGTGACCGCGGCGGATACAGCGGTGTATTATTGTGCGCGCAGCTTGGCCCGCACAACTGCAATGGATTACTGGGGTCAAGGTTCTCTTGTTACTGTTAGTTCAGATAAAACTCATACGTGTCCCCCTTGTCCAGCACCAGAATTGCTGGGAGGCCCCTCTGTGTTTTTGTTTCCTCCCAAGCCAAAAGACACCCTTATGATCAGTCGGACTCCAGAAGTCACGTGCGTTGTGGTTGATGTGTCACACGAGGATCCAGAAGTGAAATTCAACTGGTACGTTGATGGCGTTGAGGTCCATAATGCAAAAACCAAACCAAGAGAAGAACAAT ATAACAGCACATACCGGGTGGTCTCCGTTCTGACTGTGTTGCACCAGGACTGGTTGAATGGTAAGGAATATAAGTGCAAGGTGTCAAACAAAGCGTTGCCTGCTCCGATCGAAAAAACAATATCCAAGGCAAAAGGTCAACCCCGCGAGCCTCAAGTATATACTCTCCCTCCTAGCCGCGACGAGTTGACAAAGAACCAGGTTTCCTTGACATGTCTTGTCAAAGGGTTCTACCCGTCCGATATAGCTGTTGAATGGGAAAGTAATGGCCAGCCGGAAAATAATTATAAAACTACTCCACCGGTACTTGACTCAGATGGTTCATTCTTCCTTTACTCCAAACTTACAGTTGACAAATCCAGGTGGCAACAGGGAAATGTATTTTCTTGTAGTGTTATGCACGAGGCGCTGCACAATCACTATACACAAAAAAGCCTTTCTCTTAGCCCAGGAGGGGGCTCTGGAGGAGGAAGCGGCGGAGGCGGAAGCGGAGGGGGAGGTGGCTCCGGAGGCGGTGGCAGCGACACCGGACGACCGTTCGTAGAGATGTACTCTGAAATACCAGAGATAATCCACATGACTGAAGGACGGGAGCTGGTGATACCCTGCAGGGTAACATCTCCCAACATTACGGTGACTCTCAAGAAGTTCCCTCTTGATACACTGATTCCGGATGGTAAACGGATCATATGGGATAGTCGAAAAGGTTTTATAATCAGCAATGCAACCTATAAGGAGATTGGGCTCTTGACCTGCGAAGCCACTGTTAATGGGCATCTTTATAAGACGAACTATCTTACCCATCGCCAGACAAACACCATTATAGATGTGGTTTTGTCCCCTAGTCACGGGATAGAACTCTCAGTGGGCGAGAAGCTGGTCCTCAATTGTACTGCCAGGACCGAACTTAATGTGGGTATCGATTTCAATTGGGAATATCCATCTTCAAAACACCAACACAAAAAGCTCGTTAACAGGGACTTGAAGACCCAATCTGGATC TGAGATGAAGAAGTTCCTTTCTACATTGACAATTGACGGCGTTACGCGAAGCGACCAAGGCTTGTATACTTGCGCAGCGTCATCCGGTCTGATGACCAAAAAAAACAGCACTTTTGTAAGAGTTCACGAAAAG (SEQ ID NO: 75)

MPLLLLLPLLWAGALASDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSGGGSGGGGSGGGGGSGGGGDIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRGGGGSGGGGSGGGGSQVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSS        (SEQ ID NO: 76)

ATGCCGCTCTTGCTCCTTCTTCCATTGCTCTGGGCGGGCGCACTGGCCAGCGACACCGGACGACCGTTCGTAGAGATGTACTCTGAAATACCAGAGATAATCCACATGACTGAAGGACGGGAGCTGGTGATACCCTGCAGGGTAACATCTCCCAACATTACGGTGACTCTCAAGAAGTTCCCTCTTGATACACTGATTCCGGATGGTAAACGGATCATATGGGATAGTCGAAAAGGTTTTATAATCAGCAATGCAACCTATAAGGAGATTGGGCTCTTGACCTGCGAAGCCACTGTTAATGGGCATCTTTATAAGACGAACTATCTTACCCATCGCCAGACAAACACCATTATAGATGTGGTTTTGTCCCCTAGTCACGGGATAGAACTCTCAGTGGGCGAGAAGCTGGTCCTCAATTGTACTGCCAGGACCGAACTTAATGTGGGTATCGATTTCAATTGGGAATATCCATCTTCAAAACACCAACACAAAAAGCTCGTTAACAGGGACTTGAAGACCCAATCTGGATCTGAGATGAAGAAGTTCCTTTCTACATTGACAATTGACGGCGTTACGCGAAGCGACCAAGGCTTGTATACTTGCGCAGCGTCATCCGGTCTGATGACCAAAAAAAACAGCACTTTTGTAAGAGTTCACGAAAAGGATAAAACTCATACGTGTCCCCCTTGTCCAGCACCAGAATTGCTGGGAGGCCCCTCTGTGTTTTTGTTTCCTCCCAAGCCAAAAGACACCCTTATGATCAGTCGGACTCCAGAAGTCACGTGCGTTGTGGTTGATGTGTCACACGAGGATCCAGAAGTGAAATTCAACTGGTACGTTGATGGCGTTGAGGTCCATAATGCAAAAACCAAACCAAGAGAAGAACAATATAACAGCACATACCGGGTGGTCTCCGTTCTGACTGTGTTGCACCAGGACTGGTTGAATGGTAAGGAATATAAGTGCAAGGTGTCAAACAAAGCGTTGCCTGCTCCGATCG AAAAAACAATATCCAAGGCAAAAGGTCAACCCCGCGAGCCTCAAGTATATACTCTCCCTCCTAGCCGCGACGAGTTGACAAAGAACCAGGTTTCCTTGACATGTCTTGTCAAAGGGTTCTACCCGTCCGATATAGCTGTTGAATGGGAAAGTAATGGCCAGCCGGAAAATAATTATAAAACTACTCCACCGGTACTTGACTCAGATGGTTCATTCTTCCTTTACTCCAAACTTACAGTTGACAAATCCAGGTGGCAACAGGGAAATGTATTTTCTTGTAGTGTTATGCACGAGGCGCTGCACAATCACTATACACAAAAAAGCCTTTCTCTTAGCCCAGGAGGGGGCTCTGGAGGAGGAAGCGGCGGAGGCGGAAGCGGAGGGGGAGGTGGCTCCGGAGGCGGTGGCGATATCCAAATGACGCAAAGTCCAAGTTCTCTTTCAGCCAGCGTCGGAGATAGAGTCACTATAACATGCCGCGCGAGCCAGGATATATCAAGCTACCTTAATTGGTATCAACAAAAACCGGGTAAAGCGCCGAAACTCTTGATTTATTATACCAGTAGGCTCCACTCCGGTGTACCAAGTCGGTTCAGTGGCTCCGGGAGTGGAACCGACTTCACATTTACAATAAGCTCTTTGCAACCAGAGGATATTGCAACTTACTATTGCCAGCAAGGCAACACGTTGCCTTACACGTTTGGACAGGGAACAAAGGTTGAGATAAAGCGAGGGGGCGGTGGCAGTGGTGGAGGGGGTAGCGGAGGCGGGGGGAGTCAAGTCCAGCTCCAAGAGTCCGGACCAGGCTTGGTCAGACCTAGCCAGACGCTTAGCTTGACATGTACGGTGAGTGGCTATTCAATTACATCCGATCATGCTTGGAGCTGGGTCCGGCAACCTCCAGGCAGAGGATTGGAGTGGATTGGTTATATCTCTTATTCTGGTATTACCACATATAACCCATCACTCAAAAGTCGGGTTACTATGCTGCGGGACACCTC CAAAAACCAATTTTCCCTTCGGCTGTCATCAGTGACCGCGGCGGATACAGCGGTGTATTATTGTGCGCGCAGCTTGGCCCGCACAACTGCAATGGATTACTGGGGTCAAGGTTCTCTTGTTACTGTTAGTTCA (SEQ ID NO: 77)

SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKQVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP        (SEQ ID NO: 78)

AGCGACACCGGCAGACCCTTCGTGGAGATGTACAGCGAGATCCCCGAGATCATCCACATGACCGAGGGCAGAGAGCTGGTGATCCCCTGCAGAGTGACCAGCCCCAACATCACCGTGACCCTGAAGAAGTTCCCCCTGGACACCCTGATCCCCGACGGCAAGAGAATCATCTGGGACAGCAGAAAGGGCTTCATCATCAGCAACGCCACCTACAAGGAGATCGGCCTGCTGACCTGCGAGGCCACCGTGAACGGCCACCTGTACAAGACCAACTACCTGACCCACAGACAGACCAACACCATCATCGACGTGGTGCTGAGCCCCAGCCACGGCATCGAGCTGAGCGTGGGCGAGAAGCTGGTGCTGAACTGCACCGCCAGAACCGAGCTGAACGTGGGCATCGACTTCAACTGGGAGTACCCCAGCAGCAAGCACCAGCACAAGAAGCTGGTGAACAGAGACCTGAAGACCCAGAGCGGCAGCGAGATGAAGAAGTTCCTGAGCACCCTGACCATCGACGGCGTGACCAGAAGCGACCAGGGCCTGTACACCTGCGCCGCCAGCAGCGGCCTGATGACCAAGAAGAACAGCACCTTCGTGAGAGTGCACGAGAAGCAGGTGCAGCTGCAGGAGAGCGGCCCCGGACTGGTGAGGCCTTCCCAGACCCTGAGCCTGACATGCACAGTGAGCGGCTACAGCATCACAAGCGACCACGCCTGGAGCTGGGTGAGACAGCCCCCCGGAAGAGGCCTGGAATGGATCGGATATATCTCCTACTCAGGCATTACCACCTACAACCCCTCTCTGAAAAGCAGAGTGACCATGCTGAGAGATACTAGCAAGAACCAGTTTAGCCTGAGACTGTCTAGCGTGACTGCCGCCGACACCGCCGTGTACTACTGCGCCAGATCCCTGGCCCGGACCACAGCCATGGATTACTGGGGCCAGGGAAGCCTGGTGACAGTGTCCTCCGCTAGCACCAAGGGCCCATCGGTCTTCC CCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCCGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG        (SEQ ID NO: 79)

DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC        (SEQ ID NO: 80)

GACATTCAGATGACCCAGAGCCCCAGCAGCCTGAGCGCCAGCGTGGGAGACAGAGTGACCATCACCTGCAGAGCCAGCCAGGACATCTCCAGCTACCTGAACTGGTATCAGCAGAAACCCGGCAAAGCCCCAAAACTGCTGATCTACTACACCAGTAGACTGCACAGCGGCGTGCCCAGCAGATTCTCAGGAAGCGGCTCCGGAACCGACTTCACCTTCACTATCAGCAGCCTGCAGCCCGAAGATATTGCTACTTACTACTGCCAGCAGGGGAACACCCTGCCCTATACCTTCGGCCAGGGCACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGTTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT                (SEQ ID NO: 81)

SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKGGSGGGSGGGGSGGGGGSGGGGQVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP        (SEQ ID NO: 82)

AGCGACACCGGCAGACCCTTCGTGGAGATGTACAGCGAGATCCCCGAGATCATCCACATGACCGAGGGCAGAGAGCTGGTGATCCCCTGCAGAGTGACCAGCCCCAACATCACCGTGACCCTGAAGAAGTTCCCCCTGGACACCCTGATCCCCGACGGCAAGAGAATCATCTGGGACAGCAGAAAGGGCTTCATCATCAGCAACGCCACCTACAAGGAGATCGGCCTGCTGACCTGCGAGGCCACCGTGAACGGCCACCTGTACAAGACCAACTACCTGACCCACAGACAGACCAACACCATCATCGACGTGGTGCTGAGCCCCAGCCACGGCATCGAGCTGAGCGTGGGCGAGAAGCTGGTGCTGAACTGCACCGCCAGAACCGAGCTGAACGTGGGCATCGACTTCAACTGGGAGTACCCCAGCAGCAAGCACCAGCACAAGAAGCTGGTGAACAGAGACCTGAAGACCCAGAGCGGCAGCGAGATGAAGAAGTTCCTGAGCACCCTGACCATCGACGGCGTGACCAGAAGCGACCAGGGCCTGTACACCTGCGCCGCCAGCAGCGGCCTGATGACCAAGAAGAACAGCACCTTCGTGAGAGTGCACGAGAAGGGAGGAAGCGGAGGAGGAAGCGGGGGAGGAGGAAGTGGAGGAGGAGGAGGGAGCGGAGGAGGGGGACAGGTGCAGCTGCAGGAGAGCGGCCCCGGACTGGTGAGGCCTTCCCAGACCCTGAGCCTGACATGCACAGTGAGCGGCTACAGCATCACAAGCGACCACGCCTGGAGCTGGGTGAGACAGCCCCCCGGAAGAGGCCTGGAATGGATCGGATATATCTCCTACTCAGGCATTACCACCTACAACCCCTCTCTGAAAAGCAGAGTGACCATGCTGAGAGATACTAGCAAGAACCAGTTTAGCCTGAGACTGTCTAGCGTGACTGCCGCCGACACCGCCGTGTACTACTGCGCCAGATCCCTGGCCCGGACCACAGCCATGG ATTACTGGGGCCAGGGAAGCCTGGTGACAGTGTCCTCCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCCGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCA GAAGAGCCTCTCCCCTGTCTCCG (SEQ ID NO: 83)

DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC        (SEQ ID NO: 84)

GACATTCAGATGACCCAGAGCCCCAGCAGCCTGAGCGCCAGCGTGGGAGACAGAGTGACCATCACCTGCAGAGCCAGCCAGGACATCTCCAGCTACCTGAACTGGTATCAGCAGAAACCCGGCAAAGCCCCAAAACTGCTGATCTACTACACCAGTAGACTGCACAGCGGCGTGCCCAGCAGATTCTCAGGAAGCGGCTCCGGAACCGACTTCACCTTCACTATCAGCAGCCTGCAGCCCGAAGATATTGCTACTTACTACTGCCAGCAGGGGAACACCCTGCCCTATACCTTCGGCCAGGGCACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGTTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT        (SEQ ID NO: 85)

SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKGGSGGGSGGGGSGGGGGSGGGGQVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK        (SEQ ID NO: 86)

AGCGACACCGGCAGACCCTTCGTGGAGATGTACAGCGAGATCCCCGAGATCATCCACATGACCGAGGGCAGAGAGCTGGTGATCCCCTGCAGAGTGACCAGCCCCAACATCACCGTGACCCTGAAGAAGTTCCCCCTGGACACCCTGATCCCCGACGGCAAGAGAATCATCTGGGACAGCAGAAAGGGCTTCATCATCAGCAACGCCACCTACAAGGAGATCGGCCTGCTGACCTGCGAGGCCACCGTGAACGGCCACCTGTACAAGACCAACTACCTGACCCACAGACAGACCAACACCATCATCGACGTGGTGCTGAGCCCCAGCCACGGCATCGAGCTGAGCGTGGGCGAGAAGCTGGTGCTGAACTGCACCGCCAGAACCGAGCTGAACGTGGGCATCGACTTCAACTGGGAGTACCCCAGCAGCAAGCACCAGCACAAGAAGCTGGTGAACAGAGACCTGAAGACCCAGAGCGGCAGCGAGATGAAGAAGTTCCTGAGCACCCTGACCATCGACGGCGTGACCAGAAGCGACCAGGGCCTGTACACCTGCGCCGCCAGCAGCGGCCTGATGACCAAGAAGAACAGCACCTTCGTGAGAGTGCACGAGAAGGGAGGAAGCGGAGGAGGAAGCGGGGGAGGAGGAAGTGGAGGAGGAGGAGGGAGCGGAGGAGGGGGACAGGTGCAGCTGCAGGAGAGCGGCCCCGGACTGGTGAGGCCTTCCCAGACCCTGAGCCTGACATGCACAGTGAGCGGCTACAGCATCACAAGCGACCACGCCTGGAGCTGGGTGAGACAGCCCCCCGGAAGAGGCCTGGAATGGATCGGATATATCTCCTACTCAGGCATTACCACCTACAACCCCTCTCTGAAAAGCAGAGTGACCATGCTGAGAGATACTAGCAAGAACCAGTTTAGCCTGAGACTGTCTAGCGTGACTGCCGCCGACACCGCCGTGTACTACTGCGCCAGATCCCTGGCCCGGACCACAGCCATGG ATTACTGGGGCCAGGGAAGCCTGGTGACAGTGTCCTCCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCCGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCA GAAGAGCCTCTCCCCTGTCTCCGGGTAAA (SEQ ID NO: 87)

DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC        (SEQ ID NO: 88)

GACATTCAGATGACCCAGAGCCCCAGCAGCCTGAGCGCCAGCGTGGGAGACAGAGTGACCATCACCTGCAGAGCCAGCCAGGACATCTCCAGCTACCTGAACTGGTATCAGCAGAAACCCGGCAAAGCCCCAAAACTGCTGATCTACTACACCAGTAGACTGCACAGCGGCGTGCCCAGCAGATTCTCAGGAAGCGGCTCCGGAACCGACTTCACCTTCACTATCAGCAGCCTGCAGCCCGAAGATATTGCTACTTACTACTGCCAGCAGGGGAACACCCTGCCCTATACCTTCGGCCAGGGCACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGTTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT                (SEQ ID NO: 89)

SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKGGSGGGSGGGGSGGGGGSGGGGQVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG        (SEQ ID NO: 90)

AGCGACACCGGCAGACCCTTCGTGGAGATGTACAGCGAGATCCCCGAGATCATCCACATGACCGAGGGCAGAGAGCTGGTGATCCCCTGCAGAGTGACCAGCCCCAACATCACCGTGACCCTGAAGAAGTTCCCCCTGGACACCCTGATCCCCGACGGCAAGAGAATCATCTGGGACAGCAGAAAGGGCTTCATCATCAGCAACGCCACCTACAAGGAGATCGGCCTGCTGACCTGCGAGGCCACCGTGAACGGCCACCTGTACAAGACCAACTACCTGACCCACAGACAGACCAACACCATCATCGACGTGGTGCTGAGCCCCAGCCACGGCATCGAGCTGAGCGTGGGCGAGAAGCTGGTGCTGAACTGCACCGCCAGAACCGAGCTGAACGTGGGCATCGACTTCAACTGGGAGTACCCCAGCAGCAAGCACCAGCACAAGAAGCTGGTGAACAGAGACCTGAAGACCCAGAGCGGCAGCGAGATGAAGAAGTTCCTGAGCACCCTGACCATCGACGGCGTGACCAGAAGCGACCAGGGCCTGTACACCTGCGCCGCCAGCAGCGGCCTGATGACCAAGAAGAACAGCACCTTCGTGAGAGTGCACGAGAAGGGAGGAAGCGGAGGAGGAAGCGGGGGAGGAGGAAGTGGAGGAGGAGGAGGGAGCGGAGGAGGGGGACAGGTGCAGCTGCAGGAGAGCGGCCCCGGACTGGTGAGGCCTTCCCAGACCCTGAGCCTGACATGCACAGTGAGCGGCTACAGCATCACAAGCGACCACGCCTGGAGCTGGGTGAGACAGCCCCCCGGAAGAGGCCTGGAATGGATCGGATATATCTCCTACTCAGGCATTACCACCTACAACCCCTCTCTGAAAAGCAGAGTGACCATGCTGAGAGATACTAGCAAGAACCAGTTTAGCCTGAGACTGTCTAGCGTGACTGCCGCCGACACCGCCGTGTACTACTGCGCCAGATCCCTGGCCCGGACCACAGCCATGG ATTACTGGGGCCAGGGAAGCCTGGTGACAGTGTCCTCCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCCGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCA GAAGAGCCTCTCCCTGTCTCCGGGT (SEQ ID NO: 91)

DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC        (SEQ ID NO: 92)

GACATTCAGATGACCCAGAGCCCCAGCAGCCTGAGCGCCAGCGTGGGAGACAGAGTGACCATCACCTGCAGAGCCAGCCAGGACATCTCCAGCTACCTGAACTGGTATCAGCAGAAACCCGGCAAAGCCCCAAAACTGCTGATCTACTACACCAGTAGACTGCACAGCGGCGTGCCCAGCAGATTCTCAGGAAGCGGCTCCGGAACCGACTTCACCTTCACTATCAGCAGCCTGCAGCCCGAAGATATTGCTACTTACTACTGCCAGCAGGGGAACACCCTGCCCTATACCTTCGGCCAGGGCACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGTTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT        (SEQ ID NO: 93)

QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP        (SEQ ID NO: 94)

CAGGTGCAGCTGCAGGAGAGCGGCCCCGGACTGGTGAGGCCTTCCCAGACCCTGAGCCTGACATGCACAGTGAGCGGCTACAGCATCACAAGCGACCACGCCTGGAGCTGGGTGAGACAGCCCCCCGGAAGAGGCCTGGAATGGATCGGATATATCTCCTACTCAGGCATTACCACCTACAACCCCTCTCTGAAAAGCAGAGTGACCATGCTGAGAGATACTAGCAAGAACCAGTTTAGCCTGAGACTGTCTAGCGTGACTGCCGCCGACACCGCCGTGTACTACTGCGCCAGATCCCTGGCCCGGACCACAGCCATGGATTACTGGGGCCAGGGAAGCCTGGTGACAGTGTCCTCCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCCGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCA TCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG        (SEQ ID NO: 95)

SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKDIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC        (SEQ ID NO: 96)

AGCGACACCGGCAGACCCTTCGTGGAGATGTACAGCGAGATCCCCGAGATCATCCACATGACCGAGGGCAGAGAGCTGGTGATCCCCTGCAGAGTGACCAGCCCCAACATCACCGTGACCCTGAAGAAGTTCCCCCTGGACACCCTGATCCCCGACGGCAAGAGAATCATCTGGGACAGCAGAAAGGGCTTCATCATCAGCAACGCCACCTACAAGGAGATCGGCCTGCTGACCTGCGAGGCCACCGTGAACGGCCACCTGTACAAGACCAACTACCTGACCCACAGACAGACCAACACCATCATCGACGTGGTGCTGAGCCCCAGCCACGGCATCGAGCTGAGCGTGGGCGAGAAGCTGGTGCTGAACTGCACCGCCAGAACCGAGCTGAACGTGGGCATCGACTTCAACTGGGAGTACCCCAGCAGCAAGCACCAGCACAAGAAGCTGGTGAACAGAGACCTGAAGACCCAGAGCGGCAGCGAGATGAAGAAGTTCCTGAGCACCCTGACCATCGACGGCGTGACCAGAAGCGACCAGGGCCTGTACACCTGCGCCGCCAGCAGCGGCCTGATGACCAAGAAGAACAGCACCTTCGTGAGAGTGCACGAGAAGGACATTCAGATGACCCAGAGCCCCAGCAGCCTGAGCGCCAGCGTGGGAGACAGAGTGACCATCACCTGCAGAGCCAGCCAGGACATCTCCAGCTACCTGAACTGGTATCAGCAGAAACCCGGCAAAGCCCCAAAACTGCTGATCTACTACACCAGTAGACTGCACAGCGGCGTGCCCAGCAGATTCTCAGGAAGCGGCTCCGGAACCGACTTCACCTTCACTATCAGCAGCCTGCAGCCCGAAGATATTGCTACTTACTACTGCCAGCAGGGGAACACCCTGCCCTATACCTTCGGCCAGGGCACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGTTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT        (SEQ ID NO: 97)

QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP        (SEQ ID NO: 98)

CAGGTGCAGCTGCAGGAGAGCGGCCCCGGACTGGTGAGGCCTTCCCAGACCCTGAGCCTGACATGCACAGTGAGCGGCTACAGCATCACAAGCGACCACGCCTGGAGCTGGGTGAGACAGCCCCCCGGAAGAGGCCTGGAATGGATCGGATATATCTCCTACTCAGGCATTACCACCTACAACCCCTCTCTGAAAAGCAGAGTGACCATGCTGAGAGATACTAGCAAGAACCAGTTTAGCCTGAGACTGTCTAGCGTGACTGCCGCCGACACCGCCGTGTACTACTGCGCCAGATCCCTGGCCCGGACCACAGCCATGGATTACTGGGGCCAGGGAAGCCTGGTGACAGTGTCCTCCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCCGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCA TCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG        (SEQ ID NO: 99)

SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKGGSGGGSGGGGSGGGGGSGGGGDIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC        (SEQ ID NO: 100)

AGCGACACCGGCAGACCCTTCGTGGAGATGTACAGCGAGATCCCCGAGATCATCCACATGACCGAGGGCAGAGAGCTGGTGATCCCCTGCAGAGTGACCAGCCCCAACATCACCGTGACCCTGAAGAAGTTCCCCCTGGACACCCTGATCCCCGACGGCAAGAGAATCATCTGGGACAGCAGAAAGGGCTTCATCATCAGCAACGCCACCTACAAGGAGATCGGCCTGCTGACCTGCGAGGCCACCGTGAACGGCCACCTGTACAAGACCAACTACCTGACCCACAGACAGACCAACACCATCATCGACGTGGTGCTGAGCCCCAGCCACGGCATCGAGCTGAGCGTGGGCGAGAAGCTGGTGCTGAACTGCACCGCCAGAACCGAGCTGAACGTGGGCATCGACTTCAACTGGGAGTACCCCAGCAGCAAGCACCAGCACAAGAAGCTGGTGAACAGAGACCTGAAGACCCAGAGCGGCAGCGAGATGAAGAAGTTCCTGAGCACCCTGACCATCGACGGCGTGACCAGAAGCGACCAGGGCCTGTACACCTGCGCCGCCAGCAGCGGCCTGATGACCAAGAAGAACAGCACCTTCGTGAGAGTGCACGAGAAGGGAGGAAGCGGAGGAGGAAGCGGGGGAGGAGGAAGTGGAGGAGGAGGAGGGAGCGGAGGAGGGGGAGACATTCAGATGACCCAGAGCCCCAGCAGCCTGAGCGCCAGCGTGGGAGACAGAGTGACCATCACCTGCAGAGCCAGCCAGGACATCTCCAGCTACCTGAACTGGTATCAGCAGAAACCCGGCAAAGCCCCAAAACTGCTGATCTACTACACCAGTAGACTGCACAGCGGCGTGCCCAGCAGATTCTCAGGAAGCGGCTCCGGAACCGACTTCACCTTCACTATCAGCAGCCTGCAGCCCGAAGATATTGCTACTTACTACTGCCAGCAGGGGAACACCCTGCCCTATACCTTCGGCCAGGGCACCAAGGTGGAGATCA AACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGTTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT        (SEQ ID NO: 101)

YSMTPPTLNITEESHVIDTGDSLSISCRGQHPLEWAWPGAQEAPATGDKDSEDTGVVRDCEGTDARPYCKVLLLHEVHANDTGSYVCYYKYIKARIEGTTAASSYVFVRDFEQPFINKPDTLLVNRKDAMWVPCLVSIPGLNVTLRSQSSVLWPDGQEVVWDDRRGMLVSTPLLHDALYLQCETTWGDQDFLSNPFLVHITGNELYDIQLLPRKSLELLVGEKLVLNCTVWAEFNSGVTFDWDYPGKQAERGKWVPERRSQQTHTELSSILTIHNVSQHDLGSYVCKANNGIQRFRESTEVIVHEN        (SEQ ID NO: 102)

TACAGCATGACCCCTCCTACCCTGAACATCACCGAGGAGAGCCACGTGATCGACACCGGCGACAGCCTGAGCATCAGCTGCAGAGGCCAGCATCCTTTAGAGTGGGCCTGGCCCGGCGCCCAGGAGGCTCCTGCCACCGGCGACAAGGACAGCGAGGACACCGGCGTGGTGAGAGACTGCGAGGGCACCGACGCCAGACCCTACTGCAAGGTGCTGCTGCTGCACGAGGTGCACGCCAACGACACCGGCAGCTACGTGTGCTACTACAAGTACATCAAGGCCAGAATCGAGGGCACCACCGCCGCCAGCAGCTACGTGTTCGTGAGAGACTTCGAGCAGCCCTTCATCAACAAGCCCGACACCCTGCTGGTGAACAGAAAGGACGCCATGTGGGTGCCCTGCCTGGTGAGCATCCCCGGCCTGAACGTGACCCTGAGAAGCCAGAGCAGCGTGCTGTGGCCCGACGGCCAGGAGGTGGTGTGGGACGACAGAAGAGGCATGCTGGTGAGCACTCCTCTGCTGCACGACGCCCTGTACCTGCAGTGCGAGACCACCTGGGGCGACCAGGACTTCCTGAGCAACCCCTTCCTGGTGCACATCACCGGCAACGAGCTGTACGACATCCAGCTGCTGCCCAGGAAGAGCCTGGAGCTGCTGGTGGGCGAGAAGCTGGTGCTGAACTGCACCGTGTGGGCCGAGTTCAACTCCGGCGTGACCTTTGACTGGGACTACCCCGGCAAGCAGGCCGAAAGGGGAAAATGGGTGCCCGAAAGAAGAAGTCAGCAGACCCACACAGAACTGAGCTCCATCCTGACAATCCACAACGTGAGCCAGCACGACCTGGGCAGCTATGTGTGCAAAGCTAACAACGGCATCCAGAGATTCAGAGAGAGCACCGAGGTGATCGTGCACGAAAAT        (SEQ ID NO: 103)

none

Fig. 1 shows the schematic diagram of the first embodiment and the second embodiment of the antibody fusion protein of the present invention, the antibody fusion protein comprises the antibody against human IL-6R, the light chain and the heavy chain of the antibody fusion protein Each of is connected to a VEGF binding unit through a flexible linker, and the VEGF binding unit comprises Ig-like domain 2 of VEGFR-1 and Ig-like domain 3 of VEGFR-2.

Figure 2 shows schematic diagrams of the third embodiment and the fourth embodiment of the antibody fusion protein of the present invention, the antibody fusion protein comprises an antibody against human IL-6R, and the light chain of the antibody fusion protein is connected to the light chain through a flexible linker The first VEGF binding unit comprising the Ig-like domain 2 of VEGFR-1 and the Ig-like domain 3 of VEGFR-2 is connected, and the heavy chain of the antibody fusion protein is connected to the Ig-like domain comprising VEGFR-3 through a flexible linker The second VEGF binding unit of 2 and 3 are connected.

Figure 3 shows a schematic diagram of a fifth embodiment of an antibody fusion protein of the present invention comprising scFv of an antibody against human IL-6R, each variable domain of the heavy chain of the antibody fusion protein It is connected to the Fc domain, and the Fc domain is further connected to the VEGF binding unit through a flexible linker, and the VEGF binding unit includes the Ig-like domain 2 of VEGFR-1 and the Ig-like domain 3 of VEGFR-2.

Fig. 4 shows the schematic diagram of the sixth embodiment of the antibody fusion protein of the present invention, the antibody fusion protein comprises the scFv of the antibody against human IL-6R, each variable domain of the heavy chain of the antibody fusion protein through The flexible linker is connected to the VEGF-binding unit, and the VEGF-binding unit comprises Ig-like domain 2 of VEGFR-1 and Ig-like domain 3 of VEGFR-2, and the Ig-like domain is further connected to the Fc domain through a flexible linker.

Figure 5 shows a schematic diagram of a seventh embodiment of an antibody fusion protein of the present invention comprising scFv of an antibody against human IL-6R, each variable domain of the heavy chain of the antibody fusion protein Connected to the first VEGF binding unit through a flexible linker, the first VEGF unit includes the Ig-like domain 2 of VEGFR-1 and the Ig-like domain 3 of VEGFR-2, and the Ig-like domain is further connected to the Fc through a flexible linker The Fc domain is connected to a second VEGF binding unit through a flexible linker, and the second VEGF binding unit comprises Ig-like domains 1 and 2 of VEGFR-3.

Figure 6 shows a schematic diagram of an eighth embodiment of an antibody fusion protein of the present invention comprising scFv of an antibody against human IL-6R, each variable domain of the heavy chain of the antibody fusion protein Linked to a first VEGF-binding unit comprising Ig-like domain 2 of VEGFR-1 and Ig-like domain 3 of VEGFR-2 through a flexible linker and binds to a second VEGF comprising Ig-like domains 1 and 2 of VEGFR-3 The units are connected, and the second VEGF binding unit is further connected to the Fc domain through a flexible linker.

Figures 7A-D show the molecular design of six antibody fusion proteins (B781401-781406) of the invention.

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

Figure 9 shows an example of a SEC-HPLC chromatogram used to purify B781401 expressed in HEK293 cells.

Figure 10 shows an example of a SEC-HPLC chromatogram used to purify B781401 expressed in CHO cells.

Figure 11 shows the comparison of the binding affinity of B781401-781406 against recombinant human VEGF-A ₁₆₅ with that of aflibercept using enzyme-linked immunosorbent assay (ELISA).

Figure 12 shows a comparison of the ELISA binding affinity of B781401-781406 against recombinant human VEGF-B ₁₆₇ and the ELISA binding affinity of aflibercept.

Figure 13 shows a comparison of the ELISA binding affinity of B781401-781406 against recombinant human PlGF with that of aflibercept.

Figure 14 shows a comparison of the ELISA binding affinity of B781401-781406 against recombinant human IL-6R with that of tocilizumab.

Figure 15 shows the effect of B781401-781406 on the inhibition of VEGF-A ₁₆₅ mediated VEGFR-2 signaling in VEGFR-2-NFAT-RE luciferase reporter cells compared to the effect of aflibercept.

Figures 16A-B show the effect of B781401-781406 on inhibiting IL-6R signaling compared to that of tocilizumab.

Figure 17 shows the effect of B781401-781406 on inhibiting IL-6R signaling compared to the effect of siltuximab and tocilizumab.

Figure 18 shows the comparison of the ELISA binding affinities of EB-DJ1, EB-vvA, EB-vvB and EB-vvC against recombinant human VEGF-A ₁₆₅ with the ELISA binding affinities of aflibercept, B781403 and B781405.

Figure 19 shows a comparison of the ELISA binding affinities of EB-DJ1, EB-vvA, EB-vvB and EB-vvC against recombinant human VEGF-B ₁₆₇ with that of aflibercept, B781402, B781403 and B781405.

Figure 20 shows the ELISA binding affinities of EB-DJ1, EB-vvA, EB-vvB and EB-vvC against recombinant human PlGF in comparison to the ELISA binding affinities of aflibercept, B781403 and B781405.

Figure 21 shows a comparison of the ELISA binding affinities of EB-DJ1, EB-vvA, EB-vvB and EB-vvC against recombinant human IL-6R with the ELISA binding affinities of tocilizumab, B781402, B781403 and B781405.

none

          Sequence Listing
           <![CDATA[ <110> Eluminex Biosciences (Suzhou) Limited]]>
           <![CDATA[ <120> Antibody fusion protein targeting IL-6 receptor and angiogenic factors]]>
           <![CDATA[ <140> TW111106352]]>
           <![CDATA[ <141> 2022-02-22]]>
           <![CDATA[ <150> US63/207,444]]>
           <![CDATA[ <151> 2021-02-27]]>
           <![CDATA[ <160> 103 ]]>
           <![CDATA[ <170> PatentIn version 3.5]]>
           <![CDATA[ <210> 1]]>
           <![CDATA[ <211> 1344]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <400> 1]]>
          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 tggt 1344
           <![CDATA[ <210> 2]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <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
           <![CDATA[ <210> 3]]>
           <![CDATA[ <211> 642]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <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
           <![CDATA[ <210> 4]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <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 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
           <![CDATA[ <210> 5]]>
           <![CDATA[ <211> 306]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <400> 5]]>
          tccgacacag gacgccccctt 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
           <![CDATA[ <210> 6]]>
           <![CDATA[ <211> 102]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <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
           <![CDATA[ <210> 7]]>
           <![CDATA[ <211> 309]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <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
           <![CDATA[ <210> 8]]>
           <![CDATA[ <211> 103]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <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
           <![CDATA[ <210> 9]]>
           <![CDATA[ <211> 615]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <400> 9]]>
          tattctatga caccgccgac cttgaacata accgaggaat cacatgtaat agacacaggg 60
          gactcacttt caatcagctg tcgaggccag caccccctgg aatgggcttg gccgggggca 120
          caagaagcac ctgctactgg tgacaaggac agcgaagata cgggagttagt 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
           <![CDATA[ <210> 10]]>
           <![CDATA[ <211> 205]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <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
           <![CDATA[ <210> 11]]>
           <![CDATA[ <211> 48]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Joint]]>
           <![CDATA[ <400> 11]]>
          ggagaaggtt ccggtgatgg aggtgagggg aggcggggatg gggaaggt 48
           <![CDATA[ <210> 12]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Joint]]>
           <![CDATA[ <400> 12]]>
          Gly Glu Gly Ser Gly Asp Gly Gly Glu Gly Ser Gly Asp Gly Glu Gly
          1 5 10 15
           <![CDATA[ <210> 13]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Joint]]>
           <![CDATA[ <400> 13]]>
          ggaggctcag gtggcggtgg ttctggcgga gga 33
           <![CDATA[ <210> 14]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Joint]]>
           <![CDATA[ <400> 14]]>
          Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
          1 5 10
           <![CDATA[ <210> 15]]>
           <![CDATA[ <211> 48]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 15]]>
          atgccgttgc tgctgctttt gccactcctt tgggccgggg ctttggca 48
           <![CDATA[ <210> 16]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 16]]>
          Met Pro Leu Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala
          1 5 10 15
           <![CDATA[ <210> 17]]>
           <![CDATA[ <211> 2058]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 cgaatggggag 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
           <![CDATA[ <210> 18]]>
           <![CDATA[ <211> 685]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 18]]>
          Met Pro Leu 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 Ser Gly Leu Met
                      660 665 670
          Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys
                  675 680 685
           <![CDATA[ <210> 19]]>
           <![CDATA[ <211> 1356]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 ggagagggggt 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
           <![CDATA[ <210> 20]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 20]]>
          Met Pro Leu 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 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
           <![CDATA[ <210> 21]]>
           <![CDATA[ <211> 2043]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 tttccccagaa cccgttactg tgtcatggaa ctctggtgct 540
          ttgacaagtg gagtccatac ttttcctgcc gttctgcaat caagtgggct ctatagcttg 600
          tcctcagttg tcacagtacc atcatcaagc ctgggtacac agacttatat atgcaatgtg 660
          aacccacaagc 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 aattgctgt cgaatggggag 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 aggggagggag 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
           <![CDATA[ <210> 22]]>
           <![CDATA[ <211> 680]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 22]]>
          Met Pro Leu 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
           <![CDATA[ <210> 23]]>
           <![CDATA[ <211> 1341]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 caactggggag 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
           <![CDATA[ <210> 24]]>
           <![CDATA[ <211> 446]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 24]]>
          Met Pro Leu 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 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 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 Ser Gly Leu
                      420 425 430
          Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys
                  435 440 445
           <![CDATA[ <210> 25]]>
           <![CDATA[ <211> 2043]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 25]]>
          atgccgcttc ttttgttgct ccccctgctg tgggcggggg ccctcgcgca agttcaactg 60
          caggagagcg gcccgggttt ggtacgacca agccaaacac tctcacttac atgcaccgtg 120
          tcagggtata gcattacctc agaccacgcg tggagctggg tacggcagcc gccgggtcga 180
          ggcctcgagt ggataggggta 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 aattgccgt cgagtggggag 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
           <![CDATA[ <210> 26]]>
           <![CDATA[ <211> 680]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 26]]>
          Met Pro Leu 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
           <![CDATA[ <210> 27]]>
           <![CDATA[ <211> 1356]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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
           <![CDATA[ <210> 28]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 28]]>
          Met Pro Leu 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 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
           <![CDATA[ <210> 29]]>
           <![CDATA[ <211> 2043]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 29]]>
          atgcccctcc tccttttgct tcctctgctg tgggcgggcg cgctggcaca agtacaattg 60
          caagagagcg gcccaggtct cgtaaggccg tcccagactt tgtctctgac atgcacagta 120
          tcagggtatt ccatcactag tgatcacgct tggtcctggg tccgacagcc gcctgggaga 180
          ggcctggagt ggataggggta 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 aacacgcaaaa aagcctcagt 1380
          ttgagtcccgggggtggtag 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 atcgaggggga 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
           <![CDATA[ <210> 30]]>
           <![CDATA[ <211> 680]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 30]]>
          Met Pro Leu 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
           <![CDATA[ <210> 31]]>
           <![CDATA[ <211> 1341]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 31]]>
          atgccgctcc tgcttcttct cccactcctc tgggccggag cgcttgccga catacagatg 60
          acccagtccc ctagtagcct cagcgcaagc gttggagatc gggtgactat aacgtgccga 120
          gcgtcccaag aatttcttc 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 ccctacact 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
           <![CDATA[ <210> 32]]>
           <![CDATA[ <211> 446]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 32]]>
          Met Pro Leu 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 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 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 Ser Gly Leu
                      420 425 430
          Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys
                  435 440 445
           <![CDATA[ <210> 33]]>
           <![CDATA[ <211> 2010]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 agggatgta cacctgcgcc gcgtcttccg ggctcatgac aaaaaaaaac 1980
          agcactttcg tacgcgtcca tgaaaaatag 2010
           <![CDATA[ <210> 34]]>
           <![CDATA[ <211> 669]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 Ser Gly Leu Met
                          645 650 655
          Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys
                      660 665
           <![CDATA[ <210> 35]]>
           <![CDATA[ <211> 1308]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 gtggagagggg 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
           <![CDATA[ <210> 36]]>
           <![CDATA[ <211> 435]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 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
           <![CDATA[ <210> 37]]>
           <![CDATA[ <211> 1995]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 attackgtgc 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 tgaacccacaa 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 ataca actct 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
          aaaggatta 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
           <![CDATA[ <210> 38]]>
           <![CDATA[ <211> 664]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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
           <![CDATA[ <210> 39]]>
           <![CDATA[ <211> 1293]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 agtacccctag cagcaagcac caacataaga agcttgtaaa ccgcgatttg 1140
          aagacgcagt caggcagtga aatgaaaaag ttcttgtcca ctttgacgat tgatggtgtt 1200
          acgagatcag accagggctt gtatacctgc gcagcgtcaa gcgggctgat gacgaagaag 1260
          aactcaactt ttgtcagagt tcacgaaaag tag 1293
           <![CDATA[ <210> 40]]>
           <![CDATA[ <211> 430]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 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 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 Ser Gly Leu
                          405 410 415
          Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys
                      420 425 430
           <![CDATA[ <210> 41]]>
           <![CDATA[ <211> 1995]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 tccggggactt 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
           <![CDATA[ <210> 42]]>
           <![CDATA[ <211> 664]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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
           <![CDATA[ <210> 43]]>
           <![CDATA[ <211> 1308]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 agcgttgtgtgtctcctgaa 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 ctggattct cggaaagggt ttattatctc aaacgctacg 900
          tacaaagaaa tagggctttt gacttgtgag gctacagtta atggacatct ttataaaacg 960
          aattatctta cgcaccgaca gacaaacacc aataagatg 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
           <![CDATA[ <210> 44]]>
           <![CDATA[ <211> 435]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 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
           <![CDATA[ <210> 45]]>
           <![CDATA[ <211> 1995]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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
           <![CDATA[ <210> 46]]>
           <![CDATA[ <211> 664]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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
           <![CDATA[ <210> 47]]>
           <![CDATA[ <211> 1292]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 tttacctta 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 cctacctatag 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
           <![CDATA[ <210> 48]]>
           <![CDATA[ <211> 430]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 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 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 Ser Gly Leu
                          405 410 415
          Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys
                      420 425 430
           <![CDATA[ <210> 49]]>
           <![CDATA[ <211> 446]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 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
           <![CDATA[ <210> 50]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 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
           <![CDATA[ <210> 51]]>
           <![CDATA[ <211> 443]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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
           <![CDATA[ <210> 52]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 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
           <![CDATA[ <210> 53]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 53]]>
          Ser Asp His Ala Trp Ser
          1 5
           <![CDATA[ <210> 54]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 54]]>
          Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 55]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 55]]>
          Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr
          1 5 10
           <![CDATA[ <210> 56]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 56]]>
          Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn
          1 5 10
           <![CDATA[ <210> 57]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 57]]>
          Tyr Thr Ser Arg Leu His Ser
          1 5
           <![CDATA[ <210> 58]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 58]]>
          Gln Gln Gly Asn Thr Leu Pro Tyr Thr
          1 5
           <![CDATA[ <210> 59]]>
           <![CDATA[ <211> 2103]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 gggggggcgg tggcagtggt ggagggggta gcgggaggcgg 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 cgggaacacct 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 aggacggggag 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
           <![CDATA[ <210> 60]]>
           <![CDATA[ <211> 700]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 60]]>
          Met Pro Leu 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 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 Ser Gly Leu Met Thr
                  675 680 685
          Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys
              690 695 700
           <![CDATA[ <210> 61]]>
           <![CDATA[ <211> 2151]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 taccccagtcg gtttagtggg 240
          tccggctccg gaacggattt tacgtttact atcagtagcc tgcagccgga ggacattgcc 300
          acgtactatt gtcagcaggg aaatactctc ccctatacat ttggacaagg cacgaaagtc 360
          gaaattaaac gcggcggcgg tggatctggc gggggaggct caggggggtgg aggagccag 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 tccccagatgg 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
           <![CDATA[ <210> 62]]>
           <![CDATA[ <211> 716]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 62]]>
          Met Pro Leu 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 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 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
           <![CDATA[ <210> 63]]>
           <![CDATA[ <211> 2799]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 63]]>
          atgccattgc ttctcttgct gccactcctt tgggctggag ccctcgctga cattcaaatg 60
          accccagagtc 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 gggtggcgg 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
          ctccccaccct 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 ttgatacgggg ggactctttg tccattcct 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 aggaggttgtttgggacgac agacggggca tgctcgtgtc aacccctctg 2700
          cttcatgatg ccctctattt gcagtgtgag acgacgtggg gtgaccagga ttttctgtca 2760
          aacccttttc tggtgcacat cacgggcaat gagctctag 2799
           <![CDATA[ <210> 64]]>
           <![CDATA[ <211> 932]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 64]]>
          Met Pro Leu 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 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 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
           <![CDATA[ <210> 65]]>
           <![CDATA[ <211> 2805]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 ggtgggggggg 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 acggggatt 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 tgaatggggag tctaacgggc aaccggaaaa taactataaa 2640
          accactccgc cggtgcttga cagcgacggt tcttttttcc tgtacagtaa actcaccgtt 2700
          gataaatcta ggtggcagca gggtaacgtc tttagttgca gcgttatgca tgaggctctt 2760
          cataatcatt atactcaaaa atctttgagt ctgtctcccg gatag 2805
           <![CDATA[ <210> 66]]>
           <![CDATA[ <211> 934]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 66]]>
          Met Pro Leu 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 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 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
           <![CDATA[ <210> 67]]>
           <![CDATA[ <211> 45]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 67]]>
          gggggcggtg gcagtggtgg aggggggtagc ggaggcgggg ggagt 45
           <![CDATA[ <210> 68]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 68]]>
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
          1 5 10 15
           <![CDATA[ <210> 69]]>
           <![CDATA[ <211> 48]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 69]]>
          ggtggatcag ggggcggagg atccggcggc ggtagcgggg gtggtggt 48
           <![CDATA[ <210> 70]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 70]]>
          Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly
          1 5 10 15
           <![CDATA[ <210> 71]]>
           <![CDATA[ <211> 39]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 71]]>
          ggtggcggtg gttcaggtgg gggatcaggc gggggcggt 39
           <![CDATA[ <210> 72]]>
           <![CDATA[ <211> 13]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 72]]>
          Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly
          1 5 10
           <![CDATA[ <210> 73]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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
           <![CDATA[ <210> 74]]>
           <![CDATA[ <211> 711]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 74]]>
          Met Pro Leu 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 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
           <![CDATA[ <210> 75]]>
           <![CDATA[ <211> 2133]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 gggggggcgg tggcagtggt ggagggggta gcgggaggcgg 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 cgggaacacct 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 tggagggagga agcggcggag gcggaagcgg aggggggaggt 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
           <![CDATA[ <210> 76]]>
           <![CDATA[ <211> 711]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <400> 76]]>
          Met Pro Leu 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 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 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
           <![CDATA[ <210> 77]]>
           <![CDATA[ <211> 2133]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 aggggggcggt 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
           <![CDATA[ <210> 78]]>
           <![CDATA[ <211> 652]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 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 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
           <![CDATA[ <210> 79]]>
           <![CDATA[ <211> 1956]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 gcaacccaa 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 gccgcggggag 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 gtgggagc aatgggcagc cggagaacaa ctacaagacc 1800
          acgcctcccg tgctggactc cgacggctcc ttcttcctct acaagcaagct caccgtggac 1860
          aagagcaggt ggcagcaggg gaacgtcttc tcatgctccg tgatgcatga ggctctgcac 1920
          aacccaactaca cgcagaagag cctctccctg tctccg 1956
           <![CDATA[ <210> 80]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 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
           <![CDATA[ <210> 81]]>
           <![CDATA[ <211> 642]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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
           <![CDATA[ <210> 82]]>
           <![CDATA[ <211> 674]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 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
           <![CDATA[ <210> 83]]>
           <![CDATA[ <211> 2022]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 agaaggggagg aagcggagga ggaagcgggg gaggaggaag tggagggagga 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 accacgtttag cctgagactg tctagcgtga ctgccgccga caccgccgtg 960
          tactactgcg ccagatccct ggcccggacc acagccatgg attackgggg 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 gcagggggaac gtcttctcat gctccgtgat gcatgaggct 1980
          ctgcacaacc actacacgca gaagagcctc tccctgtctc cg 2022
           <![CDATA[ <210> 84]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 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
           <![CDATA[ <210> 85]]>
           <![CDATA[ <211> 642]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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
           <![CDATA[ <210> 86]]>
           <![CDATA[ <211> 676]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 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
           <![CDATA[ <210> 87]]>
           <![CDATA[ <211> 2028]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 agaaggggagg aagcggagga ggaagcgggg gaggaggaag tggagggagga 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 accacgtttag cctgagactg tctagcgtga ctgccgccga caccgccgtg 960
          tactactgcg ccagatccct ggcccggacc acagccatgg attackgggg 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 gcagggggaac gtcttctcat gctccgtgat gcatgaggct 1980
          ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggtaaa 2028
           <![CDATA[ <210> 88]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 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
           <![CDATA[ <210> 89]]>
           <![CDATA[ <211> 642]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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
           <![CDATA[ <210> 90]]>
           <![CDATA[ <211> 675]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 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
           <![CDATA[ <210> 91]]>
           <![CDATA[ <211> 2025]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 agaaggggagg aagcggagga ggaagcgggg gaggaggaag tggagggagga 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 accacgtttag cctgagactg tctagcgtga ctgccgccga caccgccgtg 960
          tactactgcg ccagatccct ggcccggacc acagccatgg attackgggg 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 gcagggggaac gtcttctcat gctccgtgat gcatgaggct 1980
          ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggt 2025
           <![CDATA[ <210> 92]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 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
           <![CDATA[ <210> 93]]>
           <![CDATA[ <211> 642]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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
           <![CDATA[ <210> 94]]>
           <![CDATA[ <211> 447]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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
           <![CDATA[ <210> 95]]>
           <![CDATA[ <211> 1341]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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
           <![CDATA[ <210> 96]]>
           <![CDATA[ <211> 419]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 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 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
           <![CDATA[ <210> 97]]>
           <![CDATA[ <211> 1257]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 tctatccccag 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
           <![CDATA[ <210> 98]]>
           <![CDATA[ <211> 447]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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
           <![CDATA[ <210> 99]]>
           <![CDATA[ <211> 1341]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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
           <![CDATA[ <210> 100]]>
           <![CDATA[ <211> 441]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 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 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
           <![CDATA[ <210> 101]]>
           <![CDATA[ <211> 1323]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Artificial Sequence]]>
           <![CDATA[ <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 agaaggggagg aagcggagga ggaagcgggg gaggaggaag tggagggagga 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
           <![CDATA[ <210> 102]]>
           <![CDATA[ <211> 306]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <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
           <![CDATA[ <210> 103]]>
           <![CDATA[ <211> 918]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <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 agggggaaaat gggtgcccga aagaagaagt 780
          cagcagaccc acacagaact gagctccatc ctgacaatcc acaacgtgag ccagcacgac 840
          ctgggcagct atgtgtgcaa agctaacaac ggcatccaga gattcagaga gagcaccgag 900
          gtgatcgtgc acgaaaat 918
          
      

Claims (33)

An antibody fusion protein, or an antigen-binding fragment or domain thereof, capable of substantially binding IL-6R and one or more VEGF family members. The antibody fusion protein according to claim 1, which comprises an antibody against IL-6R or an antigen-binding fragment or domain thereof linked to a VEGF binding unit, the VEGF binding unit comprising an Ig-like domain selected from the group consisting of: The Ig-like domain of a first VEGF receptor, the Ig-like domain of a second VEGF receptor, the Ig-like domain of a third VEGF receptor, and combinations thereof. The antibody fusion protein according to claim 1, which comprises an antibody against IL-6R or its antigen-binding fragment or domain; wherein (1) the light chain or its antigen-binding fragment or domain and (2) the heavy chain or its At least one of the antigen-binding fragments or domains 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, a second VEGF receptor The Ig-like domain of a body, the Ig-like domain of a third VEGF receptor, and combinations thereof. The antibody fusion protein according to claim 3, wherein the IL-6R is human IL-6R. The antibody fusion protein according to 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) human Ig-like domain 3 or substantially Ig-like domain 3 of 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 of human VEGFR-3 or substantially Ig-like domains 1, 2 and 3. The antibody fusion protein according to claim 4, wherein the light chain of the IL-6R antibody part or its antigen-binding fragment or domain and the heavy chain or its antigen-binding fragment or domain are connected to a VEGF binding unit, the 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. The antibody fusion protein according to claim 4, wherein (1) the light chain of the IL-6R antibody part or its antigen-binding fragment or domain is connected to the first VEGF-binding unit, and the first VEGF-binding unit comprises: (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) all The heavy chain of the antibody fusion protein or an antigen-binding fragment or domain thereof is linked to a second VEGF-binding unit comprising: (a) Ig-like domains 1 and 2 of human VEGFR-3 or substantially 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 of human VEGFR-3 1, 2 and 3 or substantially Ig-like domains 1, 2 and 3. According to the antibody fusion protein described in Claim 6, wherein its heavy chain has the complementarity determining regions HCCDR1, HCCDR2 and HCCDR3 of the amino acid sequences shown in SEQ ID NO: 53, 54 and 55. According to the antibody fusion protein described in Claim 6, wherein its light chain has the complementarity determining regions LCCDR1, LCCDR2 and LCCDR3 of the amino acid sequences shown in SEQ ID NO: 56, 57 and 58. The antibody fusion protein according to claim 6, wherein a pair of heavy chain and light chain has an amino acid sequence selected from the group consisting of: SEQ ID NO: 34 and 36, SEQ ID NO: 38 and 40, SEQ ID NO : 42 and 44, SEQ ID NO: 46 and 48, SEQ ID NO: 78 and 80, SEQ ID NO: 82 and 84, SEQ ID NO: 86 and 88, SEQ ID NO: 90 and 92, SEQ ID NO: 94 and 96 and SEQ ID NO: 98 and 100. The antibody fusion protein according to claim 2, which comprises 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. The antibody fusion protein according to claim 2, which comprises an amino acid sequence starting from amino acid 17 of 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. The antibody fusion protein according to any one of claims 1 to 12, wherein the antibody fusion protein binds to IL-6R and VEGF family members with a dissociation constant K _d ≤ 10 ^-9 M. The antibody fusion protein according to any one of claims 1 to 12, wherein the antibody fusion protein binds to IL-6R and VEGF family members with a dissociation constant K _d ≤ 10 ⁻¹⁰ M. An isolated nucleic acid molecule encoding the antibody fusion protein according to any one of claims 1-12. 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. A vector comprising the nucleic acid molecule according to claim 15 or 16. The vector according to claim 17, comprising the nucleic acid molecule operably linked to an expression control sequence. A host-vector system comprising the expression vector according to claim 18 in a host cell. A kind of host-vector system, it comprises expression carrier pair, and described expression carrier pair comprises and is selected from a pair of nucleotide sequences of lower group: SEQ ID NO: 17 and 19; SEQ ID NO: 21 and 23; SEQ ID NO: 25 and 27; SEQ ID NO: 29 and 31; SEQ ID NO: 79 and 81; SEQ ID NO: 83 and 85; SEQ ID NO: 87 and 89; SEQ ID NO: 91 and 93; SEQ ID NO: 95 and 97; and SEQ ID NO: 99 and 101. A kind of host-vector system, it comprises expression vector, and described expression vector comprises the nucleotide sequence selected from the group: SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 75 and SEQ ID NO: 77. A method of producing a substantially purified antibody fusion protein, the method comprising: (a) growing cells of the host-vector system according to 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. A method for treating or managing at least one disease, condition or disorder in a subject in need thereof, wherein the etiology of the disease, condition or disorder is abnormal angiogenesis or inflammation; wherein said method comprises administering to said subject The subject is administered an amount of a composition of antibody fusion proteins comprising substantially as SEQ ID NOs: 34 and 36; SEQ ID NOs: 38 and 40; SEQ ID NOs: 42 and 44; SEQ ID NO: 46 and 48; SEQ ID NO: 78 and 80; SEQ ID NO: 82 and 84; SEQ ID NO: 86 and 88; SEQ ID NO: 90 and 92; SEQ ID NO: 94 and 96; 100; SEQ ID NO: 60; SEQ ID NO: 62; SEQ ID NO: 64; SEQ ID NO: 66; SEQ ID NO: 74; or the amino acid sequence set forth in SEQ ID NO: 76. The method according to claim 23, wherein said 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 leak, Macular edema, nonproliferative and proliferative diabetic retinopathy, corneal neovascularization, corneal inflammation, myopic neovascularization, and neovascular glaucoma. The method according to claim 24, wherein a dose of about 25-4000 micrograms of the antibody fusion protein is administered to the subject. According to the method described in claim 25, wherein the composition is formulated as eye drops, punctal plugs, intracameral injections, retrobulbar injections, subconjunctival injections, peribulbar injections, subcapsular injections, scleral The subject is administered in the form of a para-injection, a transscleral injection, an intravitreal injection, a subretinal injection or a suprachoroidal injection. The method of claim 25, wherein if administered intraocularly, the composition is administered to the subject for a period of at least one month. The method of claim 25, wherein if administered intraocularly, the composition is administered to the subject at a frequency of at least once a month. A method for treating or managing at least one systemic disease, condition or disorder in a subject in need thereof, wherein the etiology of the disease, condition or disorder is abnormal angiogenesis or inflammation; wherein the method comprises introducing The subject is administered an amount of a composition of an antibody fusion protein or antigen-binding fragment thereof capable of substantially binding IL-6R and one or more VEGF family members. A method for treating or managing at least one systemic disease, condition or disorder in a subject in need thereof, wherein the etiology of the disease, condition or disorder is abnormal angiogenesis or inflammation; wherein the method comprises introducing The subject is administered a certain amount of a composition of antibody fusion protein comprising substantially as SEQ ID NO: 34 and 36; SEQ ID NO: 38 and 40; SEQ ID NO: 42 and 44; SEQ ID NO: 42 and 44; NO: 46 and 48; SEQ ID NO: 78 and 80; SEQ ID NO: 82 and 84; SEQ ID NO: 86 and 88; SEQ ID NO: 90 and 92; SEQ ID NO: 94 and 96; 98 and 100; SEQ ID NO: 60; SEQ ID NO: 62; SEQ ID NO: 64; SEQ ID NO: 66; SEQ ID NO: 74; The method of claim 30, wherein the systemic disease, condition or condition is related to tumor growth, tumor metastasis, or both. The method of claim 30, wherein the systemic disease, condition or disorder is atherosclerosis. The method of claim 30, wherein the systemic disease, condition or disorder is psoriasis.

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