CN116635057A - Methods of using activin receptor type II variants - Google Patents

Abstract

The application provides polypeptides that include extracellular ActRII variants, such as ActRIIA variants, actRIIB variants, or ActRII chimeras. In some embodiments, the polypeptides of the application include extracellular ActRII variants fused to an Fc domain monomer or portion. The application also provides pharmaceutical compositions comprising the polypeptides and methods of using the polypeptides to treat diseases and conditions treatable with erythropoietin or erythropoiesis stimulating agents.

Description

Methods of using activin receptor type II variants

Sequence listing

The present application contains a sequence listing that has been electronically submitted in ASCII format and is incorporated by reference herein in its entirety. ASCII copies were created at 2021, 10/1, under the name 51184-026wo4_sequence_listing_10_1_21_st25 and size 546,175 bytes.

Background

Erythropoietin (EPO) is a hormone that is secreted primarily by the kidneys typically in response to low oxygen content. It is known to promote erythropoiesis, but it has also been found to stimulate mobilization, proliferation and differentiation of endothelial progenitor cells, improve gastrointestinal motility disorders, have broad neuroprotective and anti-inflammatory capabilities, and play a key role in tissue protection and recovery. Recombinant EPO and EPO mimetics, such as epoetin alpha (epoetin alfa) and epoetin beta, are often referred to as Erythropoiesis Stimulators (ESAs), which are currently used to treat anemia associated with chronic kidney disease and anemia associated with cancer or chemotherapy. However, recombinant EPO therapy requires intravenous administration once to three times a week for up to twelve weeks, a treatment regimen that is inconvenient for the patient. Furthermore, treatment with high doses of EPO may lead to proliferation of cancer cells in subjects with cancer or to tumor recurrence in subjects previously afflicted with cancer. Thus, there is a need for alternative therapies for EPO.

Disclosure of Invention

The invention provides polypeptides comprising an extracellular activator receptor type II (ActRII) variant, such as an extracellular ActRIIA variant, an extracellular ActRIIB variant, or an extracellular ActRII chimera. In some embodiments, the polypeptides of the invention include an N-terminal or C-terminal extracellular ActRII variant fused to a monomer or portion of an Fc domain. Such moieties may be linked by amino acids or other covalent bonds and may increase the stability of the polypeptide. Polypeptides comprising extracellular ActRII variants fused to an Fc domain monomer may also form dimers (e.g., homodimers or heterodimers) through interactions between two Fc domain monomers. The polypeptides of the invention may be used in place of EPO to treat a subject having a disease or condition treatable with EPO or ESA, such as end-stage renal disease, renal insufficiency, polycythemia, a disease associated with endothelial progenitor cell dysfunction, a neurological disorder or inflammatory brain disease, gastrointestinal motility disorder, ischemia (e.g., central Nervous System (CNS) ischemia, liver ischemia, kidney ischemia or heart ischemia), hypoxia or a disease or condition having an inflammatory or autoimmune component, or for treating a subject undergoing renal dialysis, a subject to be operated on, or a subject that has recently received stem cell transplantation. The polypeptides of the invention may also be used to increase EPO levels and EPO receptor levels in a subject in need thereof. In addition, the polypeptides of the invention may also be used to affect myostatin, activin (activin a and/or activin B), and/or bone morphogenic protein 9 (BMP 9) signaling in a subject at risk of developing or suffering from a disease or disorder described herein.

Exemplary embodiments of the present invention are described in the following paragraphs.

E1. A method of treating a subject suffering from or at risk of developing a disease or disorder treatable with erythropoietin or an erythropoiesis stimulating agent by administering to the subject a therapeutically effective amount of a composition of table 10, a composition of table 11, or a composition of table 12.

E2. A method of affecting myostatin, activin a, activin B, and/or BMP9 signaling (e.g., reducing or inhibiting binding of myostatin, activin a, activin B, and/or BMP9 to its endogenous receptor) in a subject suffering from or at risk of developing a disease or disorder treatable with erythropoietin or an erythropoiesis stimulating agent by administering to the subject a therapeutically effective amount of a composition of table 10, a composition of table 11, or a composition of table 12.

E3. The method of E1 or E2, wherein the disease or condition treatable with erythropoietin or an erythropoiesis stimulating agent is anemia due to dialysis or anemia of premature infants.

E4. The method of E1 or E2, wherein the disease or condition treatable with erythropoietin or erythropoiesis stimulating agent is end-stage renal disease, renal insufficiency, polycythemia, hemochromatosis, a disease or condition associated with endothelial progenitor cell dysfunction, a disease or condition having an autoimmune or inflammatory component, a neurological or inflammatory brain disease, gastrointestinal motility disorders, an endocrine system disease, a reproductive system disease, aging, pregnancy (e.g., a hematological abnormality associated with pregnancy), menstrual disorder, ischemia or ischemic condition or disorder, hypoxia or anaerobic condition or disorder, an ulcer, a burn, a wound (e.g., a chronic wound), ischemia-reperfusion injury, asthma, hypertension, a viral disease or infection, a systemic microbial infection, a gastrointestinal tract disease, arteriosclerosis, cancer, psychosis, a genetic disease, an inflammatory disease, a graft versus host disease, a cardiovascular disease, an allergic reaction, or arthritis.

E5. A method of increasing erythropoietin levels in a subject in need thereof by administering to the subject a therapeutically effective amount of a composition of table 10, a composition of table 11, or a composition of table 12.

E6. A method of increasing the level of an erythropoietin receptor in a subject in need thereof by administering to the subject a therapeutically effective amount of a composition of table 10, a composition of table 11, or a composition of table 12.

E7. The method of E5 or E6, wherein the subject has or is at risk of developing anemia due to dialysis or anemia of premature infants.

E8. The method of E5 or E6, wherein the subject has or is at risk of developing: end stage renal disease, renal insufficiency, polycythemia, hemochromatosis, diseases or conditions associated with dysfunction of endothelial progenitor cells, diseases or conditions having an autoimmune or inflammatory component, neurological or inflammatory encephalopathy, gastrointestinal motility disorders, endocrinological disorders, diseases of the reproductive system, aging, pregnancy (e.g., a hematological abnormality associated with pregnancy), menstrual disorder, ischemic or ischemic disorders or conditions, anoxic or anoxic disorders or conditions, ulcers, burns, wounds (e.g., chronic wounds), ischemia-reperfusion injury, asthma, hypertension, viral diseases or infections, systemic microbial infections, gastrointestinal diseases, arteriosclerosis, cancer, psychosis, genetic diseases, inflammatory diseases, graft versus host disease, cardiovascular diseases, allergic reactions or arthritis.

E9. The method of E4 or E8, wherein the disease or disorder treatable with erythropoietin or an erythropoiesis stimulating agent is ischemia, or wherein the subject has ischemia or is at risk of developing ischemia.

E10. The method of E9, wherein the ischemia is central nervous system ischemia, liver ischemia, kidney ischemia, or cardiac ischemia.

E11. The method of E4 or E8, wherein the disease or disorder treatable with erythropoietin or an erythropoiesis stimulating agent is an ischemic condition or disorder, or wherein the subject has or is at risk of developing an ischemic condition or disorder.

E12. The method of E11, wherein the ischemic condition or disorder is an obstructive arterial disease, chronic venous insufficiency, circulatory shock (e.g., hemorrhagic, septic or cardiogenic shock), pulmonary embolism, myocardial infarction, ischemic stroke, acute respiratory failure, chronic heart failure, atherosclerosis, cardiac cirrhosis, macular degeneration, sleep apnea, raynaud's disease, systemic sclerosis, non-bacterial thrombotic endocarditis, transient ischemic attacks, or ischemia caused by general anesthesia.

E13. The method of E4 or E8, wherein the disease or disorder treatable with erythropoietin or an erythropoiesis stimulating agent is an hypoxic disorder or condition, or wherein the subject has or is at risk of developing an hypoxic disorder or condition.

E14. The method of E13, wherein the hypoxic condition or disorder is a pulmonary condition (e.g., chronic obstructive pulmonary disease), perinatal hypoxia, severe pneumonia, pulmonary edema, hyaline membrane disease, liver disease, kidney disease, cancer, or altitude disease.

E15. The method of E4 or E8, wherein the disease or condition treatable with erythropoietin or an erythropoiesis stimulating agent is a viral disease or infection, or wherein the subject has or is at risk of developing a viral disease or infection.

E16. The method of E15, wherein the viral disease or infection is a hepatitis C virus infection or an HIV infection.

E17. The method of E4 or E8, wherein the disease or disorder treatable with erythropoietin or an erythropoiesis stimulating agent is a disease or disorder associated with endothelial progenitor cell dysfunction, or wherein the subject has or is at risk of developing a disease or disorder associated with endothelial progenitor cell dysfunction.

E18. The method of E17, wherein the disease or disorder associated with endothelial progenitor cell dysfunction is heart failure, angina, endothelial proliferation, reticuloendotheliosis, age-related cardiovascular disorder, coronary heart disease, atherosclerosis, myocardial ischemia, hypercholesterolemia, limb ischemic disorder, raynaud's disease, preeclampsia, pregnancy induced hypertension, endothelial-mediated chronic inflammatory disorder (e.g., vascular inflammation), wound healing, chronic renal failure (chronic kidney disease), or acute renal failure (acute kidney failure).

E19. The method of E18, wherein the disease or disorder associated with endothelial progenitor cell dysfunction is chronic renal failure (chronic kidney disease).

E20. The method of E4 or E8, wherein the disease or condition treatable with erythropoietin or an erythropoiesis stimulating agent is an autoimmune or inflammatory disease or condition, or wherein the subject has or is at risk of developing an autoimmune or inflammatory disease or condition.

E21. The method of E20, wherein the autoimmune or inflammatory disease or disorder is acute cerebrovascular injury, acute brain injury, acute cardiovascular injury, arthritis, autoimmune disease, stroke, nerve injury, or immune-mediated inflammation.

E22. The method of E4 or E8, wherein the disease or condition treatable with erythropoietin or an erythropoiesis stimulating agent is a neurological disorder or inflammatory brain disease, or wherein the subject has or is at risk of developing a neurological disorder or inflammatory brain disease.

E23. The method of E22, wherein the neurological disorder or inflammatory brain disease is a demyelinating disease, epilepsy, spinal cord injury (e.g., acute spinal cord injury), complications following traumatic brain injury (e.g., symptoms for treating traumatic brain injury such as hypotension, hypoxia, brain swelling, headache, neck pain, memory difficulties, difficulty concentrating, difficulty making decisions, fatigue, mood changes, nausea, photophobia, blurred vision, tinnitus, loss of taste and smell, seizures, coma, muscle weakness, paralysis or progressive decline in neurological function), chronic inflammatory brain disease, or neurological disorders associated with surgery (e.g., thoracoabdominal aortic surgery).

E24. The method of E23, wherein the chronic inflammatory brain disease is a neurodegenerative disease.

E25. The method of E24, wherein the neurodegenerative disease is Alzheimer's disease, parkinson's disease, huntington's disease, amyotrophic Lateral Sclerosis (ALS), or age-related macular degeneration (AMD).

E26. The method of E23, wherein the demyelinating disease is multiple sclerosis, neuromyelitis optica, acute disseminated encephalomyelitis, or transverse myelitis.

E27. The method of E4 or E8, wherein the disease or condition treatable with erythropoietin or an erythropoiesis stimulating agent is gastrointestinal motility disorder, or wherein the subject has or is at risk of developing gastrointestinal motility disorder.

E28. The method of E27, wherein the gastrointestinal motility disorder is associated with: intestinal injury, abdominal trauma, inflammatory disorders of the intestinal tract, intestinal infection, chronic constipation, postoperative ileus, neurodegenerative injury, neurotraumatic injury, congenital problems or malnutrition-malabsorption problems.

E29. The method of E28, wherein the intestinal infection is a bacterial infection (e.g., an infection that causes sepsis or bacteremia), peritonitis, or ascites.

E30. The method of E28, wherein the intestinal inflammatory disorder is inflammatory bowel disease, crohn's disease, or ulcerative colitis.

E31. The method of E28, wherein the chronic transmission constipation is chronic constipation, idiopathic constipation, constipation due to post-operative ileus, or constipation caused by opiate use.

E32. The method of E28, wherein the congenital problem is abdominal fissure, umbilical hernia, ganglionic megacolon, helschsprong's disease, chronic intestinal pseudo-obstruction, left small colon syndrome, anorectal abnormalities, esophageal dysplasia and closure, anal closure, congenital hernia, or internal anal sphincter relaxant.

E33. The method of E28, wherein the malnutrition-malabsorption problem is associated with: intestinal injury, abdominal trauma, intestinal inflammatory disorders, intestinal infection, constipation, post-operative ileus, neurodegenerative injury, neurotraumatic injury, congenital problems, gaucher's disease, refeeding syndrome, very low birth weight, cancer cachexia, infection, cancer, spinal cord dysfunction, spinal cord insufficiency, spinal column fissure, tumors, central nervous system dysfunction, peripheral neuropathy, removal of a portion of the gastrointestinal tract, hemorrhage, liver dysfunction, celiac disease, cystic fibrosis, muscular dystrophy, or cerebral palsy.

E34. The method of E4 or E8, wherein the disease or condition treatable with erythropoietin or an erythropoiesis stimulating agent is end stage renal disease, or wherein the subject has or is at risk of developing end stage renal disease.

E35. The method of E4 or E8, wherein the disease or disorder treatable with erythropoietin or erythropoiesis stimulating agent is polycythemia, or wherein the subject has or is at risk of developing polycythemia.

E36. The method of any one of E1-E35, wherein the composition of table 10, table 11, or table 12 is administered to the subject prior to surgery (e.g., for increasing red blood cell count prior to surgery), after stem cell transplantation, prior to or during space flight, during or after tissue or organ transplantation, to promote neovascular growth, to form granulation tissue, to perform wound therapy, or to perform post-vascular transplantation therapy.

The method of any one of E37-E36, wherein the subject is undergoing kidney dialysis.

E38. The method of any one of E1, E2, E4-E6, and E8-E37, wherein the subject does not have anemia.

E39. The method of any one of E1, E2, E4-E6, and E8-E38, wherein the subject has normal hematopoiesis.

E40. The method of any one of E1-E39, wherein the subject has low serum erythropoietin.

E41. A method of preparing a tissue or organ for transplantation by contacting the tissue or organ (e.g., while in or after removal from the tissue or organ donor) with a therapeutically effective amount of a composition of table 10, a composition of table 11, or a composition of table 12.

E42. The method of any one of E1-E41, wherein the method comprises administering to the subject a therapeutically effective amount of a composition of table 10.

E43. The method of any one of E1-E41, wherein the method comprises administering to the subject a therapeutically effective amount of the composition of table 11.

E44. The method of any one of E1-E41, wherein the method comprises administering to the subject a therapeutically effective amount of the composition of table 12.

E45. The method of any one of E1-E44, wherein the composition is administered in an amount sufficient to increase EPO levels, increase EPO receptor levels, promote neovascular growth and/or replace damaged vascular areas, promote granulation tissue formation, reduce infiltration of monocytes into the brain of the subject, improve neurological deficit, reduce axonal damage, reduce neuronal cell death, reduce glial cell death, affect myostatin, activin a, activin B, and/or BMP9 signaling in the subject, or reduce or inhibit binding of activin a, activin B, and/or myostatin to its receptor.

E46. The method of any one of E1-E45, wherein the method does not cause vascular complications in the subject.

E47. The method of E46, wherein the method does not increase vascular permeability or leakage.

E48. The method of any one of E1-E47, wherein the subject is a human.

Definition of the definition

To facilitate an understanding of the invention, a number of terms are defined below. The terms defined herein have meanings as commonly understood by one of ordinary skill in the art to which the invention pertains. Terms such as "a," "an," and "the" are not intended to refer to only a singular entity, but rather include the general class of which a particular example may be used for illustration. Unless outlined in the claims, the terminology herein is used to describe a particular embodiment of the invention, but its use is not limiting of the invention.

As used herein, the term "about" means a value that is within 10% of the value described.

As used herein, any value provided as a range of values includes upper and lower bounds and any values contained within the upper and lower bounds.

As used herein, the terms "extracellular activin receptor type IIA (ActRIIA) variant" and "ActRIIA variant" refer to peptides that include a soluble extracellular portion of a single transmembrane receptor ActRIIA that has at least one amino acid substitution relative to wild-type extracellular ActRIIA (e.g., bold portions of the sequence of SEQ ID NO:75, shown below) or extracellular ActRIIA having any of the sequences of SEQ ID NOs 76-96. The sequence of the wild-type human ActRIIA precursor protein (SEQ ID NO: 75) is shown below, with the signal peptide in italics and the extracellular portion in bold.

Wild type human ActRIIA precursor protein (SEQ ID NO: 75):

the extracellular ActRIIA variant may have the sequence of any of SEQ ID NOs 1-72. In a particular embodiment, the extracellular ActRIIA variant has the sequence of any one of SEQ ID NOs 6-72 (table 2). In some embodiments, the extracellular ActRIIA variant may have at least 85% (e.g., at least 85%, 87%, 90%, 92%, 95%, 97% or more) amino acid sequence identity with the sequence of wild-type extracellular ActRIIA (SEQ ID NO: 73).

As used herein, the terms "extracellular activator receptor type IIB (ActRIIB) variant" and "ActRIIB variant" refer to peptides that include a soluble extracellular portion of a single transmembrane receptor ActRIIB that has at least one amino acid substitution relative to wild-type extracellular ActRIIB (e.g., the bold portion of the sequence of SEQ ID NO:173, shown below). The sequence of wild-type human ActRIIB (SEQ ID NO: 173) is shown below, with the signal peptide in italics and the extracellular portion in bold.

Wild type human ActRIIB (SEQ ID NO: 173):

the extracellular ActRIIB variant may have the sequence of any one of SEQ ID NOs 157-171. In a particular embodiment, the extracellular ActRIIB variant has the sequence of any one of SEQ ID NOs 158-171 (table 5). In some embodiments, an extracellular ActRIIB variant may have at least 85% (e.g., at least 85%, 87%, 90%, 92%, 95%, 96%, 97%, 98%, 99% or more) amino acid sequence identity with the sequence of wild-type extracellular ActRIIB (SEQ ID NO: 74). Extracellular ActRIIB variants may also have an N-terminal truncation of 1-7 amino acids relative to the extracellular portion of ActRIIB.

As used herein, the terms "extracellular activin receptor type II (ActRII) chimera," "extracellular ActRII chimera," and "ActRII chimera" refer to peptides that include the soluble extracellular portion of the single transmembrane receptor ActRIIB as well as the soluble extracellular portion of the single transmembrane receptor ActRIIA. ActRII chimeras described herein result from ligating the N-terminal portion of extracellular ActRIIB with the C-terminal portion of extracellular ActRIIA such that the sequence is continuous (e.g., the ActRIIA sequence continues at the stop of the ActRIIB sequence starting with the next amino acid located at the corresponding position of ActRIIA). The extracellular ActRII chimera may also include one or more amino acid substitutions in a chimeric portion of the sequence corresponding to ActRIIB (e.g., bold portions of the sequence of SEQ ID NO:173, shown above) as compared to wild-type extracellular ActRIIB, and one or more amino acid substitutions in a chimeric portion of the sequence corresponding to ActRIIA (e.g., bold portions of the sequence of SEQ ID NO:75, shown above) as compared to wild-type extracellular ActRIIA. Extracellular ActRII chimeras may also be N-terminal truncated by 1-9 amino acids relative to the extracellular portion of ActRIIB or ActRIIA. The sequences of wild-type human ActRIIB (SEQ ID NO: 173) and wild-type human ActRIIA (SEQ ID NO: 75) are shown in the above definitions, wherein the signal peptide is in italics and the extracellular portion is in bold. The extracellular ActRII chimera may have the sequence of any one of SEQ ID NOs 174-216. In a particular embodiment, the extracellular ActRII chimera has the sequence of any one of SEQ ID NOs 195-216 (table 7).

As used herein, the term "extracellular activator receptor type II (ActRII) variant" refers to an extracellular ActRIIA variant, an extracellular ActRIIB variant, or an extracellular ActRII chimeric described herein.

As used herein, the term "N-terminally truncated" refers to the deletion of 1-7 amino acids (e.g., 1, 2, 3, 4, 5, 6, or 7 amino acids) from the N-terminus of an extracellular ActRIIB variant (e.g., an extracellular ActRIIB variant having the sequence of any one of SEQ ID NOs: 157-171 (e.g., SEQ ID NOs: 158-171)) or the deletion of 1-9 amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9 amino acids) from the N-terminus of an extracellular ActRII chimera (e.g., an extracellular ActRII chimera having the sequence of any one of SEQ ID NOs: 174-216 (e.g., SEQ ID NOs: 195-216)). The N-terminal truncation may remove amino acids up to the two amino acids before the first cysteine (e.g., two amino acids before the first cysteine (RE) are retained in the N-terminal truncated extracellular ActRIIB variant, and two amino acids before the first cysteine (RE or QE) are retained in the N-terminal truncated extracellular ActRII chimera).

As used herein, the term "linker" refers to a linking moiety between two elements (e.g., peptide or protein domains). The polypeptides described herein may include an extracellular ActRII variant (e.g., an extracellular ActRIIA variant having the sequence of any of SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72)), an extracellular ActRIIB variant (e.g., an extracellular ActRIIB variant having the sequence of any of SEQ ID NOs: 157-171 (e.g., SEQ ID NOs: 158-171)), or an extracellular ActRII chimeric (e.g., an extracellular ActRII chimeric having the sequence of any of SEQ ID NOs: 174-216 (e.g., SEQ ID NOs: 195-216)), which may increase the stability of the polypeptide or improve the pharmacokinetic properties thereof the portion (e.g., an Fc domain monomer, an Fc domain (e.g., a wild-type Fc domain), an Fc domain having amino acid substitution (e.g., one or more substitutions that reduce dimerization), an albumin binding peptide, a fibronectin domain, or a human serum albumin) may be attached to the polypeptide via a linker, may be a spacer, a chemical bond, e.g., a disulfide bond, or a covalent bond, or any type of bond formed by a chemical reaction (e.g., chemical conjugation). The term "spacer" refers to a moiety (e.g., a polyethylene glycol (PEG) polymer) or amino acid sequence (e.g., 1-200 amino acid sequences) that is present between two elements (e.g., peptide or protein domains) to provide spacing and/or flexibility between the two elements. An amino acid spacer is a portion of the primary sequence of a polypeptide (e.g., fused to a spacer peptide via a polypeptide backbone). For example, the formation of disulfide bonds between two hinge regions forming an Fc domain is not considered a linker.

As used herein, the term "Fc domain" refers to a dimer of two Fc domain monomers. Fc domain and at least comprising C _H 2 domain and C _H The human Fc domain of domain 3 has at least 80% sequence identity (e.g., at least 85%, 90%, 95%, 97% or 100% sequence identity). The Fc domain monomer comprises the second and third antibody constant domains (C _H 2 and C _H 3). In some embodiments, the Fc domain monomer further comprises a hinge domain. The Fc domain does not include any portion of an immunoglobulin that is capable of acting as an antigen recognition region, such as a variable domain or Complementarity Determining Region (CDR). In the wild-type Fc domain, two Fc domain monomers pass through two cs _H 3 interaction between antibody constant domains and one or more disulfide formed between hinge domains of two dimerized Fc domain monomersThe bond dimerizes. In some embodiments, the Fc domain may be mutated to lack effector function, which is characteristic of a "dead Fc domain. In certain embodiments, each of the Fc domain monomers in the Fc domain is at C _H 2 include amino acid substitutions in the antibody constant domain to reduce the interaction or binding between the Fc domain and the fcγ receptor. In some embodiments, the Fc domain contains one or more amino acid substitutions that reduce or inhibit dimerization of the Fc domain. The Fc domain may be any immunoglobulin antibody isotype, including IgG, igE, igM, igA or IgD. In addition, the Fc domain may be of the IgG subtype (e.g., igG1, igG2a, igG2b, igG3, or IgG 4). The Fc domain may also be a non-naturally occurring Fc domain, such as a recombinant Fc domain.

As used herein, the term "albumin binding peptide" refers to an amino acid sequence of 12 to 16 amino acids that has affinity for serum albumin and is used to bind serum albumin. Albumin binding peptides may be of different origin, e.g. human, mouse or rat. In some embodiments, the albumin binding peptide has sequence DICLPRWGCLW (SEQ ID NO: 151).

As used herein, the term "fibronectin domain" refers to a high molecular weight glycoprotein or fragment thereof that binds to the extracellular matrix, e.g., transmembrane receptor proteins (such as integrins) and extracellular matrix components (such as collagen and fibrin). In some embodiments, the fibronectin domain is a polypeptide having the UniProt ID number: the fibronectin type III domain of amino acids 610-702 of the sequence of P02751 (SEQ ID NO: 152). In other embodiments, the fibronectin domain is an adnectin protein.

As used herein, the term "human serum albumin" refers to albumin present in human plasma. Human serum albumin is the most abundant protein in blood. It constitutes about half of the serum proteins. In some embodiments, the human serum albumin has a UniProt ID number: p02768 (SEQ ID NO: 153).

As used herein, the term "endogenous" describes a molecule (e.g., a polypeptide, nucleic acid, or cofactor) that naturally occurs in a particular organism (e.g., a human) or at a particular location within an organism (e.g., an organ, tissue, or cell, such as a human cell, e.g., a human red blood cell, platelet, neutrophil, or muscle cell).

As used herein, the term "fusion" is used to describe the combination or attachment of two or more elements, components, or protein domains (e.g., peptides or polypeptides) by means including chemical conjugation, recombinant means, and chemical bonds (e.g., amide bonds). For example, two single peptides in tandem may be fused by chemical conjugation, chemical linkage, peptide linker, or any other covalent linkage means to form one continuous protein structure (e.g., polypeptide). In some embodiments of the polypeptides described herein, an extracellular ActRII variant (e.g., an extracellular ActRIIA variant having the sequence of any of SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72)), an extracellular ActRIIB variant (e.g., an extracellular ActRIIB variant having the sequence of any of SEQ ID NOs: 157-171 (e.g., SEQ ID NOs: 158-171)), or an extracellular ActRII chimera (e.g., an extracellular ActRII chimera having the sequence of any of SEQ ID NOs: 174-216 (e.g., SEQ ID NOs: 195-216)) may be fused in series by a linker to a portion (e.g., an Fc domain monomer (e.g., the sequence of SEQ ID NOs: 97)), an Fc domain (e.g., a wild-type Fc domain (e.g., the sequence of SEQ ID NOs: 150 or SEQ ID NOs: 155)), an Fc domain having amino acid substitution (e.g., one or more substitutions that reduce dimerization), an albumin binding peptide (e.g., SEQ ID NOs: 174-216 (e.g., SEQ ID NOs: 195-216) (e.g., the sequence of SEQ ID NOs: 195-216)), a fusion domain (e.g., a fusion of a human serum albumin), an amino-end domain (e.g., a fusion domain, an amino-terminal polypeptide (e.g., an Fc domain of a human serum albumin), or a variant (e.g., a variant of a Fc domain, an amino acid domain such as exemplified by a Fc domain) Fibronectin domain or human serum albumin), wherein the N-terminus of the peptide linker is fused to the C-terminus of the extracellular ActRII variant by a chemical bond (e.g., a peptide bond), and the C-terminus of the peptide linker is fused to the N-terminus of the moiety (e.g., an Fc domain monomer, an Fc domain (e.g., a wild-type Fc domain), an Fc domain with amino acid substitution (e.g., one or more substitutions that reduce dimerization), an albumin binding peptide, a fibronectin domain, or human serum albumin) by a chemical bond (e.g., a peptide bond).

As used herein, the term "C-terminal extension" refers to the addition of one or more amino acids to the C-terminus of an extracellular ActRIIA variant (e.g., an extracellular ActRIIA variant having the sequence of any one of SEQ ID NOs: 1-70 (e.g., SEQ ID NOs: 6-70)) or to the C-terminus of an extracellular ActRII chimera (e.g., an extracellular ActRII chimera having the sequence of any one of SEQ ID NOs: 174-216 (e.g., SEQ ID NOs: 195-216)). The C-terminal extension may be one or more amino acids, such as 1-6 amino acids (e.g., 1, 2, 3, 4, 5, 6 or more amino acids). The C-terminal extension may include amino acids from the corresponding position of a wild-type ActRIIA (for ActRIIA variants) or from a wild-type ActRIIA or ActRIIB (for ActRII chimeras). Exemplary C-terminal extensions are amino acid sequence NP (diamino acid C-terminal extension) and amino acid sequence NPVTPK (SEQ ID NO: 154) (hexaamino acid C-terminal extension). Any amino acid sequence that does not disrupt the activity of the polypeptide can be used. SEQ ID NO. 71 is the sequence of SEQ ID NO. 69 with the C-terminal extension of NP and SEQ ID NO. 72 is the sequence of SEQ ID NO. 69 with the C-terminal extension of NPVTPK, both representing two possible ways in which the polypeptides of the invention may be modified to include C-terminal extension.

As used herein, the term "percent identity (%)" refers to the percentage of amino acid (or nucleic acid) residues in a candidate sequence (e.g., an extracellular ActRIIA variant, extracellular ActRIIB variant, or extracellular ActRII chimera) that are identical to amino acid (or nucleic acid) residues in a reference sequence (e.g., wild-type extracellular ActRIIA (e.g., SEQ ID NO: 73) or wild-type extracellular ActRIIB (e.g., SEQ ID NO: 74)) after aligning the sequences and introducing gaps, if necessary, to achieve the greatest percent identity (i.e., gaps may be introduced in one or both of the candidate sequence and the reference sequence to obtain the optimal alignment and non-homologous sequences may be ignored for comparison purposes). Alignment for the purpose of determining percent identity may be accomplished in a variety of ways within the skill of the art, for example using publicly available computer software such as BLAST, ALIGN, or Megalign (DNASTAR) software. One skilled in the art can determine appropriate parameters for measuring the alignment, including any algorithms needed to achieve maximum alignment over the entire length of the compared sequences. In some embodiments, the percent amino acid (or nucleic acid) sequence identity (or expressed as a percent amino acid (or nucleic acid) sequence identity) of a given candidate sequence pair, with or to a given reference sequence, is calculated as follows:

100x (fraction A/B)

Wherein a is the number of amino acid (or nucleic acid) residues that are rated identical in the alignment of the candidate sequence and the reference sequence, and wherein B is the total number of amino acid (or nucleic acid) residues in the reference sequence. In some embodiments where the length of the candidate sequence is not equal to the length of the reference sequence, the percentage of amino acid (or nucleic acid) sequence identity of the candidate sequence to the reference sequence will not be equal to the percentage of amino acid (or nucleic acid) sequence identity of the reference sequence to the candidate sequence.

In particular embodiments, a reference sequence aligned for comparison to a candidate sequence may indicate that the candidate sequence exhibits 50% to 100% identity over the entire length of the candidate sequence or consecutive amino acid (or nucleic acid) residues of a selected portion of the candidate sequence. The length of the candidate sequences aligned for comparison purposes is at least 30%, such as at least 40%, such as at least 50%, 60%, 70%, 80%, 90% or 100% of the length of the reference sequence. When a position in the candidate sequence is occupied by an amino acid (or nucleic acid) residue that is identical to the corresponding position in the reference sequence, then the molecules are identical at that position.

As used herein, the term "serum half-life" in the context of administration of a therapeutic protein to a subject refers to the time required for the plasma concentration of the protein in the subject to be reduced by half. Proteins may be redistributed or cleared from the blood stream, or degraded, for example, by proteolysis. Serum half-life comparisons can be made by comparing the serum half-lives of Fc fusion proteins.

As used herein, the term "affinity" or "binding affinity" refers to the strength of a binding interaction between two molecules. General purpose medicineOften, binding affinity refers to the strength of the sum of the non-covalent interactions between a molecule and its binding partner (such as an extracellular ActRIIA variant, extracellular ActRIIB variant, or extracellular ActRII chimeric with BMP9 or activin a). Unless otherwise indicated, binding affinity refers to an intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair. The binding affinity between two molecules is generally determined by the dissociation constant (K _D ) Or affinity constant (K) _A ) Description. Two molecules with weak binding affinity to each other typically bind slowly, tend to dissociate easily, and exhibit a large K _D . Two molecules with high affinity for each other typically bind easily, tend to remain bound for longer periods of time, and exhibit a small K _D . K of two interacting molecules _D May be determined using methods and techniques well known in the art, such as surface plasmon resonance. At k _{Dissociation of} /k _{Association with} To calculate K in terms of the ratio of _D 。

As used herein, the phrase "affecting myostatin, activin a, activin B, and/or BMP9 signaling" means altering the binding of myostatin, activin a, activin B, and/or BMP9 to its receptor (e.g., actRIIA, actRIIB and/or BMPRII (e.g., actRIIA or ActRIIB, e.g., endogenous ActRIIA or ActRIIB)). In some embodiments, a polypeptide described herein that includes an extracellular ActRIIA variant, extracellular ActRIIB variant, or extracellular ActRII chimera reduces or inhibits the binding of myostatin, activin a, activin B, and/or BMP9 to its receptor (e.g., actRIIA, actRIIB and/or BMPRII (e.g., actRIIA or ActRIIB, e.g., endogenous ActRIIA or ActRIIB)).

As used herein, the terms "increase" and "decrease" refer to a function, expression, or activity that is modulated to produce a greater or lesser amount of a metric, respectively, relative to a reference. For example, after administration of a polypeptide of the invention including an extracellular ActRIIA variant, an extracellular ActRIIB variant, or an extracellular ActRII chimera in a method described herein, the amount of a marker in a subject that measures (e.g., EPO or EPO receptor levels) as described herein may be increased relative to the amount of the marker prior to administration. Typically, the metric is measured after administration when the administration has had the listed effects (e.g., at least one week, one month, 3 months, or 6 months after initiation of the treatment regimen).

As used herein, the term "anemia" refers to any abnormality of hemoglobin or red blood cells that results in a decrease in oxygen content in the blood. Anemia may be associated with abnormal production, processing or manifestation of red blood cells and/or hemoglobin. The term anemia refers to any reduction in the number of red blood cells and/or hemoglobin levels in blood relative to normal blood levels and can be diagnosed using routine testing (such as whole blood counting).

As used herein, the term "normal hematopoiesis" refers to the process of producing components of blood and plasma, including the formation of red blood cells (erythrocytes), white blood cells (leukocytes, which include the formation of lymphocytes, neutrophils, eosinophils, basophils, and macrophages), and platelets (thrombocytes). If the production of these cells is not impaired and the number of these cells in the blood is within the range considered normal by the medical professional, then the subject has normal hematopoiesis. For example, human normal Red Blood Cells (RBCs) range from 470 to 610 tens of thousands of cells per microliter (mcL), non-pregnant women range from 420 to 540 tens of thousands of mcL, and children range from 400 to 550 tens of thousands of mcL.

As used herein, the term "disease or condition treatable with EPO or ESA" refers to a disease or condition that is currently treated by administration of EPO, recombinant EPO, an EPO mimetic, or another agent that increases EPO or EPO receptor levels; diseases or conditions that would be expected to benefit from increased EPO or EPO receptor levels based on studies conducted in cell culture conditions, animal models, or human trials; or a disease or condition associated with low serum EPO. Such diseases and conditions include end stage renal disease, renal insufficiency, renal dialysis, spinal cord injury, iron overload conditions (e.g., hemochromatosis), inflammatory brain diseases, gastrointestinal motility disorders, ischemia, and other diseases and conditions as described in U.S. patent nos. 5,013,718, 7,745,387, 8,466,172, 8,729,030, and 10,695,402, and U.S. patent application publication nos. US20180303903A1 and US20170312268A1, each of which is incorporated herein by reference.

As used herein, the term "low serum erythropoietin" refers to serum erythropoietin levels that are below the normal range. The normal level of erythropoietin is in the range of 4 to 26 milliunits per liter (mU/mL).

"hypercholesterolemia" is characterized by elevated concentrations of cholesterol in the blood. By far, the most common form of primary hypercholesterolemia is polygenic hypercholesterolemia. Secondary hypercholesterolemia often occurs in combination with diabetes, nephrotic syndrome, hypothyroidism and liver disorders.

An "endothelial-mediated chronic inflammatory disorder" is a disorder or condition in the human or animal body that originates from the defensive response of the body and its tissues to harmful stimuli, wherein certain signaling molecules alter the characteristics of endothelial cells so that, consistent with the activation of other cell types, leukocytes remain attached to the endothelial cells, eventually penetrating into the tissues and initiating inflammation there. An example of an endothelial-mediated inflammation is leukocyte vasculitis. The transcription factor NF- κb plays a key role in the activation of endothelial-mediated inflammatory events. Another system that leads to the development of endothelial cell-mediated chronic inflammation is the AGE-RAGE system.

"endothelial proliferation" refers to degenerative and proliferative endothelial changes associated with thrombocytopenic purpura. "reticuloendotheliosis" refers to diseases of the reticulocyte system, such as reticulosis, reticulocytosis, han-koch-g's disease (Hand-schuller-Christian disease).

"myocardial ischemia" refers to the absence of blood or hypoperfusion, i.e., an impaired blood supply to the heart muscle wall due to an insufficient or absent arterial blood supply.

"myocardial infarction" or "myocardial infarction" is the necrosis of a localized area of the heart muscle that usually occurs as an acute event concurrent with chronic coronary heart disease.

"coronary heart disease" or "ischemic heart disease" is degenerative coronary artery disease that results in a decrease in the blood supply to the heart muscle due to the contraction or closure of the coronary blood vessels of the heart.

"angina" refers to acute coronary insufficiency or stenocardia associated with coronary heart disease, coronary artery spasm, impaired blood flow, arrhythmia, hypertension or hypotension, which can be induced by an imbalance of oxygen supply and oxygen demand.

"Raynaud's disease" refers to an ischemic condition caused by vasoconstriction (i.e., vasospasm), and commonly occurs by chance in the arteries of the finger. Primary raynaud's disease is a purely functional injury of small blood vessels supplying the distal part of the limb, while secondary raynaud's disease has another underlying disease, such as vascular inflammation.

"preeclampsia" is the endothelial and vascular disease of the mother and appears to be the effect of pro-endothelial functional substances from the placenta. Preeclampsia is a multi-system condition that can lead to dysfunction of many organs and manifests itself as various symptoms. An impaired blood supply, which is a typical feature of a disorder, may have local variations in severity as a result of increased vascular resistance. Endothelial dysfunction is considered to be a central component of the pathogenesis of preeclampsia.

"renal failure" refers to a limitation in the ability of the kidneys to secrete substances normally secreted in urine, and there is also a loss of ability to regulate electrolyte, water, and acid-base balance in the late stages. End-stage renal failure is characterized by a breakdown in the secretory and endocrine functions of the kidneys.

"heart failure" refers to a pathological condition also known as myocardial insufficiency or myocardial weakness. Heart failure is characterized by insufficient heart function and the heart no longer can supply blood efficiently to meet its requirements. Heart failure may be classified according to various aspects. For example, it is classified into right heart failure, left heart failure, and both side failure (total failure) according to the affected section of the heart. Compensatory and decompensated heart failure are distinguished by the stability of the balance affected by physiological and therapeutic mechanisms. Classified according to time course as acute and chronic heart failure. The cause of heart failure is in particular myocardial infarction, cardiomyopathy, congenital or acquired heart defects, idiopathic or pulmonary hypertension, cardiac arrhythmias, coronary heart disease or myocarditis.

The term "ischemia" refers to a decrease in blood flow. Ischemia is associated with a reduction in nutrients (including oxygen) delivered to the tissue. Ischemia may result from conditions such as atherosclerosis, thrombosis in an artery or vein, or occlusion of an artery or vein by an embolic, occlusion of a blood vessel due to other causes (e.g., vasospasm). Such conditions may reduce blood flow, create a state of hypoperfusion to an organ or tissue, or block blood flow entirely. Other conditions that may produce ischemia include tissue damage due to trauma or injury (such as spinal cord injury); viral infections, which can lead to congestive heart failure, for example, and the like. The terms "ischemic conditions" and "ischemic disorders" refer to acute ischemic conditions, including myocardial infarction, ischemic stroke, pulmonary embolism, perinatal hypoxia, circulatory shock (including, for example, hemorrhagic shock, septic shock, cardiogenic shock, etc.), acute respiratory failure, etc.; chronic ischemic conditions including atherosclerosis, chronic venous insufficiency, chronic heart failure, cardiac cirrhosis, macular degeneration, sleep apnea, raynaud's disease, systemic sclerosis, non-bacterial thrombotic endocarditis, obstructive arterial disease, angina pectoris, TIA, chronic alcoholic liver disease, etc. Ischemic conditions can also develop when an individual is placed under general anesthesia and can cause tissue damage in preparing the organ for transplantation.

The terms "hypoxia" and "anoxic" refer to environments in which the oxygen content level is below normal. Hypoxia may be induced in cells by culturing the cells in a hypoxic environment, or the cells may be treated with compounds that mimic hypoxia. Determining the oxygen content defining hypoxia in cell cultures is well within the skill of the art. The terms "hypoxic condition" and "hypoxic condition" include ischemic conditions (hypoxia of low blood flow) such as those listed above, wherein hypoxia is caused by a reduction in circulation; pulmonary disorders (hypoxia anoxia), such as Chronic Obstructive Pulmonary Disease (COPD), severe pneumonia, pulmonary oedema, hyaline membranopathy, etc., wherein hypoxia is caused by reduced oxygenation in the pulmonary blood; liver or kidney disease, cancer or other chronic diseases, high altitude disease, etc.

"wound healing" refers to the physiological process of regenerating damaged tissue and closing the wound, especially the formation of new connective tissue and capillaries. Wound healing may be primary wound healing (primary healing) characterized by rapid and uncomplicated closure and substantially complete recovery due to minimal formation of new connective tissue between the wound edges, with good blood supply and, where appropriate, a substantially clean wound. Wounds with far apart wound edges and especially crushed or necrotic and infected wounds experience delayed secondary wound healing (second phase healing) in which due to (a) bacterial inflammation, granulation tissue is present filling the tissue defect and forming scar tissue thoroughly. Epithelialization from the margin terminates wound healing. Wound healing is divided into three phases, namely latency, proliferation and repair. The latency period is again divided into an oxidation phase, in particular within the first few hours after the wound has emerged, to form scab; and an absorption phase accompanied by catabolic autolysis, which extends for a period of one to three days after the wound has occurred. The proliferative phase is characterized by anabolic repair with collagen production by fibroblasts and occurs from the fourth to seventh days after wound appearance. The repair phase occurs after the eighth day after the wound has occurred and is characterized by the transformation of granulation tissue into scars.

"wound" refers to an interruption in the consistency of body tissue with or without loss of material and caused by mechanical injury or physically induced cellular damage. Types of wounds are mechanical, thermal, chemical, radiation, and disease-related. Mechanical wounds are created by traumatic violence and are in particular in the form of cuts and punctures, presses, scratches, tears and bruises, scratches and bites. Thermal wounds are created by exposure to heat or cold. Chemical wounds are specifically created by the action of acids or bases. Radiation wounds are produced, for example, by exposure to actinic and ionizing radiation. Wounds that arise with respect to the disease are in particular occlusion-related wounds, traumatic wounds, diabetic wounds, etc.

The term "inflammatory brain disease or condition" as used herein refers to a brain disease or condition caused by an acute or chronic inflammatory response in the central nervous system. Acute inflammatory responses of the brain include activation of microglia, appearance of dendritic cells, and release of pro-inflammatory cytokines and chemokines in the central nervous system. Chronic inflammatory responses include prolonged activation of microglial cells and subsequent sustained release of inflammatory mediators. Such prolonged activation of microglia causes additional microglia to activate and proliferate and further release inflammatory factors. Examples of chronic inflammatory brain diseases or disorders include demyelinating diseases, such as multiple sclerosis; and neurodegenerative diseases such as Alzheimer's Disease (AD), parkinson's Disease (PD), huntington's disease, amyotrophic Lateral Sclerosis (ALS), and age-related macular degeneration (AMD).

As used herein, the term "vascular complication" refers to a vascular condition or any damage to a blood vessel, such as damage to the vessel wall. Damage to the vessel wall may cause increased vessel permeability or leakage. The term "vascular permeability or leakage" refers to the ability of the vessel wall to allow small molecules, proteins, and cells to flow into and out of the vessel. Increased vascular permeability or leakage may be caused by increased voids (e.g., increased size and/or number of voids) between endothelial cells lining the vessel wall and/or thinning of the vessel wall.

As used herein, the term "polypeptide" describes a single polymer in which monomers are amino acid residues covalently conjugated together by amide bonds. Polypeptides are intended to encompass any amino acid sequence that occurs naturally, recombinantly or synthetically prepared.

As used herein, the term "homodimer" refers to a molecular construct formed from two identical macromolecules (such as proteins or nucleic acids). The two identical monomers may form a homodimer by covalent or non-covalent bonds. For example, if two Fc domain monomers contain the same sequence, the Fc domain may be a homodimer of two Fc domain monomers. In another example, a polypeptide described herein that includes an extracellular ActRIIA variant, an extracellular ActRIIB variant, or an extracellular ActRII chimera fused to an Fc domain monomer may form a homodimer by the interaction of two Fc domain monomers that form an Fc domain in the homodimer.

As used herein, the term "heterodimer" refers to a molecular construct formed from two different macromolecules (such as proteins or nucleic acids). The two monomers may form a heterodimer by covalent or non-covalent bonds. For example, a polypeptide described herein that includes an extracellular ActRIIA variant, an extracellular ActRIIB variant, or an extracellular ActRII chimera fused to an Fc domain monomer may form a heterodimer by the interaction of two Fc domain monomers, each fused to a different extracellular ActRIIA variant, extracellular ActRIIB variant, or extracellular ActRII chimera, respectively, that form an Fc domain in the heterodimer (e.g., the heterodimer may contain two different extracellular ActRIIA variants, two different extracellular ActRIIB variants, or two different extracellular ActRII chimeras).

As used herein, the term "host cell" refers to a vehicle that includes the necessary cellular components (e.g., organelles) required to express a protein from a corresponding nucleic acid. Nucleic acids are typically included in nucleic acid vectors that can be introduced into host cells by conventional techniques known in the art (transformation, transfection, electroporation, calcium phosphate precipitation, direct microinjection, etc.). The host cell may be a prokaryotic cell, such as a bacterial cell; or eukaryotic cells, such as mammalian cells (e.g., CHO cells or HEK293 cells).

As used herein, the term "therapeutically effective amount" refers to an amount of a polypeptide, nucleic acid or vector of the invention or a pharmaceutical composition comprising a polypeptide, nucleic acid or vector of the invention that is effective to achieve a desired therapeutic effect when treating a patient suffering from or at risk of developing a disease or disorder, such as a disease or disorder treatable with EPO or ESA, e.g., end stage renal disease, renal insufficiency, renal dialysis, spinal cord injury, iron overload conditions (e.g., hemochromatosis), inflammatory brain disease, ischemia, or gastrointestinal motility disorders. In particular, therapeutically effective amounts of the polypeptide, nucleic acid or vector avoid deleterious side effects.

As used herein, the term "pharmaceutical composition" refers to a medical or pharmaceutical formulation that includes an active ingredient, and excipients and diluents that enable the active ingredient to be suitable for the method of administration. The pharmaceutical compositions of the invention comprise a pharmaceutically acceptable component compatible with the polypeptide, nucleic acid, or vector. The pharmaceutical composition may be in the form of a tablet or capsule for oral administration, or in aqueous form for intravenous or subcutaneous administration.

As used herein, the term "pharmaceutically acceptable carrier or excipient" refers to an excipient or diluent in a pharmaceutical composition. The pharmaceutically acceptable carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient. In the present invention, a pharmaceutically acceptable carrier or excipient must provide sufficient pharmaceutical stability for a polypeptide including an extracellular ActRIIA variant, an extracellular ActRIIB variant, or an extracellular ActRII chimera, one or more nucleic acid molecules encoding the polypeptide, or a carrier containing such one or more nucleic acid molecules. The nature of the carrier or excipient will vary with the mode of administration. For example, for intravenous administration, aqueous carriers are typically used; for oral administration, solid carriers are preferred.

As used herein, the term "treating and/or preventing" refers to treating and/or preventing a disease or disorder, such as a disease or disorder that can be treated with EPO or ESA, such as end stage renal disease, renal insufficiency, renal dialysis, spinal cord injury, iron overload conditions (e.g., hemochromatosis), inflammatory brain diseases, ischemia, or gastrointestinal motility disorders, using the methods and compositions of the present invention. Typically, treatment of a disease or condition treatable with EPO or ESA occurs after the subject has developed the disease or condition. Prevention of a disease or disorder treatable with EPO or ESA refers to a step or procedure taken when a subject is at risk of developing the disease or disorder. The subject may show signs or mild symptoms of a disease or condition for which a physician decides to develop an indication or risk factor for a disease or condition treatable with EPO or ESA, have another disease or condition associated with a disease or condition for which EPO or ESA is being developed, are undergoing treatment that may cause a disease or condition treatable with EPO or ESA, or have a family history or genetic susceptibility to develop a disease or condition treatable with EPO or ESA, but have not yet developed the disease or condition.

As used herein, the term "subject" refers to a mammal, such as preferably a human. Mammals include, but are not limited to, humans as well as domestic and farm animals such as monkeys (e.g., cynomolgus monkeys), mice, dogs, cats, horses, cows, etc.

Drawings

FIG. 1 is a sequence alignment showing the wild-type sequences of extracellular ActRIIA and ActRIIB and the sequences of exemplary extracellular ActRIIA variants.

Fig. 2 is a sequence alignment showing amino acid substitutions in the wild-type sequences of extracellular ActRIIA and ActRIIB and exemplary extracellular ActRIIB variants.

FIG. 3 is a sequence alignment showing the sequences of an exemplary extracellular ActRII chimera.

FIG. 4 is a series of graphs showing that single 10mg/kg doses of ActRIIA/B-mFc (SEQ ID NO:69 linked to the mouse Fc domain) administered by Intraperitoneal (IP) injection into 11 week old male mice increased serum EPO levels at 4, 7 and 14 days after injection, as compared to vehicle. Red blood cells increased at each time point. P <0.05, p <0.01, p <0.0001 between ActRIIA/B-mFc treatment and vehicle at each time point using two-way ANOVA followed by a dak post-test. Data are shown as mean ± SEM.

FIG. 5 is a graph showing that a single 10mg/kg dose of ActRIIA/B-mFc administered by Intraperitoneal (IP) injection into 11-week-old male mice has a long-acting effect on EPO and increases serum EPO levels by day 4 through day 37. P.ltoreq.0.05 between ActRIIA/B-mFc treatment and vehicle at each time point by t-test; * P is less than or equal to 0.01; p is less than or equal to 0.0001. Data are shown as mean ± SEM.

Fig. 6 is a series of graphs showing that ActRIIA/B-mFc at a single 10mg/kg dose administered by intraperitoneal injection into 11-week-old male mice increased EPO receptor levels in bone marrow cells on days 7 and 14 after injection, as compared to vehicle. Error bars represent SEM.

Detailed Description

The invention provides polypeptides comprising an extracellular activator receptor type II (ActRII) variant, such as an extracellular ActRIIA variant, an extracellular ActRIIB variant, or an extracellular ActRII chimera. In some embodiments, the polypeptides of the invention include extracellular ActRII variants fused to a moiety (e.g., an Fc domain monomer, an Fc domain (e.g., a wild-type Fc domain), an Fc domain with amino acid substitutions (e.g., one or more substitutions that reduce dimerization), an albumin binding peptide, a fibronectin domain, or human serum albumin). Polypeptides comprising extracellular ActRII variants fused to an Fc domain monomer may also form dimers (e.g., homodimers or heterodimers) through interactions between two Fc domain monomers. ActRII variants described herein have a weak binding affinity or no binding affinity for bone morphogenic protein 9 (BMP 9) as compared to activin (e.g., activin a and/or activin B) and myostatin. The invention also includes methods of treating diseases and conditions treatable with EPO or ESA (e.g., diseases or conditions treatable by increasing EPO or EPO receptor levels) by administering to a subject a polypeptide described herein that includes an extracellular ActRII variant.

I. Extracellular activator receptor type II (ActRII) variants

Activin type II receptors are single transmembrane domain receptors that regulate the signaling of ligands in the transforming growth factor β (TGF- β) superfamily. Ligands in the TGF- β superfamily are involved in many physiological processes such as muscle growth, vascular growth, cell differentiation, homeostasis, hematopoiesis, and osteogenesis. Examples of ligands in the TGF- β superfamily include, for example, activin a, activin B, inhibin, growth Differentiation Factors (GDFs) (e.g., GDF8, also known as myostatin, and GDF 11), and Bone Morphogenic Proteins (BMP) (e.g., BMP 9).

There are two types of activin type II receptors: actRIIA and ActRIIB. Studies have shown that BMP9 binds ActRIIB with about 300-fold higher binding affinity than ActRIIA (see, e.g., townson et al, j. Biol. Chem.287:27313,2012). ActRIIA-Fc is known to have a longer half-life than ActRIIB-Fc. Three types of ActRII variants are described herein: 1) An extracellular ActRIIA variant constructed by introducing amino acid residues of ActRIIB into ActRIIA, targeted to confer the physiological properties conferred by ActRIIB while also maintaining the beneficial physiological and pharmacokinetic properties of ActRIIA; 2) An extracellular ActRIIB variant constructed by introducing amino acid residues of ActRIIA into ActRIIB or by introducing novel amino acid substitutions, with the goal of reducing BMP9 binding to prevent or reduce disruption of endogenous BMP9 signaling; and 3) extracellular ActRII chimeras constructed by combining portions of extracellular ActRIIA and ActRIIB, targeted to produce proteins that bind to ActRII ligands (e.g., activin a, activin B, myostatin, and GDF 11) and retain the function of wild-type extracellular ActRII proteins.

The present invention is based in part on the discovery that administration of a polypeptide described herein that includes an ActRIIA variant (ActRIIA variant-Fc polypeptide) increases serum EPO levels in a mouse in the absence of compensatory down-regulation of bone marrow EPO receptor. Administration of ActRIIA variant-Fc polypeptides increases EPO levels in serum as well as EPO receptor levels in bone marrow precursors. An increase in serum EPO was observed four days after injection and continued until at least day 14 after injection, and an increase in bone marrow EPO receptor expression was observed seven days and 14 days after injection. These data indicate that not only polypeptides comprising ActRIIA variants can be used to increase EPO and EPO receptor levels and thus be used as an alternative to EPO therapy, but also polypeptides comprising ActRIIA variants can be administered less frequently based on the sustained increase in EPO and EPO receptor levels observed in these studies compared to current EPO therapies. Less frequent dosing will greatly improve patient convenience and can potentially reduce adverse effects. Thus, polypeptides described herein, including ActRIIA variants, are useful for treating diseases or conditions treatable with EPO or ESA.

ActRIIA variants

In some embodiments, actRII variants for use in accordance with the methods described herein are extracellular ActRIIA variants that are constructed by introducing amino acid residues of ActRIIB into ActRIIA with the goal of conferring the physiological properties conferred by ActRIIB while also maintaining the beneficial physiological and pharmacokinetic properties of ActRIIA. Preferred ActRIIA variants also exhibit similar or improved binding to activin and/or myostatin compared to wild-type ActRIIA, which allows them to compete for ligand binding with endogenous activin receptors and reduce or inhibit endogenous activin receptor signaling. In some embodiments, amino acid substitutions may be introduced into extracellular ActRIIA variants to reduce or eliminate the binding affinity of the variants to BMP 9. The wild-type amino acid sequences of the extracellular portions of human ActRIIA and ActRIIB are shown below.

Human ActRIIA extracellular portion (SEQ ID NO: 73):

GAILGRSETQECLFFNANWEKDRTNQTGVEPCYGDKDKRRHCFATWKNISGSIEIVKQGCWLDDINCYDRTDCVEKKDSPEVYFCCCEGNMCNEKFSYFPEMEVTQPTS

human ActRIIB extracellular portion (SEQ ID NO: 74):

GRGEAETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWLDDFNCYDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPTAPT

the polypeptides described herein include extracellular ActRIIA variants having at least one amino acid substitution relative to wild-type extracellular ActRIIA having the sequence of SEQ ID NO:73 or extracellular ActRIIA having any of the sequences of SEQ ID NOs 76-96. Possible amino acid substitutions may be introduced into the extracellular ActRIIA variant at 27 different positions (table 1). In some embodiments, the extracellular ActRIIA variant may have at least 85% (e.g., at least 85%, 87%, 90%, 92%, 95%, 97% or more) amino acid sequence identity with the sequence of wild-type extracellular ActRIIA (SEQ ID NO: 73). An extracellular ActRIIA variant may have one or more (e.g., 1-27, 1-25, 1-23, 1-21, 1-19, 1-17, 1-15, 1-13, 1-11, 1-9, 1-7, 1-5, 1-3, or 1-2; e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27) amino acid substitutions relative to the sequence of wild-type extracellular ActRIIA (SEQ ID NO: 73). In some embodiments, an extracellular ActRIIA variant (e.g., an extracellular ActRIIA variant having the sequence of SEQ ID NO: 1) may include amino acid substitutions at all 27 positions as listed in table 1. In some embodiments, extracellular ActRIIA variants may include amino acid substitutions at a number of positions, for example, amino acid substitutions at 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, or 26 of the 27 positions as listed in table 1.

Amino acid substitutions may worsen or improve the activity and/or binding affinity of ActRIIA variants of the invention. To maintain polypeptide function, position X in the sequences shown in tables 1 and 2 (SEQ ID NOS: 1-72 (e.g., SEQ ID NOS: 6-72)) is maintained ₁₇ Lysine (K) of (B) is important. Substitution of the positions may cause loss of activity. For example, actRIIA variants having sequence GAILGRSETQECLFYNANWELERTNQTGVERCEGEKDKRLHCYA TWRNISGSIEIVAKGCWLDDFNCYDRTDCVETEENPQVYFCCCEG NMCNEKFSYFPEMEVTQPTS (SEQ ID NO: 149) have reduced in vivo activity, indicating substitution of X at alanine (a) ₁₇ Lysine (K) at this position is not tolerated. Thus, actRIIA variants of the invention, including the variants in tables 1 and 2 (e.g., SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72), remain in position X ₁₇ Amino acid K of (a).

ActRIIA variants of the invention preferably have reduced, weak binding to BMP9 or substantially no binding to BMP 9. At X ₂₃ 、X ₂₄ 、X ₂₅ X is as follows ₂₆ In ActRIIA variants containing the amino acid sequence ten (SEQ ID NO: 374) at position and at position X ₂₄ Maintaining amino acid K and at position X ₂₃ 、X ₂₄ 、X ₂₅ X is as follows ₂₆ BMP9 binding is reduced (e.g., reduced compared to wild-type ActRIIA) in variants having the amino acid sequence TKEN (SEQ ID NO: 375). In ActRIIA variants of the invention (e.g., the variants in tables 1 and 2, e.g., SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72)), the sequences ten (SEQ ID NO: 374) and TKEN (SEQ ID NO: 375) are used interchangeably to provide reduced BMP9 binding.

ActRIIA variants of the invention may further include a C-terminal extension (e.g., additional amino acids at the C-terminal). C-terminal extension one or more additional amino acids (e.g., 1, 2, 3, 4, 5, 6 or more additional amino acids) may be added at the C-terminus to any of the variants shown in tables 1 and 2, e.g., SEQ ID NOS: 1-70 (e.g., SEQ ID NOS: 6-70). The C-terminal extension may correspond to a sequence from the same position in the wild-type ActRIIA. One potential C-terminal extension that may be included in ActRIIA variants of the invention is the amino acid sequence NP. For example, the sequence comprising C-terminally extended NPs is SEQ ID NO:71 (e.g., SEQ ID NO:69 with C-terminal extension of NPs). Another exemplary C-terminal extension that may be included in actriiA variants of the invention is the amino acid sequence NPVTPK (SEQ ID NO: 154). For example, the sequence comprising C-terminal extended NPVTPK is SEQ ID NO:72 (e.g., SEQ ID NO:69 with C-terminal extension of NPVTPK).

TABLE 1 amino acid substitutions in extracellular ActRIA variants having the sequence of any one of SEQ ID NOs 1-5

In some embodiments of extracellular ActRIIA variants having the sequence of SEQ ID NO:1 or 2, X ₃ Is E, X ₆ Is R, X ₁₁ Is D, X ₁₂ Is K, X ₁₃ Is R, X ₁₆ Is K or R, X ₁₇ Is K, X ₁₉ Is W, X ₂₀ Is L, X ₂₁ Is D, and X ₂₂ I or F. In some embodiments of extracellular ActRIIA variants having the sequence of SEQ ID No. 1, X ₂ Y is; x is X ₄ Is L; x is X ₈ E is; x is X ₉ E is; x is X ₁₄ Is L; x is X ₁₈ Is K; x is X ₂₃ Is T; x is X ₂₅ E is; x is X ₂₆ Is N; and X is ₂₇ Q. These substitutions in SEQ ID NO. 1 can also be made in SEQ ID NO. 2-5. In some embodiments of extracellular ActRIIA variants having the sequence of SEQ ID No. 1, X ₁ Is F or Y; x is X ₂ Y is; x is X ₄ Is L; x is X ₅ Is D or E; x is X ₇ P or R; x is X ₈ E is; x is X ₉ E is; x is X ₁₀ Is K or Q; x is X ₁₄ Is L; x is X ₁₅ Is F or Y; x is X ₁₆ Is K or R; x is X ₁₈ Is K; x is X ₂₂ Is I or F; x is X ₂₃ Is T; x is X ₂₄ K or E; x is X ₂₅ E is; x is X ₂₆ Is N; and X is ₂₇ Q. In some embodiments of extracellular ActRIIA variants having the sequence of SEQ ID No. 1, X ₁ Is F or Y; x is X ₂ Y is; x is X ₃ E is; x is X ₄ Is L; x is X ₅ Is D or E; x is X ₆ R is R; x is X ₇ P or R; x is X ₈ E is; x is X ₉ E is; x is X ₁₀ Is K or Q; x is X ₁₁ Is D; x is X ₁₂ Is K; x is X ₁₃ R is R; x is X ₁₄ Is L; x is X ₁₅ Is F or Y; x is X ₁₆ Is K or R; x is X ₁₇ Is K; x is X ₁₈ Is K; x is X ₁₉ W is the same as W; x is X ₂₀ Is L; x is X ₂₁ Is D; x is X ₂₂ Is I or F; x is X ₂₃ Is T; x is X ₂₄ K or E; x is X ₂₅ E is; x is X ₂₆ Is N; and X is ₂₇ Q. In some embodiments of extracellular ActRIIA variants having the sequence of SEQ ID NO:1 or 2, X ₁₇ K is the number. In some embodiments of extracellular ActRIIA variants having the sequence of SEQ ID NOs 1-3, X ₁₇ Is K, X ₂₃ Is T, X ₂₄ Is E, X ₂₅ Is E and X ₂₆ Is N. In some embodiments of extracellular ActRIIA variants having the sequence of any one of SEQ ID NOs 1-5, X is ₁₇ Is K, X ₂₃ Is T, X ₂₄ Is K, X ₂₅ Is E and X ₂₆ Is N.

In some embodiments, the polypeptides described herein include extracellular ActRIIA variants having the sequence of any one of SEQ ID NOs 6-72 (table 2).

TABLE 2 extracellular ActRIA variants with the sequences of SEQ ID NOS: 6-72

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In some embodiments, the invention includes polypeptides of extracellular ActRIIA variants (e.g., any of SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72)) at X ₁₇ The position has amino acid K. Change in position X ₁₇ Can result in reduced activity. For example, actRIIA variants having sequence GAILGRSETQECLFYNANWELERTNQTGVERCEGE KDKRLHCYATWRNISGSIEIVAKGCWLDDFNCYDRTDCVETEEN PQVYFCCCEGNMCNEKFSYFPEMEVTQPTS (SEQ ID NO: 149) have reduced in vivo activity, indicating that a substitution is at X ₁₇ Where K is not allowed.

In some embodiments, at position X ₂₃ 、X ₂₄ 、X ₂₅ X is as follows ₂₆ A polypeptide of the invention including extracellular ActRIA variants (e.g., any of SEQ ID NOS: 1-72 (e.g., SEQ ID NOS: 6-72)) having the sequence TEEN (SEQ ID NO: 374) may have the amino acid K pair position X ₂₄ Amino acid E substitution of (c). In one placeIn some embodiments, at position X ₂₃ 、X ₂₄ 、X ₂₅ X is as follows ₂₆ A polypeptide of the invention including extracellular ActRIA variants (e.g., any of SEQ ID NOS: 1-72 (e.g., SEQ ID NOS: 6-72)) having the sequence TKEN (SEQ ID NO: 375) may have the amino acid E pair position X ₂₄ Amino acid K substitution of (c). In position X ₂₃ 、X ₂₄ 、X ₂₅ X is as follows ₂₆ A polypeptide having the sequence TEEN (SEQ ID NO: 374) or TKEN (SEQ ID NO: 375) has reduced or weak binding to BMP9 (e.g., reduced binding to BMP9 as compared to that of wild-type actRIA).

In some embodiments, polypeptides of the invention that include extracellular ActRIIA variants (e.g., any of SEQ ID NOs: 1-70 (e.g., SEQ ID NOs: 6-70)) may further include a C-terminal extension (e.g., one or more additional amino acids at the C-terminal). The C-terminal extension may correspond to a sequence from the same position in the wild-type ActRIIA. In some embodiments, the C-terminal extension is the amino acid sequence NP. For example, the sequence comprising C-terminally extended NPs is SEQ ID NO:71 (e.g., SEQ ID NO:69 with C-terminal extension of NPs). In some embodiments, the C-terminal extension is of the amino acid sequence NPVTPK (SEQ ID NO: 154). For example, the sequence comprising C-terminal extended NPVTPK is SEQ ID NO:72 (e.g., SEQ ID NO:69 with C-terminal extension of NPVTPK). The C-terminal extension may add one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, or more additional amino acids) at the C-terminal end.

In some embodiments, a polypeptide of the invention comprising an extracellular ActRIIA variant may further comprise a moiety (e.g., an Fc domain monomer, an Fc domain (e.g., wild-type Fc domain), an Fc domain with amino acid substitutions (e.g., one or more substitutions that reduce dimerization), an albumin binding peptide, a fibronectin domain, or human serum albumin) that may be fused to the N-terminus or C-terminus (e.g., C-terminus) of the extracellular ActRIIA variant by means of a linker or other covalent bond. Polypeptides comprising extracellular ActRIIA variants fused to Fc domain monomers may form dimers (e.g., homodimers or heterodimers) through interactions between two Fc domain monomers that combine to form an Fc domain in the dimer.

In some embodiments, the extracellular ActRIIA variants described herein do not have the sequence of any of SEQ ID NOs 76-96 shown in table 3 below.

TABLE 3 excluded extracellular ActRIA variants

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Furthermore, in some embodiments, the polypeptides described herein (e.g., actRIIA variant-Fc fusion proteins) have a serum half-life of at least 7 days in humans. Polypeptides comprising extracellular ActRIA variants may have a K of 10pM or higher _D Binds to activin a. In some embodiments, polypeptides comprising extracellular ActRIIA variants do not bind to BMP9 or activin a. In some embodiments, polypeptides comprising extracellular ActRIIA variants bind to activin a, activin B, and/or myostatin and exhibit reduced (e.g., weak) binding to BMP9 (e.g., reduced BMP9 binding compared to BMP9 binding of wild-type ActRIIA). In some embodiments, polypeptides comprising extracellular ActRIIA variants with reduced or weak binding to BMP9 are at position X ₂₃ 、X ₂₄ 、X ₂₅ X is as follows ₂₆ Has the sequence TEEN (SEQ ID NO: 374) or TKEN (SEQ ID NO: 375). In some embodiments, polypeptides comprising extracellular ActRIIA variants do not substantially bind to human BMP9.

In some embodiments, a polypeptide comprising an extracellular ActRIIA variant may have a K of about 800pM or less _D (e.g., about 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1pM or less)K of (2) _D For example, a K of between about 800pM and about 200pM _D ) Binds to human activin a. In some embodiments, a polypeptide comprising an extracellular ActRIIA variant may be K800 pM or less _D (e.g., K of about 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1pM or less) _D For example, a K of between about 800pM and about 200pM _D ) Binds to human activin B. Polypeptides comprising extracellular ActRIA variants may also have a K of about 5pM or higher _D (e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200pM or higher K) _D ) Binds to growth and differentiation factor 11 (GDF-11).

ActRIIB variants

In some embodiments, an ActRII variant for use in accordance with the methods described herein is an extracellular ActRIIB variant that is constructed by introducing amino acid residues of ActRIIA into ActRIIB or by introducing novel amino acid substitutions into ActRIIB with the goal of reducing BMP9 binding to prevent or reduce disruption of endogenous BMP9 signaling. Amino acid substitutions may also confer beneficial physiological and pharmacokinetic properties to ActRIIA, such as a longer half-life as an Fc fusion protein. Preferred ActRIIB variants also exhibit similar or improved binding to activin and/or myostatin compared to wild-type ActRIIB, which allows them to compete for ligand binding with endogenous activin receptors and reduce or inhibit endogenous activin receptor signaling. In some embodiments, amino acid substitutions may be introduced into an extracellular ActRIIB variant to reduce or eliminate the binding affinity of the variant to BMP 9. The polypeptides described herein, including ActRIIB variants, are useful for increasing EPO and EPO receptor levels, and thus are useful as alternative therapies to EPO therapy. These polypeptides may also be administered less frequently than current EPO therapies, which will greatly improve patient convenience and may potentially reduce adverse effects. Thus, polypeptides described herein, including ActRIIB variants, may be used to treat diseases or conditions treatable with EPO or ESA.

The polypeptides described herein include extracellular ActRIIB variants having at least one amino acid substitution relative to wild-type extracellular ActRIIB having the sequence of SEQ ID NO: 74. Possible amino acid substitutions may be introduced into the extracellular ActRIIB variant at 28 different positions (table 4). An extracellular ActRIIB variant may have one or more (e.g., 1-28, 1-25, 1-23, 1-21, 1-19, 1-17, 1-15, 1-13, 1-11, 1-9, 1-7, 1-5, 1-3, or 1-2; e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28) amino acid substitutions relative to the sequence of wild-type extracellular ActRIIB (SEQ ID NO: 74). In some embodiments, an extracellular ActRIIB variant (e.g., an extracellular ActRIIB variant having the sequence of SEQ ID NO: 1) may include amino acid substitutions at all 28 positions as set forth in table 4. In some embodiments, the extracellular ActRIIB variants may include amino acid substitutions at a number of positions, for example, at 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 16, 18, 20, 22, 24, 26, or 27 positions, e.g., at 28 positions as listed in table 4. In some embodiments, the substitution is a substitution of an amino acid from ActRIIA to the same position in ActRIIB. In some embodiments, the substitution is a novel change (e.g., an amino acid substitution that is not at the corresponding position of ActRIIA, e.g., S48T, I51L, Q D or E70T).

Amino acid substitutions may worsen or improve the activity and/or binding affinity of an ActRIIB variant of the invention (e.g., an extracellular ActRIIB variant having the sequence of any one of SEQ ID NOs: 157-171 (e.g., SEQ ID NOs: 158-171)). In some embodiments, amino acid substitutions worsen the binding affinity of ActRIIB variants to BMP9 (e.g., variants have reduced binding to BMP9 relative to wild-type extracellular ActRIIB, or have lower binding to BMP9 than other ActRIIB ligands (e.g., activin a or B, myostatin, or GDF-11). In some embodiments, actRIIB variants have reduced, weak binding to BMP9 or substantially no binding to BMP 9. In some embodiments, amino acid substitutions improve the binding affinity of ActRIIB to myostatin, activin a or B, and/or GDF-11 (e.g., the variant has improved binding affinity relative to wild-type extracellular ActRIIB, or binds more strongly to myostatin, activin a or B, or GDF-11 than BMP 9). In some embodiments, the amino acid substitution reduces the binding affinity of ActRIIB to myostatin, activin a or B, and/or GDF-11 (e.g., the variant has a reduced binding affinity relative to wild-type extracellular ActRIIB, or binds to myostatin, activin a or B, or GDF-11 weaker than BMP 9). In some embodiments, the amino acid substitution does not substantially alter extracellular ActRIIB function (e.g., an ActRIIB variant is functionally equivalent to wild-type extracellular ActRIIB). In some embodiments, amino acid substitutions confer ActRIIA characteristics or activity to the ActRIIB variant (e.g., actRIIB variant has a longer half-life as an Fc fusion protein as compared to WT extracellular ActRIIB-Fc). Preferably, actRIIB variants have one or more, two or more, or three or more of the above properties (e.g., reduced BMP9 binding and improved binding to activin a or B, myostatin, and/or GDF-11, or reduced BMP9 binding and being functionally equivalent to wild-type ActRIIB).

The ActRIIB variants of the invention (e.g., extracellular ActRIIB variants having the sequence of any one of SEQ ID NOs: 157-171 (e.g., SEQ ID NOs: 158-171)) preferably have one or more amino acid substitutions that reduce BMP9 binding. In some embodiments, the amino acid substitution that reduces BMP9 binding is E75K (e.g., X in SEQ ID NO:157 ₂₄ K). In some embodiments, amino acid substitutions that reduce BMP9 binding are Q69T and E70D (e.g., X in SEQ ID NO:157 ₂₁ Is T and X ₂₂ D). In some embodiments, amino acid substitutions that reduce BMP9 binding are Q69D and E70T (e.g., X in SEQ ID NO:157 ₂₁ Is D and X ₂₂ T). In some embodiments, amino acid substitutions that reduce BMP9 binding are T74K, E75K, E76D, N77S and Q79E (e.g., X in SEQ ID NO:157 ₂₃ 、X ₂₄ 、X ₂₅ 、X ₂₆ X is as follows ₂₈ K, K, D, S and E), respectively). In some embodimentsActRIIB variants have more than one of the above amino acid substitutions that reduce BMP9 binding (e.g., substitution E75K and substitutions Q69D and E70T, or substitution E75K and substitutions Q69T and E70D). In some embodiments, actRIIB variants of the invention have one or more amino acid substitutions that reduce BMP9 binding, and one or more additional amino acid substitutions. The additional amino acid substitutions may confer other beneficial properties, such as altered binding to activin or myostatin, or improved activity. For example, amino acid substitutions T74K, E75K, E76D, N S and Q79E result in reduced ActRIIB variant activity (e.g., as compared to wild-type extracellular ActRIIB), but include the additional substitutions S25T and S47I; E31Y, E D and Q34K; or Y41F, R45K and K56Q improves the effect of ActRIIB variants. Additional amino acid substitutions may include one or more of substitutions I11L, Y F, L5225T, L27V, R29P, E Y, E D, Q34 4815R, Y F, R K, S47I, S51 7962 50S, I51L, L53I, K Q and F63I, T74 38395 76D, N77S, Q E or F89M.

In some embodiments, the polypeptides described herein include extracellular ActRIIB variants having the sequence of SEQ ID No. 157.

TABLE 4 amino acid substitutions in extracellular ActRIIB variants with the sequence of SEQ ID NO:157

In some embodiments, the polypeptides described herein include extracellular ActRIIB variants having the sequence of any one of SEQ ID NOs 158-171 (table 5).

TABLE 5 extracellular ActRIIB variants with the sequences of SEQ ID NOS 158-171

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In some embodiments, the extracellular ActRIIB variants described herein have an N-terminal truncation of 1-7 amino acids (e.g., 1, 2, 3, 4, 5, 6, or 7 amino acids). N-terminal truncation may involve the removal of 1-7 amino acids from the N-terminus of any of the ActRIIB variants shown in tables 4 and 5. The N-terminal truncation may remove amino acids up to two amino acids before the first cysteine (e.g., the N-terminal of the truncated ActRIIB variant retains two amino acids (REs) before the first cysteine).

In some embodiments, a polypeptide of the invention comprising an extracellular ActRIIB variant may further comprise a moiety (e.g., an Fc domain monomer, an Fc domain (e.g., wild-type Fc domain), an Fc domain with amino acid substitutions (e.g., one or more substitutions that reduce dimerization), an albumin binding peptide, a fibronectin domain, or human serum albumin) that may be fused to the N-terminus or C-terminus (e.g., C-terminus) of the extracellular ActRIIB variant by means of a linker or other covalent bond. Polypeptides comprising extracellular ActRIIB variants fused to Fc domain monomers may form dimers (e.g., homodimers or heterodimers) through interactions between two Fc domain monomers that combine to form an Fc domain in the dimer.

Furthermore, in some embodiments, the polypeptides described herein (e.g., actRIIB variant-Fc fusion proteins) have a serum half-life of at least 7 days in humans. Polypeptides comprising extracellular ActRIIB variants may have a K of 10pM or higher _D Binds to activin a. In some embodiments, polypeptides comprising extracellular ActRIIB variants do not bind to BMP9 or activin a. In some embodiments, polypeptides comprising extracellular ActRIIB variants bind to activin a, activin B, and/or myostatin and exhibit reduced (e.g., weak) binding to BMP9. In some embodiments, polypeptides comprising extracellular ActRIIB variants do not substantially bind to human BMP9.

In some implementationsIn embodiments, polypeptides comprising extracellular ActRIIB variants may have a K of about 800pM or less _D (e.g., K of about 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1pM or less) _D For example, a K of between about 800pM and about 200pM _D ) Binds to human activin a. In some embodiments, a polypeptide comprising an extracellular ActRIIB variant may have a K of 800pM or less _D (e.g., K of about 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1pM or less) _D For example, a K of between about 800pM and about 200pM _D ) Binds to human activin B. Polypeptides comprising extracellular ActRIIB variants may also have a K of about 5pM or higher _D (e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200pM or higher K) _D ) Binds to growth and differentiation factor 11 (GDF-11).

ActRII chimeras

In some embodiments, the ActRII variants for use in accordance with the methods described herein are extracellular ActRII chimeras constructed by combining portions of extracellular ActRIIA and ActRIIB, targeting the production of proteins that bind to ActRII ligands (e.g., activin a, activin B, myostatin, and GDF 11) and retain the function of wild-type extracellular ActRII proteins. In some embodiments, the ActRII chimera exhibits reduced BMP9 binding relative to wild-type extracellular ActRIIB, which may prevent or reduce disruption of endogenous BMP9 signaling. In some embodiments, the chimera has the characteristics of both ActRIIA (e.g., weak binding affinity to BMP9 and/or longer serum half-life as an Fc fusion protein) and ActRIIB (e.g., strong binding affinity to activin a and B). ActRII chimeras may exhibit similar or improved binding to activins (e.g., activin a and/or activin B) and/or myostatin as compared to wild-type extracellular ActRIIA and/or ActRIIB, thereby allowing them to compete for ligand binding with endogenous activin receptors and reduce or inhibit endogenous activin receptor signaling. The polypeptides described herein, including ActRII chimeras, are useful for increasing EPO and EPO receptor levels, and thus, are useful as replacement therapies for EPO therapy. These polypeptides may also be administered less frequently than current EPO therapies, which will greatly improve patient convenience and may potentially reduce adverse effects. Thus, the polypeptides described herein, including ActRII chimeras, are useful in treating diseases or conditions treatable with EPO or ESA.

The polypeptides described herein include extracellular ActRII chimeras comprising sequences from both the extracellular portion of ActRIIB and the extracellular portion of ActRIIA. The ActRII chimeras described herein result from ligating the N-terminal portion of extracellular ActRIIB (SEQ ID NO:74 shown above) with the C-terminal portion of extracellular ActRIIA (SEQ ID NO:73 shown above) such that the sequences are contiguous (e.g., the ActRIIA sequence continues at the stop of the ActRIIB sequence to begin with the next amino acid located at the corresponding position of ActRIIA). In some embodiments, the N-terminus of the ActRII chimera includes six amino acids present at the N-terminus of extracellular ActRIIA linked to the fifth amino acid of extracellular ActRIIB. In some embodiments, the N-terminus of the ActRII chimera begins with the first amino acid located at the N-terminus of extracellular ActRIIB. Thus, in some embodiments, the N-terminal portion of ActRIIB begins with amino acid (a) in the fifth position of SEQ ID NO:74, while in other embodiments (e.g., in embodiments in which the six amino acids present at the N-terminus of extracellular ActRIIA are not included in the chimera), the N-terminal portion of ActRIIB begins with amino acid (G) in the first position of SEQ ID NO: 74. In some embodiments, the N-terminus of the ActRII chimera includes the first ten amino acids present at the N-terminus of extracellular ActRIIA linked to the ninth amino acid of extracellular ActRIIB, in which case the N-terminal portion of ActRIIB begins with amino acid (E) in the ninth position of SEQ ID NO: 74. The extracellular ActRII chimera may also include one or more amino acid substitutions in a portion of the chimera corresponding to the sequence of ActRIIB (e.g., SEQ ID NO:74 shown above) as compared to wild-type extracellular ActRIIB, and one or more amino acid substitutions in a portion of the chimera corresponding to the sequence of ActRIIA (e.g., SEQ ID NO:73 shown above) as compared to wild-type extracellular ActRIIA. Amino acid substitutions at 9 different positions can be introduced into the extracellular ActRII chimera (table 6). An extracellular ActRII chimera may have one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) amino acid substitutions relative to the sequence of the wild-type sequence (e.g., relative to the sequence of the wild-type extracellular ActRIIB (SEQ ID NO: 74) if a portion of the chimera corresponds to a region of the wild-type extracellular ActRIIA), or relative to the sequence of the wild-type extracellular ActRIIA (SEQ ID NO: 73). The positions at which amino acid substitutions can be made and the amino acids at which substitutions can occur are listed in Table 6.

Amino acid substitutions may alter the activity and/or binding affinity of the extracellular ActRII chimeras of the invention. In some embodiments, the extracellular ActRII chimera binds to activin a, activin B, myostatin, and/or GDF11 with sufficient affinity to compete with endogenous activin receptors for binding to one or more of these ligands. In some embodiments, the extracellular ActRII chimeras of the invention have reduced, weak, or no substantial binding to BMP9 (e.g., as compared to wild-type ActRIIB). In position X ₃ 、X ₄ 、X ₅ X is as follows ₆ BMP9 binding may be reduced in extracellular ActRII chimeras containing the amino acid sequence TEEN (SEQ ID NO: 374) or TKEN (SEQ ID NO: 375). In some embodiments, the invention is included at position X ₃ 、X ₄ 、X ₅ X is as follows ₆ A polypeptide of an extracellular ActRII chimera, e.g., any of SEQ ID NOs 174-216 (e.g., any of SEQ ID NOs 195-216), having the sequence ten (SEQ ID NO: 374) may be at position X ₄ Has a substitution of amino acid K for amino acid E. In some embodiments, the invention is included at position X ₃ 、X ₄ 、X ₅ X is as follows ₆ In extracellular ActRII chimeras having the sequence TKEN (SEQ ID NO: 375) (e.g., SEQ ID NOs: 174-216 (e.g., SEQ ID NOs: 195-216) Any of the polypeptides of (a) may be at position X) ₄ Having amino acid E substituted for amino acid K. In the extracellular ActRII chimeras of the invention (e.g., the chimeras of tables 6 and 7, e.g., SEQ ID NOs: 174-216 (e.g., SEQ ID NOs: 195-216)), the sequences ten (SEQ ID NO: 374) and TKEN (SEQ ID NO: 375) are used interchangeably.

The extracellular ActRII chimeras of the invention may also include a C-terminal extension (e.g., additional amino acids at the C-terminal). C-terminal extension one or more additional amino acids (e.g., 1, 2, 3, 4, 5, 6 or more additional amino acids) may be added at the C-terminus to any of the chimeras shown in tables 6 and 7, e.g., SEQ ID NOS: 174-216 (e.g., SEQ ID NOS: 195-216). The C-terminal extension may correspond to a sequence from the same position in wild-type ActRIIA or ActRIIB. For example, it may be included in the extracellular ActRII chimeras of the invention that extend C-terminally to the amino acid sequence NP and the amino acid sequence NPVTPK (SEQ ID NO: 154) that correspond to sequences present at the same position in wild-type ActRIIA.

TABLE 6 amino acid substitutions in extracellular ActRII chimeras having the sequence of any of SEQ ID NOS 174-194

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In some embodiments, X is in the extracellular ActRII chimera of SEQ ID NOs 174-216 (shown in table 6) ₁ Is D, X ₂ I, F or E, X ₃ Is N or T, X ₄ Is A or E, X ₅ Is T or K, X ₆ Is E or K, X ₇ Is E or D, X ₈ Is N or S, and X ₉ E or Q. In some embodiments, the sequence in SEQ ID NO 174-216 extracellularIn ActRII chimera, X ₁ Is D, X ₂ Is I or F, X ₃ Is N, X ₄ Is A or E, X ₅ Is T or K, X ₆ Is E or K, X ₇ Is E or D, X ₈ Is N or S, and X ₉ E or Q.

In some embodiments, the polypeptides described herein include extracellular ActRII chimeras having the sequence of any one of SEQ ID NOs 195-216 (table 7).

TABLE 7 extracellular ActRII chimeras with the sequences of SEQ ID NOs 195-216

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In some embodiments, the extracellular ActRII chimeras described herein have an N-terminal truncation of 1-9 amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9 amino acids). N-terminal truncation may involve the removal of 1-9 amino acids from the N-terminus of any of the chimeras shown in tables 6 and 7, e.g., SEQ ID NOS: 174-216 (e.g., SEQ ID NOS: 195-216). The N-terminal truncation may remove amino acids up to two amino acids before the first cysteine (e.g., two amino acids (RE or QE) before the first cysteine are retained in the N-terminal truncated ActRII chimera). Exemplary ActRII chimeras with N-terminal truncations are provided in table 8 below.

TABLE 8 extracellular ActRII chimeras with N-terminal truncations

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In some embodiments, a polypeptide of the invention comprising an extracellular ActRII chimera may further comprise a moiety (e.g., an Fc domain monomer, an Fc domain (e.g., wild-type Fc domain), an Fc domain with amino acid substitutions (e.g., one or more substitutions that reduce dimerization), an albumin binding peptide, a fibronectin domain, or human serum albumin) that may be fused to the N-terminus or C-terminus (e.g., C-terminus) of the extracellular ActRII chimera by a linker or other covalent bond. Polypeptides comprising extracellular ActRII chimeras fused to Fc domain monomers may form dimers (e.g., homodimers or heterodimers) through interactions between two Fc domain monomers that combine to form an Fc domain in the dimer. Exemplary polypeptides comprising ActRII chimeras, fc domains, and linkers are provided in table 9 below. In some embodiments, the Fc domain lacks a terminal lysine in the amino acid sequence.

TABLE 9 Polypeptides comprising extracellular ActRII chimeras fused to Fc domains by a linker

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Furthermore, in some embodiments, the polypeptides described herein (e.g., actRII chimeric-Fc fusion proteins) have a serum half-life of at least 7 days in humans. Polypeptides including extracellular ActRII chimeras may have a K of 10pM or greater _D Binds to activin a. In some embodiments, polypeptides comprising extracellular ActRII chimeras bind to activin a, activin B, and/or myostatin and exhibit reduced (e.g., weak) binding to BMP9 (e.g., as compared to wild-type extracellular ActRIIB). In some embodiments, polypeptides comprising extracellular ActRII chimeras with reduced or weak binding to BMP9 are at position X ₃ 、X ₄ 、X ₅ X is as follows ₆ Has the sequence TEEN (SEQ ID NO: 374) or TKEN (SEQ ID NO: 375). In some embodiments, polypeptides comprising extracellular ActRII chimeras with reduced or weak binding to BMP9 are at position X ₃ 、X ₄ 、X ₅ X is as follows ₆ Having the sequence KKDS or TKDS. In some embodiments, the polypeptide comprising the extracellular ActRII chimera does not substantially bind to human BMP9.

In some embodiments, a polypeptide comprising an extracellular ActRII chimera may have a K of about 800pM or less _D (e.g., K of about 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1pM or less) _D For example, a K of between about 800pM and about 30pM _D ) Binds to human activin a. In some embodiments, the polypeptide comprising an extracellular ActRII chimera may have a K of 800pM or less _D (e.g., about 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 5)0. 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1pM or less _D For example, a K of between about 800pM and about 5pM _D ) Binds to human activin B. Polypeptides including extracellular ActRII chimeras may also have a K of about 5pM or greater _D (e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200pM or higher K) _D ) Binds to growth and differentiation factor 11 (GDF-11).

Fc domain

In some embodiments, a polypeptide described herein can include an extracellular ActRII variant (e.g., an extracellular ActRIIA variant, an extracellular ActRIIB variant, or an extracellular ActRII chimer) fused to an Fc domain monomer or fragment of an Fc domain of an immunoglobulin to increase the serum half-life of the polypeptide. Polypeptides comprising extracellular ActRII variants fused to an Fc domain monomer may form a dimer (e.g., homodimer or heterodimer) by interaction between two Fc domain monomers that form an Fc domain in the dimer. As generally known in the art, an Fc domain is a protein structure that is present at the C-terminus of an immunoglobulin. The Fc domain comprises a polypeptide comprising C _H 3 interaction between antibody constant domains dimerizes two Fc domain monomers. The wild-type Fc domain forms the smallest structure that binds to an Fc receptor, e.g., fcγri, fcγriia, fcγriib, fcγriiia, fcγriiib, fcγriv. In some embodiments, the Fc domain may be mutated to lack effector function, which is characteristic of "dead" Fc domains. For example, an Fc domain may include specific amino acid substitutions known to minimize interactions between the Fc domain and fcγ receptor. In some embodiments, the Fc domain is from an IgG1 antibody and comprises amino acid substitutions L234A, L235A and G237A. In some embodiments, the Fc domain is from an IgG1 antibody and comprises amino acid substitutions D265A, K322A and N434A. The amino acid position was determined according to Kabat (Sequences of Proteins of Immunological Interest, 5 th edition Public Health)Service, national Institutes of Health, bethesda, MD. (1991)). The Kabat numbering of amino acid residues of a given antibody can be determined by alignment in regions of homology of antibody sequences having "standard" Kabat numbering sequences. Furthermore, in some embodiments, the Fc domain does not induce any immune system-related responses. For example, the Fc domain in dimers of polypeptides comprising extracellular ActRII variants fused to an Fc domain monomer may be modified to reduce interaction or binding between the Fc domain and fcγ receptor. The sequence of the Fc domain monomer that can be fused to an extracellular ActRII variant (e.g., an extracellular ActRIIA variant, an extracellular ActRIIB variant, or an extracellular ActRII chimera) is shown below (SEQ ID NO: 97):

In some embodiments, the Fc domain is from an IgG1 antibody and comprises amino acid substitutions L12A, L A and G15A relative to the sequence of SEQ ID NO: 97. In some embodiments, the Fc domain is from an IgG1 antibody and comprises amino acid substitutions D43A, K100A and N212A relative to the sequence of SEQ ID NO: 97. In some embodiments, the Fc domain monomer having the sequence of SEQ ID NO. 97 lacks a terminal lysine. In some embodiments, extracellular ActRII variants described herein (e.g., extracellular ActRIIA variants having the sequence of any one of SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72), extracellular ActRIIB variants having the sequence of any one of SEQ ID NOs: 157-171 (e.g., SEQ ID NOs: 158-171), or extracellular ActRII chimeras having the sequence of any one of SEQ ID NOs: 174-216 (e.g., SEQ ID NOs: 195-216)) may be fused to the N-or C-terminus of an Fc domain monomer (e.g., SEQ ID NO: 97) by conventional genetic or chemical means (e.g., chemical conjugation). If desired, a linker (e.g., a spacer) may be inserted between the extracellular ActRII variant and the Fc domain monomer. The Fc domain monomer may be fused to the N-terminus or the C-terminus (e.g., the C-terminus) of the extracellular ActRII variant.

In some embodiments, a polypeptide described herein can include an extracellular ActRII variant (e.g., an extracellular ActRIIA variant, an extracellular ActRIIB variant, or an extracellular ActRII chimeric) fused to an Fc domain. In some embodiments, the Fc domain contains one or more amino acid substitutions that reduce or inhibit dimerization of the Fc domain. In some embodiments, the Fc domain comprises a hinge domain. The Fc domain may belong to immunoglobulin antibody isotype IgG, igE, igM, igA or IgD. In addition, the Fc domain may be of the IgG subtype (e.g., igG1, igG2a, igG2b, igG3, or IgG 4). The Fc domain may also be a non-naturally occurring Fc domain, such as a recombinant Fc domain.

Methods of engineering Fc domains with reduced dimerization are known in the art. In some embodiments, C may be _H 3-C _H 3 dimer interface introduces one or more amino acids with large side chains (e.g., tyrosine or tryptophan) to hinder dimer formation due to steric clash. In other embodiments, C may be _H 3-C _H 3 dimer interfaces incorporate one or more amino acids with small side chains (e.g., alanine, valine, or threonine) to eliminate favorable interactions. For example, YING et al (J Biol chem.287:19399-19408,2012), U.S. patent publication No. 2006/007425, U.S. patent publication Nos. 8,216,805 and 5,731,168, ridgway et al (Protein Eng.9:617-612, 1996), atwell et al (J Mol Biol.270:26-35, 1997) describe in C in Merchant et al (Nat Biotechnol.16:677-681, 1998) _H 3 domain of amino acids with large or small side chains, all of which are incorporated herein by reference in their entirety.

In other embodiments, C _H The 3 domain constitutes C between two Fc domains _H 3-C _H One or more amino acid residues of the 3 interface are replaced with positively charged amino acid residues (e.g. lysine, arginine or histidine) or negatively charged amino acid residues (e.g. aspartic acid or glutamic acid) such that the interaction becomes electrostatically unfavorable depending on the particular charged amino acid introduced. For example, YING et al (J Biol chem.287:19399-19408,2012), U.S. patent publication Nos. 2006/0074125, 2012/0244778, 2014/0024111 describe in C _H Introduction of charging into 3 domainsCharged amino acids are incorporated herein by reference in their entirety in a manner that is detrimental to or prevents dimer formation.

In some embodiments of the invention, the Fc domain comprises one or more of the following amino acid substitutions relative to the sequence of human IgG 1: t366 366 366 394 405 349 349 351 351 351 352 353 356 356 357 357 357 357 364 366 368 368 368 370 370 370 392 395 394 397 397 397 399 399 405 405 405 405 407 409 409T and K409I. In some embodiments, the Fc domain lacks a terminal lysine in the amino acid sequence. In a particular embodiment, the Fc domain comprises the amino acid substitution T366W relative to the sequence of human IgG 1. The sequence of the wild-type Fc domain is shown in SEQ ID NO:150 as follows:

DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK。

An exemplary sequence of a wild-type Fc domain lacking a terminal lysine is provided as follows (SEQ ID NO: 155):

DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG。

albumin binding peptides

In some embodiments, a polypeptide described herein can include an extracellular ActRII variant (e.g., an extracellular ActRIIA variant, an extracellular ActRIIB variant, or an extracellular ActRII chimeric) fused to a serum protein-binding peptide. Binding to serum protein peptides can improve the pharmacokinetics of protein drugs.

As one example, albumin binding peptides useful in the methods and compositions described herein are generally known in the art. In one embodiment, the albumin binding peptide comprises sequence DICLPRWGCLW (SEQ ID NO: 151).

In the present invention, albumin binding peptides may be linked to the N-terminus or C-terminus (e.g., C-terminus) of an extracellular ActRII variant described herein (e.g., an extracellular ActRIIA variant having the sequence of any one of SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72), an extracellular ActRIIB variant having the sequence of any one of SEQ ID NOs: 157-171 (e.g., SEQ ID NOs: 158-171), or an extracellular ActRII chimera having the sequence of any one of SEQ ID NOs: 174-216 (e.g., SEQ ID NOs: 195-216) to increase the serum half-life of the extracellular ActRII variant. In some embodiments, the albumin-binding peptide is linked directly or through a linker to the N-terminus or the C-terminus of the extracellular ActRII variant.

In some embodiments, extracellular ActRII variants described herein (e.g., extracellular ActRIIA variants having the sequence of any one of SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72), extracellular ActRIIB variants having the sequence of any one of SEQ ID NOs: 157-171 (e.g., SEQ ID NOs: 158-171), or extracellular ActRII chimeras having the sequence of any one of SEQ ID NOs: 174-216 (e.g., SEQ ID NOs: 195-216)) may be fused to the N-or C-terminus of an albumin binding peptide (e.g., SEQ ID NO: 151) by conventional genetic or chemical means (e.g., chemical conjugation). If desired, a linker (e.g., a spacer) may be inserted between the extracellular ActRII variant and the albumin-binding peptide. Without being limited by theory, inclusion of albumin binding peptides in the extracellular ActRII variants described herein is expected to allow for prolonged retention of the therapeutic protein by binding the therapeutic protein to serum albumin.

Fibronectin domains

In some embodiments, a polypeptide described herein can include an extracellular ActRII variant (e.g., an extracellular ActRIIA variant, an extracellular ActRIIB variant, or an extracellular ActRII chimeric) fused to a fibronectin domain. Binding to the fibronectin domain may improve the pharmacokinetics of the protein drug.

Fibronectin domains are high molecular weight glycoproteins of the extracellular matrix, or fragments thereof, that bind to, for example, transmembrane receptor proteins (such as integrins) and extracellular matrix components (such as collagen and fibrin). In some embodiments of the invention, a fibronectin domain is linked to the N-or C-terminus (e.g., C-terminus) of an extracellular ActRII variant described herein (e.g., an extracellular ActRIIA variant having the sequence of any one of SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72), an extracellular ActRIIB variant having the sequence of any one of SEQ ID NOs: 157-171 (e.g., SEQ ID NOs: 158-171), or an extracellular ActRII chimera having the sequence of any one of SEQ ID NOs: 174-216 (e.g., SEQ ID NOs: 195-216) to increase the serum half-life of the extracellular ActRII variant. The fibronectin domain may be linked directly or through a linker to the N-terminus or C-terminus of the extracellular ActRII variant.

As one example, fibronectin domains useful in the methods and compositions described herein are generally known in the art. In one embodiment, the fibronectin domain is a polypeptide having the UniProt ID number: the fibronectin type III domain of amino acids 610-702 of the sequence of P02751 (SEQ ID NO:152 below).

In another embodiment, the fibronectin domain is an adnectin protein.

In some embodiments, extracellular ActRII variants described herein (e.g., extracellular ActRIIA variants having the sequence of any one of SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72), extracellular ActRIIB variants having the sequence of any one of SEQ ID NOs: 157-171 (e.g., SEQ ID NOs: 158-171), or extracellular ActRII chimeras having the sequence of any one of SEQ ID NOs: 174-216 (e.g., SEQ ID NOs: 195-216)) may be fused to the N-or C-terminus of a fibronectin domain (e.g., SEQ ID NO: 152) by conventional genetic or chemical means (e.g., chemical conjugation). If desired, a linker (e.g., a spacer) may be inserted between the extracellular ActRII variant and the fibronectin domain. Without being limited by theory, inclusion of a fibronectin domain in the extracellular ActRII variants described herein is expected to allow for prolonged retention of the therapeutic protein by binding of the therapeutic protein to integrins and extracellular matrix components (such as collagen and fibrin).

V. serum albumin

In some embodiments, a polypeptide described herein can include an extracellular ActRII variant (e.g., an extracellular ActRIIA variant, an extracellular ActRIIB variant, or an extracellular ActRII chimeric) fused to serum albumin. Binding to serum albumin can improve the pharmacokinetics of protein drugs.

Serum albumin is a globular protein, which is the most abundant blood protein in mammals. Serum albumin is produced in the liver and constitutes about half of the serum proteins. It is monomeric and soluble in blood. Some of the most important functions of serum albumin include the transport of hormones, fatty acids and other proteins in the body, buffering pH, and osmotic pressure required to maintain proper distribution of body fluids between blood vessels and body tissues. In a preferred embodiment, the serum albumin is human serum albumin. In some embodiments of the invention, human serum albumin is linked to the N-or C-terminus (e.g., C-terminus) of an extracellular ActRII variant described herein (e.g., an extracellular ActRIIA variant having the sequence of any one of SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72), an extracellular ActRIIB variant having the sequence of any one of SEQ ID NOs: 157-171 (e.g., SEQ ID NOs: 158-171), or an extracellular ActRII chimera having the sequence of any one of SEQ ID NOs: 174-216 (e.g., SEQ ID NOs: 195-216) to increase the serum half-life of the extracellular ActRII variant. Human serum albumin may be attached directly or through a linker to the N-terminus or C-terminus of the extracellular ActRII variant.

As one example, serum albumin useful in the methods and compositions described herein is generally known in the art. In one embodiment, the serum albumin comprises the UniProt ID number: p02768 (SEQ ID NO:153, below).

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In some embodiments, extracellular ActRII variants described herein (e.g., extracellular ActRIIA variants having the sequence of any one of SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72), extracellular ActRIIB variants having the sequence of any one of SEQ ID NOs: 157-171 (e.g., SEQ ID NOs: 158-171), or extracellular ActRII chimeras having the sequence of any one of SEQ ID NOs: 174-216 (e.g., SEQ ID NOs: 195-216)) may be fused to the N-or C-terminus of human serum albumin (e.g., SEQ ID NO: 153) by conventional genetic or chemical means (e.g., chemical conjugation). If desired, a linker (e.g., a spacer) may be inserted between the extracellular ActRII variant and human serum albumin. Without being limited by theory, inclusion of human serum albumin in the extracellular ActRII variants described herein is expected to allow for prolonged retention of therapeutic proteins.

VI joint

The polypeptides described herein can include extracellular ActRII variants (e.g., extracellular ActRIIA variants having the sequence of any one of SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72), extracellular ActRIIB variants having the sequence of any one of SEQ ID NOs: 157-171 (e.g., SEQ ID NOs: 158-171), or extracellular ActRII chimeras having the sequence of any one of SEQ ID NOs: 174-216 (e.g., SEQ ID NOs: 195-216)) fused to one portion by a linker. In some embodiments, the moiety increases the stability of the polypeptide. Exemplary moieties include Fc domain monomers, fc domains (e.g., wild-type Fc domains), fc domains with amino acid substitutions (e.g., one or more substitutions that reduce dimerization), albumin binding peptides, fibronectin domains, or human serum albumin. In the present invention, the linker between a portion (e.g., an Fc domain monomer (e.g., the sequence of SEQ ID NO: 97), an Fc domain (e.g., a wild-type Fc domain (e.g., SEQ ID NO:150 or SEQ ID NO: 155)), an Fc domain having amino acid substitutions (e.g., one or more substitutions that reduce dimerization), an albumin binding peptide (e.g., SEQ ID NO: 151), a fibronectin domain (e.g., SEQ ID NO: 152) or human serum albumin (e.g., SEQ ID NO: 153)) and an extracellular ActRII variant (e.g., an extracellular ActRIIA variant having the sequence of any of SEQ ID NO:1-72 (e.g., SEQ ID NO: 6-72), an extracellular ActRIIB variant having the sequence of any of SEQ ID NO:157-171 (e.g., SEQ ID NO: 158-171), or an extracellular ActRII chimera having the sequence of any of SEQ ID NO:174-216 (e.g., SEQ ID NO: 195-216)) may be an amino acid spacer comprising 1-200 amino acids. Suitable peptide spacers are known in the art and include, for example, peptide linkers containing flexible amino acid residues such as glycine, alanine, and serine. In some embodiments, the spacer may contain multiple or repeated motifs of motifs such as GA, GS, GG, GGA, GGS, GGG, GGGA (SEQ ID NO: 98), GGGS (SEQ ID NO: 99), GGGGGG (SEQ ID NO: 100), GGGGA (SEQ ID NO: 101), GGGGS (SEQ ID NO: 102), GGGGG (SEQ ID NO: 103), GGAG (SEQ ID NO: 104), GGSG (SEQ ID NO: 105), AGGG (SEQ ID NO: 106), or SGGG (SEQ ID NO: 107). In some embodiments, the spacer may contain 2 to 12 amino acids including motifs of GA or GS, such as GA, GS, GAGA (SEQ ID NO: 108), GS (SEQ ID NO: 109), GAGAGA (SEQ ID NO: 110), GSGSGS (SEQ ID NO: 111), GAGAGAGA (SEQ ID NO: 112), GSGSGSGSG (SEQ ID NO: 113), GAGAGAGAGA (SEQ ID NO: 114), GSGS GSGSGS (SEQ ID NO: 115), GAGAGAGAGAGA (SEQ ID NO: 116), and GSGSGSGSGSGS (SEQ ID NO: 117). In some embodiments, the spacer may contain 3 to 12 amino acids including motifs of GGA or GGS, such as GGA, GGS, GGAGGA (SEQ ID NO: 118), GGSGGS (SEQ ID NO: 119), GGAGGAGGA (SEQ ID NO: 120), GGSGGSGGS (SEQ ID NO: 121), GGAGGAGGAGGA (SEQ ID NO: 122), and GGSGG SGGSGGS (SEQ ID NO: 123). In other embodiments, the spacer may contain 4 to 12 amino acids including motifs of GGAG (SEQ ID NO: 104), GGSG (SEQ ID NO: 105), such as GGAG (SEQ ID NO: 104), GGSG (SEQ ID NO: 105), GGAGGGAG (SEQ ID NO: 124), GGSGGGSG (SEQ ID NO: 125), GGAGGGAGGGAG (SEQ ID NO: 126), and GGSGGGSGGGSG (SEQ ID NO: 127). In some embodiments, the spacer may contain motifs of GGGGA (SEQ ID NO: 101) or GGGGS (SEQ ID NO: 102), such as GGGGAGGGGAGGGGA (SEQ ID NO: 128) and GGG GSGGGGSGGGGS (SEQ ID NO: 129). In some embodiments of the invention, the amino acid spacer between a portion (e.g., an Fc domain monomer, an Fc domain (e.g., wild-type Fc domain), an Fc domain with amino acid substitutions (e.g., one or more substitutions that reduce dimerization), an albumin binding peptide, a fibronectin domain, or human serum albumin) and an extracellular ActRII variant (e.g., an extracellular ActRIIA variant with the sequence of any of SEQ ID NOs 1-72 (e.g., SEQ ID NOs 6-72), an extracellular ActRIIB variant with the sequence of any of SEQ ID NOs 157-171 (e.g., SEQ ID NOs 158-171), or an extracellular ActRIIB chimeric with the sequence of any of SEQ ID NOs 174-216 (e.g., SEQ ID NOs 195-216) may be GGG, GGGA (SEQ ID NO: 98), gggggg (SEQ ID NO: 100), GGGAG (SEQ ID NO: 130), GGGAGG (SEQ ID NO: 131), or GGGAGG (Q: 132).

In some embodiments, the spacer may also contain amino acids other than glycine, alanine, and serine, such as AAAL (SEQ ID NO: 133), AAAK (SEQ ID NO: 134), AAAR (SEQ ID NO: 135), EGKSSGSGSESKST (SEQ ID NO: 136), GSAGSAAGSGEF (SEQ ID NO: 137), AEAAAKEAAAKA (SEQ ID NO: 138), KESGSVSSEQLAQFRSLD (SEQ ID NO: 139), GENLYFQSGG (SEQ ID NO: 140), SACCELS (SEQ ID NO: 141), RSIAT (SEQ ID NO: 142), RPACKIPNDLKQKVMNH (SEQ ID NO: 143), GGSAGGSGSGSSGGSSGASGTGTAGGTGSGSGTGSG (SEQ ID NO: 144), AAANSSIDLISVPVDSR (SEQ ID NO: 145), or GGSGGGSEGGGSEGGGSEGGGSEGGGSEGGGSGGGS (SEQ ID NO: 146). In some embodiments, the spacer may contain multiple or repeated motifs of motifs, such as EAAAK (SEQ ID NO: 147). In some embodiments, the spacer may contain a motif, e.g., multiple or repeated motifs of proline-rich sequences, such as (XP) _n Wherein X can be any amino acid (e.g., A, K or E) and n is 1-5; PAPAAP (SEQ ID NO: 148).

The length of the peptide spacer and amino acid used can be adjusted depending on the two proteins involved and the degree of flexibility desired in the final protein fusion polypeptide. The length of the spacer may be adjusted to ensure proper protein folding and to avoid the formation of aggregates.

In some embodiments, the linker between a portion (e.g., an Fc domain monomer (e.g., the sequence of SEQ ID NO: 97), an Fc domain (e.g., a wild-type Fc domain (e.g., SEQ ID NO:150 or SEQ ID NO: 155)), an Fc domain having amino acid substitutions (e.g., one or more substitutions that reduce dimerization), an albumin binding peptide (e.g., SEQ ID NO: 151), a fibronectin domain (e.g., SEQ ID NO: 152), or human serum albumin (e.g., SEQ ID NO: 153)) and an extracellular ActRII variant described herein (e.g., an extracellular ActRII variant having the sequence of any of SEQ ID NO:1-72 (e.g., SEQ ID NO: 6-72), an extracellular actriiB variant having the sequence of any of SEQ ID NO:157-171 (e.g., SEQ ID NO: 158-171), or an extracellular ActRII chimera having the sequence of any of SEQ ID NO: 174-216) is an amino acid spacer having the sequence GGG. For example, a polypeptide of the invention may contain an extracellular ActRIIA variant (e.g., any of SEQ ID NOs: 6-72) fused to an Fc domain (e.g., SEQ ID NO: 155) via a GGG linker. Exemplary polypeptides containing ActRIIA variants of SEQ ID No. 69, GGG linkers, and Fc domains lacking a terminal lysine (SEQ ID No. 155) provide the following (SEQ ID No. 156):

GAILGRSETQECLFYNANWELERTNQTGVERCEGEKDKRLHCYATWRNISGSIEIVKKGCWLDDFNCYDRTDCVETEENPQVYFCCCEGNMCNEKFSYFPEMEVTQPTSGGGDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

In another example, a polypeptide of the invention may contain an extracellular ActRIIB variant (e.g., any of SEQ ID NOs: 158-171) fused to an Fc domain (e.g., SEQ ID NO:150 or SEQ ID NO: 155) via a GGG linker. Exemplary polypeptides comprising an ActRIIB variant of SEQ ID No. 171, a GGG linker, and an Fc domain (SEQ ID No. 150) are provided as follows (SEQ ID No. 172):

GRGEAETRECLYYNANWELERTNQSGVERCEGEKDKRLHCYASWRNSSGSLEIVKKGCWLDDFNCYDRDTCVATKENPQVYFCCCEGNMCNERFTHLPEAGGPEVTYEPPPTAPTGGGDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

VII vectors, host cells and protein production

The polypeptides of the invention may be produced by a host cell. A host cell refers to a vehicle that includes the necessary cellular components (e.g., organelles) required to express the polypeptides and fusion polypeptides described herein from the corresponding nucleic acids. The nucleic acid may be included in a nucleic acid vector that may be introduced into a host cell by conventional techniques known in the art (e.g., transformation, transfection, electroporation, calcium phosphate precipitation, direct microinjection, infection, etc.). The choice of nucleic acid vector depends in part on the host cell to be used. Generally, preferred host cells are those of eukaryotic (e.g., mammalian) or prokaryotic (e.g., bacterial) origin.

Nucleic acid vector construction and host cells

Nucleic acid sequences encoding the amino acid sequences of the polypeptides of the invention can be prepared by a variety of methods known in the art. These methods include, but are not limited to, oligonucleotide-mediated (or site-directed) mutagenesis and PCR mutagenesis. Nucleic acid molecules encoding polypeptides of the invention can be obtained using standard techniques (e.g., gene synthesis). Alternatively, standard techniques in the art (e.g., quikChange ^TM Mutagenesis) mutates a nucleic acid molecule encoding wild-type extracellular ActRIIA or ActRIIB to include specific amino acid substitutions. Nucleic acid molecules can be synthesized using nucleotide synthesizers or PCR techniques.

The nucleic acid sequences encoding the polypeptides of the invention may be inserted into vectors capable of replicating and expressing the nucleic acid molecules in prokaryotic or eukaryotic host cells. Many vectors are available in the art and can be used for the purposes of the present invention. Each vector may include various components that may be adjusted and optimized for compatibility with a particular host cell. For example, vector components may include, but are not limited to, origins of replication, selectable marker genes, promoters, ribosome binding sites, signal sequences, nucleic acid sequences encoding a protein of interest, and transcription termination sequences.

In some embodiments, mammalian cells may be used as host cells of the invention. Examples of mammalian cell types include, but are not limited toLimited to Human Embryonic Kidney (HEK) (e.g., HEK 293F), chinese Hamster Ovary (CHO), heLa, COS, PC, vero, MC3T3, NS0, sp2/0, VERY, BHK, MDCK, W138, BT483, hs578T, HTB2, BT20, T47D, NS0 (murine myeloma cell line that does not endogenously produce any immunoglobulin chain), CRL7O3O, and HsS78Bst cells. In some embodiments, E.coli cells may also be used as host cells in the present invention. Examples of E.coli (E.coli) strains include, but are not limited to, E.coli 294 # 31, 446), E.coli lambda 1776 (-/->31,537, E.coli BL21 (DE 3) (-)>BAA-1025) and E.coli RV308 (/ -E.coli)>31,608). Different host cells have characteristics and specific mechanisms for post-translational processing and modification (e.g., glycosylation) of protein products. An appropriate cell line or host system may be selected to ensure proper modification and processing of the expressed polypeptide. The expression vectors described above can be introduced into suitable host cells using techniques conventional in the art (e.g., transformation, transfection, electroporation, calcium phosphate precipitation, and direct microinjection). After introducing the vector into a host cell for the production of the protein, the host cell is cultured in conventional media modified as appropriate for inducing promoters, selecting transformants or amplifying the genes encoding the desired sequences. Methods for expressing therapeutic proteins are known in the art, see, e.g., paulina Balbas, argelia Lorence (eds.) Recombinant Gene Expression: reviews and Protocols (Methods in Molecular Biology), humana Press; version 2 2004 and Vladimir Voynov and just a. Caroavella (ed.) Therapeutic Proteins: methods and Protocols (Methods in Molecular Biology) Humana Press; version 2 2012。

Protein production, recovery and purification

Host cells useful for producing the polypeptides of the invention can be grown in media known in the art and suitable for culturing the selected host cells. Examples of suitable media for mammalian host cells include Minimal Essential Medium (MEM), dulbecco's Modified Eagle's Medium (DMEM), expi293 ^TM Expression medium, DMEM supplemented with Fetal Bovine Serum (FBS), and RPMI-1640. Examples of suitable media for bacterial host cells include the Luria Broth (LB) plus necessary supplements such as selection agents, e.g., ambicillin. The host cells are contacted with CO at a suitable temperature (such as from about 20℃to about 39 ℃, e.g., from 25℃to about 37 ℃, preferably 37 ℃) ₂ Culturing is performed at a level (such as 5 to 10%). The pH of the medium is generally about 6.8 to 7.4, e.g., 7.0, depending primarily on the host organism. If an inducible promoter is used in the expression vector of the present invention, protein expression is induced under conditions suitable for activating the promoter.

In some embodiments, depending on the expression vector and host cell used, the expressed protein may be secreted from the host cell (e.g., mammalian host cell) into the cell culture medium. Protein recovery may involve filtering the cell culture medium to remove cell debris. The protein may be further purified. The polypeptides of the invention may be purified by any method known in the art for protein purification, e.g., by chromatography (e.g., ion exchange, affinity and size exclusion column chromatography), centrifugation, differential solubility, or by any other standard technique for protein purification. For example, proteins can be separated and purified by appropriate selection of an affinity column (such as a protein a column, e.g., POROS protein a chromatography) and combining the affinity column with a chromatography column (e.g., POROS HS-50 cation exchange chromatography), filtration, ultrafiltration, salting out, and dialysis procedures.

In other embodiments, the host cells may be destroyed, for example, by osmotic shock, sonication, or lysis, to recover the expressed protein. After the cells are destroyed, cell debris can be removed by centrifugation or filtration. In some cases, the polypeptide may be conjugated to a labeling sequence (such as a peptide) to facilitate purification. An example of a tagged amino acid sequence is a hexahistidine peptide (His-tag) that binds with micromolar affinity to a nickel-functionalized agarose affinity column. Other peptide tags that may be used for purification include, but are not limited to, hemagglutinin "HA" tags that correspond to epitopes derived from influenza hemagglutinin protein (Wilson et al, cell 37:767, 1984).

Alternatively, the polypeptides of the invention may be produced by cells of a subject (e.g., human), e.g., in the case of gene therapy, by administering a vector comprising a nucleic acid molecule encoding the polypeptide of the invention, such as a viral vector (e.g., a retroviral vector, an adenoviral vector, a poxviral vector (e.g., a vaccinia viral vector such as modified vaccinia ankara (Modified Vaccinia Ankara, MVA), an adeno-associated viral vector, and an alphaviral vector)), the vector will facilitate expression of the polypeptide after entry into the cell interior of the subject (e.g., by transformation, transfection, electroporation, calcium phosphate precipitation, direct microinjection, infection, etc.), which polypeptide is then secreted from the cell.

Pharmaceutical composition and formulation

The invention provides pharmaceutical compositions comprising a polypeptide described herein (e.g., a polypeptide comprising an extracellular ActRIIA variant having the sequence of any one of SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72), an extracellular ActRIIB variant having the sequence of any one of SEQ ID NOs: 157-171 (e.g., SEQ ID NOs: 158-171), or an extracellular ActRII chimeric having the sequence of any one of SEQ ID NOs: 174-216 (e.g., 195-216). In some embodiments, the pharmaceutical compositions of the invention include polypeptides having a C-terminal extension (e.g., 1, 2, 3, 4, 5, 6, or more additional amino acids) as a therapeutic protein, including extracellular ActRII variants (e.g., extracellular ActRIIA variants having the sequence of any one of SEQ ID NOs: 1-70 (e.g., SEQ ID NOs: 6-70) or extracellular ActRII chimeras having the sequence of any one of SEQ ID NOs: 174-216 (e.g., 195-216). In some embodiments, the pharmaceutical compositions of the invention include a polypeptide comprising an extracellular ActRII variant (e.g., an extracellular ActRIIA variant having the sequence of any one of SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72), an extracellular ActRIIB variant having the sequence of any one of SEQ ID NOs: 157-171 (e.g., SEQ ID NOs: 158-171), or an extracellular ActRII chimeric having the sequence of any one of SEQ ID NOs: 174-216 (e.g., 195-216)) as a therapeutic protein fused to a moiety (e.g., an Fc domain monomer or dimer thereof, an Fc domain (e.g., wild-type Fc domain), an Fc domain having amino acid substitutions (e.g., one or more substitutions that reduce dimerization), an albumin binding peptide, a fibronectin domain, or human serum albumin). In some embodiments, the pharmaceutical compositions of the invention comprising the polypeptides of the invention may be used in combination with other agents (e.g., therapeutic biological agents and/or small molecules) or compositions in therapy. In addition to a therapeutically effective amount of the polypeptide, the pharmaceutical composition may also include one or more pharmaceutically acceptable carriers or excipients, which may be formulated by methods known to those skilled in the art. In some embodiments, the pharmaceutical compositions of the invention comprise a nucleic acid molecule (DNA or RNA, e.g., mRNA) encoding a polypeptide of the invention, or a vector containing such a nucleic acid molecule.

Acceptable carriers and excipients in the pharmaceutical compositions are non-toxic to the recipient at the dosages and concentrations employed. Acceptable carriers and excipients can include buffers such as phosphate, citrate, HEPES, and TAE; antioxidants such as ascorbic acid and methionine; preservatives such as hexamethyl ammonium chloride, octadecyl dimethyl benzyl ammonium chloride, resorcinol, and benzalkonium chloride; proteins such as human serum albumin, gelatin, dextran, and immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, histidine, arginine, and lysine; and carbohydrates such as glucose, mannose, sucrose, and sorbitol. The pharmaceutical compositions of the present invention may be administered parenterally in the form of injectable formulations. Pharmaceutical compositions for injection may be formulated using sterile solutions or any pharmaceutically acceptable liquids as vehicles. Pharmaceutically acceptable vehicles include, but are not limited to, sterile water, physiological saline, and cell culture media (e.g., dulbecco's Modified Eagle's Medium (DMEM), alpha-modified eagle's Medium (alpha-MEM), F-12 Medium). Methods of Formulation are known in the art, see, e.g., banga (incorporated) Therapeutic Peptides and Proteins:formulation, processing and Delivery Systems (3 rd edition) Taylor & Francis Group, CRC Press (2015).

The pharmaceutical compositions of the present invention may be prepared as microcapsules, such as hydroxymethyl cellulose or gelatin-microcapsules, as well as poly (methyl methacrylate) microcapsules. The pharmaceutical compositions of the invention may also be prepared in other drug delivery systems such as liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules. Such techniques are described in Remington, the Science and Practice of Pharmacy, 22 nd edition (2012). The pharmaceutical composition to be used for in vivo administration must be sterile. This is easily achieved by filtration through sterile filtration membranes.

The pharmaceutical compositions of the present invention may also be prepared as sustained release formulations. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the polypeptide of the invention. Examples of sustained-release matrices include polyesters, hydrogels, polylactides, copolymers of L-glutamic acid and gamma ethyl-L-glutamate, nondegradable ethylene vinyl acetate, degradable lactic acid-glycolic acid copolymers (such as LUPRON DEPOT ^TM ) Poly D- (-) -3-hydroxybutyric acid. Some sustained release formulations enable the release of the molecule over a period of several months (e.g. one month to six months), while other formulations release the pharmaceutical composition of the invention over a shorter period of time (e.g. days to weeks).

The pharmaceutical compositions may be formed as desired in unit dosage form. The amount of active ingredient (e.g. a polypeptide of the invention) included in the pharmaceutical formulation is such as to provide a suitable dose within the indicated range (e.g. a dose in the range of 0.01-100mg per kg body weight).

The pharmaceutical composition for gene therapy may be contained in an acceptable diluent, or may include a slow-release matrix in which the gene delivery vehicle is embedded. If hydrodynamic injection is used as a delivery method, a pharmaceutical composition containing a nucleic acid molecule encoding a polypeptide described herein or a vector (e.g., a viral vector) containing the nucleic acid molecule is delivered rapidly in a large fluid volume in an intravenous manner. Vectors that may be used as in vivo gene delivery vehicles include, but are not limited to, retroviral vectors, adenoviral vectors, poxviral vectors (e.g., vaccinia viral vectors such as modified vaccinia ankara), adeno-associated viral vectors, and alphaviral vectors.

IX. route, dosage and administration

Pharmaceutical compositions comprising the polypeptides of the invention as therapeutic proteins may be formulated for e.g. intravenous administration, parenteral administration, subcutaneous administration, intramuscular administration, intra-arterial administration, intrathecal administration or intraperitoneal administration. The pharmaceutical compositions may also be formulated for oral, nasal, spray, aerosol, rectal or vaginal administration or administration via the route. For injectable formulations, various effective pharmaceutical carriers are known in the art. See, e.g., ASHP Handbook on Injectable Drugs, toissel, 18 th edition (2014).

In some embodiments, pharmaceutical compositions comprising nucleic acid molecules encoding polypeptides of the invention or vectors containing such nucleic acid molecules may be administered by gene delivery. Methods of gene delivery are well known to those skilled in the art. Vectors useful for in vivo gene delivery and expression include, but are not limited to, retroviral vectors, adenoviral vectors, poxviral vectors (e.g., vaccinia viral vectors such as Modified Vaccinia Ankara (MVA)), adeno-associated viral vectors, and alphaviral vectors. In some embodiments, mRNA molecules encoding the polypeptides of the invention may be administered directly to a subject.

In some embodiments of the invention, nucleic acid molecules encoding polypeptides described herein or vectors containing such nucleic acid molecules may be administered using a hydrodynamic injection platform. In a hydrodynamic injection method, a nucleic acid molecule encoding a polypeptide described herein is placed under the control of a strong promoter in an engineered plasmid (e.g., a viral plasmid). Plasmids are often delivered rapidly in large fluid volumes in an intravenous fashion. Hydrodynamic injection uses controlled hydrodynamic pressure in the vein to enhance cell permeability, such that the elevated pressure due to the rapid large fluid volume injection overflows the fluid and plasmid from the vein. Expression of nucleic acid molecules is driven primarily by the liver. In mice, hydrodynamic injection is often performed by injecting the plasmid into the tail vein. In certain embodiments, hydrodynamic injection may be used to administer mRNA molecules encoding the polypeptides described herein.

The dosage of the pharmaceutical composition of the present invention depends on a variety of factors including the route of administration, the disease to be treated, and physical characteristics such as age, weight, general health of the subject. Pharmaceutical compositions of the invention may comprise a dose of a polypeptide of the invention in the range of 0.01 to 500mg/kg (e.g., 0.01, 0.1, 0.2, 0.3, 0.325, 0.35, 0.375, 0.4, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg/kg), and in a more particular embodiment in the range of about 0.1 to about 30mg/kg, and in a more particular embodiment in the range of about 0.3 to about 30 mg/kg. The dosage may be modified by the physician according to conventional factors, such as the extent of the disease, and different parameters of the subject.

The pharmaceutical composition is administered in a manner compatible with the dosage formulation and in a therapeutically effective amount such that the symptoms are ameliorated or repaired. The pharmaceutical compositions are administered in a variety of dosage forms, such as intravenous dosage forms, subcutaneous dosage forms, and oral dosage forms (e.g., ingestible solutions, drug-release capsules). Typically, the therapeutic protein is administered at 0.1-100mg/kg (e.g., 0.5-50 mg/kg). The pharmaceutical composition comprising a polypeptide of the invention may be administered to a subject in need thereof daily, weekly, biweekly, monthly, octaweekly, bi-monthly, 12-weekly, quarterly, sixteen-weekly, semi-annually, or as medically needed, e.g., one or more times (e.g., 1-10 times or more). In some embodiments, a pharmaceutical composition comprising a polypeptide of the invention may be administered to a subject in need thereof weekly, biweekly, four weeks, monthly, eight weeks, two months, twelve weeks, quarterly, or sixteen weeks. The doses may be provided in single or multiple dosing regimens. The time between administrations may decrease with an improvement in the medical condition or increase with a decrease in the patient's health.

X-ray therapeutic method

ActRII variants described herein have improved properties compared to endogenous ActRIIA and ActRIIB. For example, actRIIA variants produced by introducing residues from ActRIIB into ActRIIA retain the beneficial properties of ActRIIA, such as weak binding affinity to BMP9 and longer serum half-life as an Fc fusion protein, and obtain some beneficial properties of ActRIIB, such as increased binding to activins a and B. ActRIIB variants produced by introducing residues from ActRIIA into ActRIIB may retain beneficial properties of ActRIIB, such as high binding affinity to activins a and B, and obtain some beneficial properties of ActRIIA, such as reduced binding affinity to BMP9 and longer serum half-life as an Fc fusion protein. Furthermore, actRII chimeras produced by combining extracellular portions of ActRIIA and ActRIIB may have beneficial properties of both ActRIIB (e.g., strong binding affinity to activin a and B) and ActRIIA (e.g., reduced binding affinity to BMP9 and/or longer serum half-life as an Fc fusion protein (e.g., as compared to ActRIIB-Fc)). These ActRIIA variants, actRIIB variants, and ActRII chimeric properties contribute to a useful therapeutic agent that can compete for ligand binding with endogenous activin receptors. Because ActRIIA variants, actRIIB variants, and ActRII chimeras contain the extracellular portion of the receptor, they will be soluble and able to bind to and sequester ligands (e.g., activin a and B, myostatin, GDF 11) without activating the intracellular signaling pathway. Based on the discovery that administration of a polypeptide described herein that contains ActRIIA variants results in an increase in serum EPO levels and bone marrow EPO receptor levels at least seven to fourteen days after injection, a polypeptide described herein that contains an ActRII variant (e.g., an ActRIIA variant, an ActRIIB variant, or an ActRII chimera) can be used therapeutically in place of recombinant EPO or an EPO mimetic and can be used to treat any disease or disorder that would benefit from increased EPO and/or EPO receptor levels.

In some embodiments, polypeptides described herein (e.g., polypeptides including extracellular ActRIIA variants (e.g., extracellular ActRIIA variants having the sequence of any one of SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72), extracellular ActRIIB variants having the sequence of any one of SEQ ID NOs: 157-171 (e.g., SEQ ID NOs: 158-171), or extracellular ActRII chimeras having the sequence of any one of SEQ ID NOs: 174-216 (e.g., 195-216)) such as an effective amount of an ActRIIA variant, actRIIB variant, or ActRII chimera) can be administered to increase EPO levels (e.g., serum EPO levels) and/or EPO receptor levels (e.g., EPO receptor levels in bone marrow cells) in a subject in need thereof (e.g., a subject having low serum EPO). The invention also includes methods of treating (e.g., treating, delaying progression of, and/or preventing) a subject suffering from, or at risk of developing, a disease or disorder treatable with EPO or ESA (e.g., a disease or disorder treatable by increasing EPO or EPO receptor levels) by administering to the subject an effective amount of a polypeptide described herein (e.g., a polypeptide comprising an extracellular ActRIIA variant having the sequence of any one of SEQ ID NOs 1-72 (e.g., SEQ ID NOs 6-72), a polypeptide comprising an extracellular ActRIIB variant having the sequence of any one of SEQ ID NOs 157-171 (e.g., SEQ ID NOs 158-171), or a polypeptide comprising an extracellular ActRII chimeric having the sequence of any one of SEQ ID NOs 174-216 (e.g., 195-216), e.g., an effective amount of an ActRIIA variant, an ActRIIB variant, or an ActRII chimeric). Diseases and conditions that may be treated by increasing EPO or EPO receptor levels include end-stage renal disease, renal insufficiency, polycythemia, anemia due to dialysis, premature infant anemia, iron overload (e.g., hemochromatosis), disease states, conditions, and conditions of hematological abnormalities (such as pregnancy, menstrual disorder, and space flights), ischemia (CNS ischemia, liver ischemia, renal ischemia, or cardiac ischemia), ulcers, burns, wounds (e.g., chronic wounds), ischemia-reperfusion injury (e.g., ischemia-reperfusion injury associated with surgery or organ transplantation), ischemic conditions or disorders (e.g., myocardial infarction, ischemic stroke, obstructive arterial disease, chronic venous insufficiency, pulmonary embolism, circulatory shock (such as hemorrhagic shock, septic shock, or cardiogenic shock), acute respiratory failure, chronic heart failure, atherosclerosis, cardiogenic cirrhosis, macular degeneration, sleep apnea, raynaud's disease, systemic sclerosis, non-bacterial thrombotic endocarditis, angina, transient ischemic attacks, chronic alcoholic episodes, chronic ischemic attacks, conditions (e.g., ischemia-reperfusion injury associated with surgery or organ transplantation), conditions such as, e.g., severe liver disease, hypoxic disease, chronic fall or hypoxia, chronic conditions such as, pulmonary disease, or hypoxia (e.g., cancer), severe disease, pulmonary disease, or other conditions such as, sleep or hypoxia), and sleep disorders. The polypeptides described herein may also be used for treating a subject undergoing kidney dialysis, for treating a subject recently undergoing a stem cell transplant, for increasing the subject's red blood cell count prior to surgery or as a pretreatment or further treatment of a tissue or organ to be transplanted (such as for treating a tissue or organ to be transplanted prior to, e.g., immediately prior to, during, or immediately after transplantation).

In view of the discovery that EPO stimulates mobilization, proliferation, migration, and differentiation of endothelial progenitor cells, the polypeptides described herein can also be used to treat diseases associated with endothelial progenitor cell dysfunction. Such diseases include heart failure, angina, endothelial hyperplasia (e.g., reticuloendotheliosis), age-related cardiovascular disorders, coronary heart disease, atherosclerosis, myocardial ischemia, hypercholesterolemia, limb ischemic disorders, raynaud's disease, preeclampsia, pregnancy induced hypertension, endothelial-mediated chronic inflammatory disorders (e.g., vascular inflammation), wound healing, and chronic or acute renal failure (also known as chronic kidney disease and acute renal failure, respectively). Since EPO has been demonstrated to have mitogenic and chemotactic effects on vascular endothelial cells, actRII variant polypeptides (e.g., extracellular ActRIIA variants, actRIIB variants, or ActRII chimeras) may also be used to promote neovascular growth (angiogenesis) and/or to replace damaged vascular regions by locally forming new blood vessels, such as collateral coronary vessels (e.g., that may occur after myocardial infarction), to form granulation tissue (e.g., in damaged tissue, wounds, and ulcers), to perform wound therapy, to perform post-vascular graft therapy, and to create vascular prostheses, such as heart valves.

EPO was also found to have anti-inflammatory and neuroprotective effects. Thus, in addition to diseases or conditions having an inflammatory or autoimmune component (such as acute cerebrovascular injury, acute brain injury, acute cardiovascular injury, arthritis, autoimmune disease, stroke, nerve injury, and immune-mediated inflammation), the polypeptides described herein may be used to treat neurological disorders and/or inflammatory brain diseases such as demyelinating diseases (e.g., multiple sclerosis, neuromyelitis optica, acute disseminated encephalomyelitis, transverse myelitis), epilepsy, spinal cord injury (e.g., acute spinal cord injury), complications following traumatic brain injury (e.g., symptoms for treating traumatic brain injury such as hypotension, hypoxia, brain swelling, headache, neck pain, memory difficulties, difficulty in concentrating, making decisions, fatigue, mood changes, nausea, photophobia, vision blur, tinnitus, taste loss, and olfaction loss, seizures, coma, muscle weakness, paralysis or progressive decline in nerve function), chronic inflammatory brain diseases (e.g., neurodegenerative diseases such as Alzheimer's Disease (AD), parkinson's Disease (PD), parkinson's disease, amyotrophic Lateral Sclerosis (ALS), or related surgery) such as macular degeneration (e.g., amyotrophic lateral sclerosis) or macular degeneration). The polypeptides can treat a neurological disorder or inflammatory brain disease by reducing infiltration of monocytes into the brain of a subject, improving neurological deficits and/or reducing axonal damage, and/or reducing neuronal and/or glial cell death in at least one region of the brain of a subject that is directly or indirectly affected by a disease, disorder or condition.

EPO can also be used to treat gastrointestinal motility disorders. Thus, polypeptides described herein can be used to treat a disease or disorder due to intestinal injury, abdominal trauma, inflammatory disorders of the intestine (e.g., inflammatory Bowel Disease (IBD), such as Crohn's disease and ulcerative colitis), intestinal infection (e.g., bacterial infection, such as infections resulting in sepsis and bacteremia, and localized infections such as peritonitis and ascites), chronic constipation (e.g., chronic constipation, idiopathic constipation, constipation due to post-operative ileus or constipation caused by opiate use), post-operative ileus, neurodegenerative damage, neurotraumatic damage, congenital problems (e.g., abdominal fissures, umbilical hernias, ganglionic megacolon, helson's disease, chronic intestinal pseudo-obstruction, left small colon syndrome, anorectal abnormalities, oesophageal dysplasia and closure, anal closure, congenital hernias, anal sphincter relaxations) or malnutrition-malabsorption problems (e.g., due to intestinal damage, abdominal trauma, intestinal inflammatory disorders, intestinal infections, constipation (e.g., constipation caused by opiate use), post-operative ileus, neurodegenerative damage, neurotraumatic damage, congenital problems, high-rest disease, refeeding syndrome, very low weight infants, cancer cachexia, infections, cancer, spinal cord dysfunction, spinal cord insufficiency, spinal cord tumor, peripheral nerve system removal, dyskinesia, celiac, dysfunctional peripheral nerve system, or joint pain, peripheral nerve system movement, peripheral nerve dysfunction, or joint disorder.

The polypeptides described herein can also be used to treat chronic or recurrent diseases, such as asthma, viral diseases or infections (e.g., HIV infection or HCV infection), hypertension, systemic microbial infections, cancer, endocrine system diseases, reproductive system diseases, psychosis, genetic diseases, allergic reactions, gastrointestinal diseases, arteriosclerosis, cardiovascular diseases, graft-versus-host diseases, or inflammatory diseases. Polypeptides containing ActRII variants (e.g., actRIIA variants, actRIIB variants, or ActRII chimeras) may also be used to enhance athletic performance, improve athletic ability, and facilitate or enhance aerobic conditioning. Such methods may be used, for example, by athletes to facilitate training and by soldiers to improve endurance and endurance. In some embodiments, the methods described herein are directed to affecting myostatin, activin a, activin B, and/or BMP9 signaling (e.g., reducing or inhibiting the binding of activin a, activin B, myostatin, and/or BMP9 to its endogenous receptor (e.g., actRIIA, actRIIB and/or BMPRII)) in a subject having a disease or disorder treatable with EPO or ESA. In some embodiments, the methods described herein increase EPO levels (e.g., serum EPO levels) and/or EPO receptor levels (e.g., bone marrow EPO receptor levels) compared to measurements obtained prior to treatment or compared to measurements obtained from untreated subjects or control treated subjects with the same disease or disorder.

In some embodiments, the methods described herein (e.g., methods of treating any of the diseases or conditions described herein) do not cause any vascular complications in the subject, such as increased vascular permeability or leakage.

In any of the methods described herein, a polypeptide that includes a C-terminal extension of an extracellular ActRII variant (e.g., an extracellular ActRIIA variant having the sequence of any of SEQ ID NOs: 1-71 (e.g., SEQ ID NOs: 6-71) or an extracellular ActRII chimera having the sequence of any of SEQ ID NOs: 174-216 (e.g., 195-216)) and further includes one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, or more amino acids) may be used as a therapeutic protein. In any of the methods described herein, a dimer (e.g., homodimer or heterodimer) formed by the interaction of two Fc domain monomers each fused to a polypeptide comprising an extracellular ActRII variant (e.g., an extracellular ActRIIA variant having the sequence of any of SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72), an extracellular ActRIIB variant having the sequence of any of SEQ ID NOs: 157-171 (e.g., SEQ ID NOs: 158-171), or an extracellular ActRII chimeric having the sequence of any of SEQ ID NOs: 174-216 (e.g., 195-216) may be used as a therapeutic protein. In any of the methods described herein, a polypeptide comprising an extracellular ActRII variant (e.g., an extracellular ActRIIA variant having the sequence of any of SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72), an extracellular ActRIIB variant having the sequence of any of SEQ ID NOs: 157-171 (e.g., SEQ ID NOs: 158-171), or an extracellular ActRII chimeric having the sequence of any of SEQ ID NOs: 174-216 (e.g., 195-216)) fused to a portion (e.g., an Fc domain monomer, an Fc domain (e.g., wild-type Fc domain), an Fc domain having amino acid substitutions (e.g., one or more substitutions that reduce dimerization), an albumin binding peptide, a fibronectin domain, or human serum albumin) may be used as a therapeutic protein. Nucleic acids encoding polypeptides described herein or vectors containing the same may also be administered according to any of the methods described herein. In any of the methods described herein, the polypeptide, nucleic acid, or vector may be administered as part of a pharmaceutical composition. Compositions that can be administered to a subject according to the methods described herein are provided in tables 10, 11, and 12 below.

Table 10

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TABLE 11

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Table 12

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Examples

The following examples are provided to further illustrate some embodiments of the invention, but are not intended to limit the scope of the invention; it will be appreciated from the examples thereof that other procedures, methods or techniques known to those skilled in the art may alternatively be used.

Example 1-Effect of ActRIIA/B-Fc on erythropoietin and erythropoietin receptor levels

Assessment of serum erythropoietin levels

Eleven week old male mice (received from Taconic Biosciences) were treated with a single dose of 10mg/kg ActRIIA/B-mFc (SEQ ID NO:69 linked to the mouse Fc domain) or with vehicle by Intraperitoneal (IP) injection. Mice were sacrificed on days 2, 4, 7, 14, 37 and 51 after treatment. Blood samples were collected into EDTA tubes from submandibular/cheek hemorrhage and stored at 4 ℃ until RBC counts were analyzed at IDEXX BioAnalytics. At necropsy, whole blood was drawn through cardiac hemorrhage and collected into a Microvette tube (Sarstedt). The tube was incubated for two hours at room temperature, followed by centrifugation at 6000RPM for 10 minutes. Serum was collected and stored at-80 ℃ until analysis.

Erythropoietin (EPO) levels were measured using a mouse erythropoietin immunoassay (Quantikine ELISA kit) according to the manufacturer's instructions. Colorimetric readings of ELISA plates were measured at 450nm using a SpectraMax M5 microplate reader and background was subtracted from the readings at 540 nm. Erythropoietin concentrations were transformed by forming 4-parameter logistic curves using GraphPad Prism software. As shown in fig. 4, EPO levels increased in response to ActRIIA/B-mFc treatment, even in the case of increased RBCs. P <0.05, p <0.01, p <0.0001 between ActRIIA/B-mFc treatment and vehicle at each time point using bi-directional analysis of variance followed by a stark post-test. Data are shown as mean ± SEM. Fig. 5 shows that EPO levels were elevated in ActRIIA/B-mFc treated mice by day 4 to day 37 as compared to vehicle treated mice. P.ltoreq.0.05 between ActRIIA/B-mFc treatment and vehicle treatment at each time point by t-test; * P is less than or equal to 0.01; p is less than or equal to 0.0001. Data are shown as mean ± SEM.

Assessment of erythropoietin receptor expression

Eleven week old male mice (received from Taconic Biosciences) were treated with a single dose of 10mg/kg ActRIIA/B-mFc or with vehicle by intraperitoneal injection. Mice were sacrificed on days 4, 7, and 14 after treatment. Bone marrow cells were isolated by rinsing the bone marrow of the femur. Red blood cells were removed via lysis using ammonium chloride solution (Stem Cell Technologies). One million cells were lysed with Trizol reagent and RNA was isolated using Direct-zol RNA MicroPrep (Zymo Research) kit. cDNA was synthesized using a reverse transcription kit (Qiagen) and EpoR expression was measured by qPCR using a ViiA 7 real-time PCR system (Applied Biosystems). The primers used were: epoR forward primer: TTCAGCGGATTCTGGAGTGCCT (SEQ ID NO: 376) and EpoR reverse primer: AGCAACAGCGAGATGAGGACCA (SEQ ID NO: 377). Beta-actin was used as housekeeping gene. The primers used were: beta-actin forward primer: CATCGTGGGCCGCCCTA (SEQ ID NO: 378) and beta-actin reverse primer: CACCCACATAGGAGTCCTTCTG (SEQ ID NO: 379). Relative gene expression was determined using the ΔΔct method and plotted in GraphPad Prism. Error bars represent SEM. Statistical analysis was performed using the Schedule's t-test. As shown in fig. 6, EPO receptor expression increased following ActRIIA/B-mFc treatment.

Example 2-treatment of end stage renal disease by administration of extracellular ActRII variants

In accordance with the methods disclosed herein, a physician of skill in the art can treat a subject, such as a human patient, suffering from end stage renal disease in order to increase EPO levels. To treat a subject, a physician of skill in the art may administer to the subject a composition comprising a polypeptide including an extracellular ActRII variant (e.g., a polypeptide comprising an extracellular ActRIIA variant having the sequence of any one of SEQ ID NOs 1-72 (e.g., SEQ ID NOs 6-72), a polypeptide comprising an extracellular ActRIIB variant having the sequence of any one of SEQ ID NOs 157-171 (e.g., SEQ ID NOs 158-171), or a polypeptide comprising an extracellular ActRII chimeric having the sequence of any one of SEQ ID NOs 174-216 (e.g., SEQ ID NOs 195-216), such as a polypeptide comprising an extracellular ActRIIA variant, an extracellular ActRIIB variant, or an extracellular ActRII chimeric linked to an Fc domain). End stage renal disease may be treated, for example, by administering a composition containing an extracellular ActRII variant to a subject by parenteral injection (e.g., intravenous or subcutaneous injection). Polypeptides containing extracellular ActRIIA variants (e.g., extracellular ActRIIA variants having the sequence of any of SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72), extracellular ActRIIB variants having the sequence of any of SEQ ID NOs: 157-171 (e.g., SEQ ID NOs: 158-171), or extracellular ActRII chimeras having the sequence of any of SEQ ID NOs: 174-216 (e.g., SEQ ID NOs: 195-216)) are administered in therapeutically effective amounts, such as 0.01 to 500mg/kg (e.g., 0.01, 0.1, 0.2, 0.3, 0.325, 0.35, 0.375, 0.4, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2.25, 2.5, 3, 3.25, 3.75, 4, 4.25, 4.5, 4.75, 5, 15, 20, 25, 30, 40, 30, 200, 400, 150, or 500 mg). In some embodiments, the extracellular ActRII variants are administered once every sixteen weeks, once a quarter, once every twelve weeks, once every two months, once every eight weeks, once a month, once every four weeks, once every two weeks, or at least once a week or more (e.g., 1, 2, 3, 4, 5, 6, or 7 times a week or more). The extracellular ActRII variants are administered in an amount sufficient to increase EPO levels, increase EPO receptor levels, and/or slow disease progression.

After administration of the composition to a patient, a practitioner in the art can monitor the patient's improvement in response to therapy by a variety of methods. For example, a physician may monitor a patient's EPO level using a blood test and may measure kidney function using a blood test, a urine test, and an imaging test. It was found that the patient's EPO levels increased or the disease progressed more slowly after administration of the composition compared to the test results prior to administration of the composition, indicating that the patient was advantageously responsive to treatment. Subsequent doses may be determined and administered as desired.

Other embodiments

While the application has been described in connection with specific embodiments, it will be understood that the application is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the application following, in general, the principles of the application and including such departures from the present disclosure as come within known or customary practice within the art to which the application pertains and as may be applied to the essential features hereinbefore set forth.

All publications, patents, and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

Other embodiments are within the following claims.

<110> kolesi therapy company (Keros Therapeutics, inc.)

<120> methods of using activin receptor type II variants

<130> 51184-026WO4

<150> US 63/163,655

<151> 2021-03-19

<150> US 63/156,870

<151> 2021-03-04

<150> US 63/111,476

<151> 2020-11-09

<150> US 63/111,460

<151> 2020-11-09

<150> US 63/111,337

<151> 2020-11-09

<150> US 63/086,894

<151> 2020-10-02

<150> US 63/086,860

<151> 2020-10-02

<150> US 63/086,858

<151> 2020-10-02

<160> 379

<170> PatentIn version 3.5

<210> 1

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

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<223> synthetic construct

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<221> MISC_FEATURE

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<221> MISC_FEATURE

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<223> Xaa is Phe or Tyr

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<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa is Glu or Ala

<220>

<221> MISC_FEATURE

<222> (21)..(21)

<223> Xaa is Lys or Leu

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<221> MISC_FEATURE

<222> (22)..(22)

<223> Xaa is Asp or Glu

<220>

<221> MISC_FEATURE

<222> (23)..(23)

<223> Xaa is Arg or Ala

<220>

<221> MISC_FEATURE

<222> (31)..(31)

<223> Xaa is Pro or Arg

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<221> MISC_FEATURE

<222> (33)..(33)

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<221> MISC_FEATURE

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<221> MISC_FEATURE

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<221> MISC_FEATURE

<222> (37)..(37)

<223> Xaa is Asp or Ala

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<221> MISC_FEATURE

<222> (38)..(38)

<223> Xaa is Lys or Ala

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<221> MISC_FEATURE

<222> (39)..(39)

<223> Xaa is Arg or Ala

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<221> MISC_FEATURE

<222> (40)..(40)

<223> Xaa is Arg or Leu

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<221> MISC_FEATURE

<222> (43)..(43)

<223> Xaa is Phe or Tyr

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<221> MISC_FEATURE

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<221> MISC_FEATURE

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<221> MISC_FEATURE

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<221> MISC_FEATURE

<222> (61)..(61)

<223> Xaa is Trp or Ala

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<221> MISC_FEATURE

<222> (62)..(62)

<223> Xaa is Leu or Ala

<220>

<221> MISC_FEATURE

<222> (63)..(63)

<223> Xaa is Asp, lys, arg, ala, phe, gly, met, asn or Ile

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<221> MISC_FEATURE

<222> (65)..(65)

<223> Xaa is Ile, phe or Ala

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<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Lys or Thr

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<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Lys or Glu

<220>

<221> MISC_FEATURE

<222> (78)..(78)

<223> Xaa is Asp or Glu

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Ser or Asn

<220>

<221> MISC_FEATURE

<222> (81)..(81)

<223> Xaa is Glu or Gln

<400> 1

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Xaa Xaa Asn

1 5 10 15

Ala Asn Trp Xaa Xaa Xaa Xaa Thr Asn Gln Thr Gly Val Glu Xaa Cys

20 25 30

Xaa Gly Xaa Xaa Xaa Xaa Xaa Xaa His Cys Xaa Ala Thr Trp Xaa Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Xaa Xaa Gly Cys Xaa Xaa Xaa Asp

50 55 60

Xaa Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Xaa Xaa Xaa Xaa Pro

65 70 75 80

Xaa Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 2

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<221> MISC_FEATURE

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<221> MISC_FEATURE

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<221> MISC_FEATURE

<222> (23)..(23)

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<220>

<221> MISC_FEATURE

<222> (31)..(31)

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<221> MISC_FEATURE

<222> (33)..(33)

<223> Xaa is Tyr or Glu

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<221> MISC_FEATURE

<222> (35)..(35)

<223> Xaa is Asp or Glu

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<221> MISC_FEATURE

<222> (37)..(37)

<223> Xaa is Asp or Ala

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<221> MISC_FEATURE

<222> (38)..(38)

<223> Xaa is Lys or Ala

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<221> MISC_FEATURE

<222> (39)..(39)

<223> Xaa is Arg or Ala

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<221> MISC_FEATURE

<222> (40)..(40)

<223> Xaa is Arg or Leu

<220>

<221> MISC_FEATURE

<222> (43)..(43)

<223> Xaa is Phe or Tyr

<220>

<221> MISC_FEATURE

<222> (47)..(47)

<223> Xaa is Lys, arg or Ala

<220>

<221> MISC_FEATURE

<222> (57)..(57)

<223> Xaa is Lys, ala, tyr, phe or Ile

<220>

<221> MISC_FEATURE

<222> (58)..(58)

<223> Xaa is Gln or Lys

<220>

<221> MISC_FEATURE

<222> (61)..(61)

<223> Xaa is Trp or Ala

<220>

<221> MISC_FEATURE

<222> (62)..(62)

<223> Xaa is Leu or Ala

<220>

<221> MISC_FEATURE

<222> (63)..(63)

<223> Xaa is Asp, lys, arg, ala, phe, gly, met, asn or Ile

<220>

<221> MISC_FEATURE

<222> (65)..(65)

<223> Xaa is Ile, phe or Ala

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Lys or Thr

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Lys or Glu

<220>

<221> MISC_FEATURE

<222> (78)..(78)

<223> Xaa is Asp or Glu

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Ser or Asn

<220>

<221> MISC_FEATURE

<222> (81)..(81)

<223> Xaa is Glu or Gln

<400> 2

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Xaa Asn

1 5 10 15

Ala Asn Trp Xaa Xaa Xaa Xaa Thr Asn Gln Thr Gly Val Glu Xaa Cys

20 25 30

Xaa Gly Xaa Lys Xaa Xaa Xaa Xaa His Cys Xaa Ala Thr Trp Xaa Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Xaa Xaa Gly Cys Xaa Xaa Xaa Asp

50 55 60

Xaa Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Xaa Xaa Xaa Xaa Pro

65 70 75 80

Xaa Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 3

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

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<223> synthetic construct

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<221> MISC_FEATURE

<222> (15)..(15)

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<220>

<221> MISC_FEATURE

<222> (21)..(21)

<223> Xaa is Lys or Leu

<220>

<221> MISC_FEATURE

<222> (22)..(22)

<223> Xaa is Asp or Glu

<220>

<221> MISC_FEATURE

<222> (31)..(31)

<223> Xaa is Pro or Arg

<220>

<221> MISC_FEATURE

<222> (33)..(33)

<223> Xaa is Tyr or Glu

<220>

<221> MISC_FEATURE

<222> (35)..(35)

<223> Xaa is Asp or Glu

<220>

<221> MISC_FEATURE

<222> (40)..(40)

<223> Xaa is Arg or Leu

<220>

<221> MISC_FEATURE

<222> (43)..(43)

<223> Xaa is Phe or Tyr

<220>

<221> MISC_FEATURE

<222> (47)..(47)

<223> Xaa is Lys, arg or Ala

<220>

<221> MISC_FEATURE

<222> (58)..(58)

<223> Xaa is Gln or Lys

<220>

<221> MISC_FEATURE

<222> (65)..(65)

<223> Xaa is Ile, phe or Ala

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Lys or Thr

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Lys or Glu

<220>

<221> MISC_FEATURE

<222> (78)..(78)

<223> Xaa is Asp or Glu

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Ser or Asn

<220>

<221> MISC_FEATURE

<222> (81)..(81)

<223> Xaa is Glu or Gln

<400> 3

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Xaa Asn

1 5 10 15

Ala Asn Trp Glu Xaa Xaa Arg Thr Asn Gln Thr Gly Val Glu Xaa Cys

20 25 30

Xaa Gly Xaa Lys Asp Lys Arg Xaa His Cys Xaa Ala Thr Trp Xaa Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Xaa Gly Cys Trp Leu Asp Asp

50 55 60

Xaa Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Xaa Xaa Xaa Xaa Pro

65 70 75 80

Xaa Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

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<223> synthetic construct

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<221> MISC_FEATURE

<222> (15)..(15)

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<220>

<221> MISC_FEATURE

<222> (21)..(21)

<223> Xaa is Lys or Leu

<220>

<221> MISC_FEATURE

<222> (31)..(31)

<223> Xaa is Pro or Arg

<220>

<221> MISC_FEATURE

<222> (33)..(33)

<223> Xaa is Tyr or Glu

<220>

<221> MISC_FEATURE

<222> (35)..(35)

<223> Xaa is Asp or Glu

<220>

<221> MISC_FEATURE

<222> (40)..(40)

<223> Xaa is Arg or Leu

<220>

<221> MISC_FEATURE

<222> (43)..(43)

<223> Xaa is Phe or Tyr

<220>

<221> MISC_FEATURE

<222> (47)..(47)

<223> Xaa is Lys, arg or Ala

<220>

<221> MISC_FEATURE

<222> (58)..(58)

<223> Xaa is Gln or Lys

<220>

<221> MISC_FEATURE

<222> (65)..(65)

<223> Xaa is Ile, phe or Ala

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Lys or Thr

<220>

<221> MISC_FEATURE

<222> (78)..(78)

<223> Xaa is Asp or Glu

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Ser or Asn

<220>

<221> MISC_FEATURE

<222> (81)..(81)

<223> Xaa is Glu or Gln

<400> 4

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Xaa Asn

1 5 10 15

Ala Asn Trp Glu Xaa Asp Arg Thr Asn Gln Thr Gly Val Glu Xaa Cys

20 25 30

Xaa Gly Xaa Lys Asp Lys Arg Xaa His Cys Xaa Ala Thr Trp Xaa Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Xaa Gly Cys Trp Leu Asp Asp

50 55 60

Xaa Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Xaa Lys Xaa Xaa Pro

65 70 75 80

Xaa Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 5

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<212> PRT

<213> Artificial sequence (Artificial Sequence)

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<221> MISC_FEATURE

<222> (15)..(15)

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<220>

<221> MISC_FEATURE

<222> (21)..(21)

<223> Xaa is Lys or Leu

<220>

<221> MISC_FEATURE

<222> (33)..(33)

<223> Xaa is Tyr or Glu

<220>

<221> MISC_FEATURE

<222> (35)..(35)

<223> Xaa is Asp or Glu

<220>

<221> MISC_FEATURE

<222> (40)..(40)

<223> Xaa is Arg or Leu

<220>

<221> MISC_FEATURE

<222> (58)..(58)

<223> Xaa is Gln or Lys

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Lys or Thr

<220>

<221> MISC_FEATURE

<222> (78)..(78)

<223> Xaa is Asp or Glu

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Ser or Asn

<220>

<221> MISC_FEATURE

<222> (81)..(81)

<223> Xaa is Glu or Gln

<400> 5

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Xaa Asn

1 5 10 15

Ala Asn Trp Glu Xaa Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Xaa Gly Xaa Lys Asp Lys Arg Xaa His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Xaa Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Xaa Lys Xaa Xaa Pro

65 70 75 80

Xaa Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 6

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<400> 6

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 7

<211> 109

<212> PRT

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<220>

<223> synthetic construct

<400> 7

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 8

<211> 109

<212> PRT

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<220>

<223> synthetic construct

<400> 8

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 9

<211> 109

<212> PRT

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<400> 9

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 10

<211> 109

<212> PRT

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<400> 10

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 11

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 11

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 12

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 12

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 13

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 13

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 14

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 14

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 15

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 15

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 16

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 16

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 17

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 17

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 18

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 18

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 19

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 19

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 20

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 20

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 21

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 21

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 22

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 22

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 23

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 23

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 24

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 24

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 25

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 25

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 26

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 26

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 27

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 27

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 28

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 28

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 29

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 29

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 30

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 30

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 31

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 31

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 32

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 32

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 33

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 33

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 34

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 34

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 35

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 35

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 36

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 36

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 37

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 37

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 38

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 38

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 39

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 39

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 40

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 40

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 41

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 41

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 42

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 42

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 43

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 43

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 44

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 44

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 45

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 45

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 46

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 46

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 47

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 47

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 48

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 48

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 49

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 49

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 50

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 50

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 51

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 51

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 52

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 52

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 53

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 53

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 54

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 54

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 55

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 55

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 56

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 56

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 57

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 57

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 58

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 58

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 59

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 59

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 60

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 60

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 61

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 61

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 62

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 62

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 63

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 63

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 64

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 64

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 65

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 65

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 66

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 66

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Phe Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 67

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 67

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Asp Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 68

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 68

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 69

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 69

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 70

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 70

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Tyr Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

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

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 71

<211> 111

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 71

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Asn Pro

100 105 110

<210> 72

<211> 115

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 72

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Asn Pro Val

100 105 110

Thr Pro Lys

115

<210> 73

<211> 109

<212> PRT

<213> Homo sapiens (Homo sapiens)

<400> 73

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn

1 5 10 15

Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 74

<211> 115

<212> PRT

<213> Homo sapiens (Homo sapiens)

<400> 74

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His

85 90 95

Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr

100 105 110

Ala Pro Thr

115

<210> 75

<211> 513

<212> PRT

<213> Homo sapiens (Homo sapiens)

<400> 75

Met Gly Ala Ala Ala Lys Leu Ala Phe Ala Val Phe Leu Ile Ser Cys

1 5 10 15

Ser Ser Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe

20 25 30

Phe Asn Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu

35 40 45

Pro Cys Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp

50 55 60

Lys Asn Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu

65 70 75 80

Asp Asp Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp

85 90 95

Ser Pro Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu

100 105 110

Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Asn

115 120 125

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

130 135 140

Val Pro Leu Met Leu Ile Ala Gly Ile Val Ile Cys Ala Phe Trp Val

145 150 155 160

Tyr Arg His His Lys Met Ala Tyr Pro Pro Val Leu Val Pro Thr Gln

165 170 175

Asp Pro Gly Pro Pro Pro Pro Ser Pro Leu Leu Gly Leu Lys Pro Leu

180 185 190

Gln Leu Leu Glu Val Lys Ala Arg Gly Arg Phe Gly Cys Val Trp Lys

195 200 205

Ala Gln Leu Leu Asn Glu Tyr Val Ala Val Lys Ile Phe Pro Ile Gln

210 215 220

Asp Lys Gln Ser Trp Gln Asn Glu Tyr Glu Val Tyr Ser Leu Pro Gly

225 230 235 240

Met Lys His Glu Asn Ile Leu Gln Phe Ile Gly Ala Glu Lys Arg Gly

245 250 255

Thr Ser Val Asp Val Asp Leu Trp Leu Ile Thr Ala Phe His Glu Lys

260 265 270

Gly Ser Leu Ser Asp Phe Leu Lys Ala Asn Val Val Ser Trp Asn Glu

275 280 285

Leu Cys His Ile Ala Glu Thr Met Ala Arg Gly Leu Ala Tyr Leu His

290 295 300

Glu Asp Ile Pro Gly Leu Lys Asp Gly His Lys Pro Ala Ile Ser His

305 310 315 320

Arg Asp Ile Lys Ser Lys Asn Val Leu Leu Lys Asn Asn Leu Thr Ala

325 330 335

Cys Ile Ala Asp Phe Gly Leu Ala Leu Lys Phe Glu Ala Gly Lys Ser

340 345 350

Ala Gly Asp Thr His Gly Gln Val Gly Thr Arg Arg Tyr Met Ala Pro

355 360 365

Glu Val Leu Glu Gly Ala Ile Asn Phe Gln Arg Asp Ala Phe Leu Arg

370 375 380

Ile Asp Met Tyr Ala Met Gly Leu Val Leu Trp Glu Leu Ala Ser Arg

385 390 395 400

Cys Thr Ala Ala Asp Gly Pro Val Asp Glu Tyr Met Leu Pro Phe Glu

405 410 415

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

420 425 430

Val His Lys Lys Lys Arg Pro Val Leu Arg Asp Tyr Trp Gln Lys His

435 440 445

Ala Gly Met Ala Met Leu Cys Glu Thr Ile Glu Glu Cys Trp Asp His

450 455 460

Asp Ala Glu Ala Arg Leu Ser Ala Gly Cys Val Gly Glu Arg Ile Thr

465 470 475 480

Gln Met Gln Arg Leu Thr Asn Ile Ile Thr Thr Glu Asp Ile Val Thr

485 490 495

Val Val Thr Met Val Thr Asn Val Asp Phe Pro Pro Lys Glu Ser Ser

500 505 510

Leu

<210> 76

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 76

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn

1 5 10 15

Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Ala Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 77

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 77

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn

1 5 10 15

Ala Asn Trp Ala Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 78

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 78

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn

1 5 10 15

Ala Asn Trp Glu Lys Asp Ala Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 79

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 79

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn

1 5 10 15

Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Tyr Gly Asp Lys Ala Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 80

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 80

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn

1 5 10 15

Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Tyr Gly Asp Lys Asp Ala Arg Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 81

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 81

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn

1 5 10 15

Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Tyr Gly Asp Lys Asp Lys Ala Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 82

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 82

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn

1 5 10 15

Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Ala Gln Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 83

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 83

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn

1 5 10 15

Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Tyr Gln Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 84

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 84

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn

1 5 10 15

Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Phe Gln Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 85

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 85

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn

1 5 10 15

Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Ile Gln Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 86

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 86

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn

1 5 10 15

Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Ala Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 87

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 87

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn

1 5 10 15

Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Ala Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 88

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 88

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn

1 5 10 15

Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Lys Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 89

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 89

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn

1 5 10 15

Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Arg Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 90

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 90

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn

1 5 10 15

Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Ala Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 91

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 91

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn

1 5 10 15

Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Phe Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 92

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 92

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn

1 5 10 15

Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Gly Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 93

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 93

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn

1 5 10 15

Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Met Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 94

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 94

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn

1 5 10 15

Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asn Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 95

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 95

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn

1 5 10 15

Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Ile Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 96

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 96

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn

1 5 10 15

Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys

20 25 30

Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Ala Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 97

<211> 225

<212> PRT

<213> Homo sapiens (Homo sapiens)

<400> 97

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

Lys

225

<210> 98

<211> 4

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 98

Gly Gly Gly Ala

1

<210> 99

<211> 4

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 99

Gly Gly Gly Ser

1

<210> 100

<211> 4

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 100

Gly Gly Gly Gly

1

<210> 101

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 101

Gly Gly Gly Gly Ala

1 5

<210> 102

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 102

Gly Gly Gly Gly Ser

1 5

<210> 103

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 103

Gly Gly Gly Gly Gly

1 5

<210> 104

<211> 4

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 104

Gly Gly Ala Gly

1

<210> 105

<211> 4

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 105

Gly Gly Ser Gly

1

<210> 106

<211> 4

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 106

Ala Gly Gly Gly

1

<210> 107

<211> 4

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 107

Ser Gly Gly Gly

1

<210> 108

<211> 4

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 108

Gly Ala Gly Ala

1

<210> 109

<211> 4

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 109

Gly Ser Gly Ser

1

<210> 110

<211> 6

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 110

Gly Ala Gly Ala Gly Ala

1 5

<210> 111

<211> 6

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 111

Gly Ser Gly Ser Gly Ser

1 5

<210> 112

<211> 8

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 112

Gly Ala Gly Ala Gly Ala Gly Ala

1 5

<210> 113

<211> 8

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 113

Gly Ser Gly Ser Gly Ser Gly Ser

1 5

<210> 114

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 114

Gly Ala Gly Ala Gly Ala Gly Ala Gly Ala

1 5 10

<210> 115

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 115

Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser

1 5 10

<210> 116

<211> 12

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 116

Gly Ala Gly Ala Gly Ala Gly Ala Gly Ala Gly Ala

1 5 10

<210> 117

<211> 12

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 117

Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser

1 5 10

<210> 118

<211> 6

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 118

Gly Gly Ala Gly Gly Ala

1 5

<210> 119

<211> 6

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 119

Gly Gly Ser Gly Gly Ser

1 5

<210> 120

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 120

Gly Gly Ala Gly Gly Ala Gly Gly Ala

1 5

<210> 121

<211> 9

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 121

Gly Gly Ser Gly Gly Ser Gly Gly Ser

1 5

<210> 122

<211> 12

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 122

Gly Gly Ala Gly Gly Ala Gly Gly Ala Gly Gly Ala

1 5 10

<210> 123

<211> 12

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 123

Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser

1 5 10

<210> 124

<211> 8

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 124

Gly Gly Ala Gly Gly Gly Ala Gly

1 5

<210> 125

<211> 8

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 125

Gly Gly Ser Gly Gly Gly Ser Gly

1 5

<210> 126

<211> 12

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 126

Gly Gly Ala Gly Gly Gly Ala Gly Gly Gly Ala Gly

1 5 10

<210> 127

<211> 12

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 127

Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly

1 5 10

<210> 128

<211> 15

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 128

Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala

1 5 10 15

<210> 129

<211> 15

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 129

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

1 5 10 15

<210> 130

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 130

Gly Gly Gly Ala Gly

1 5

<210> 131

<211> 6

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 131

Gly Gly Gly Ala Gly Gly

1 5

<210> 132

<211> 7

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 132

Gly Gly Gly Ala Gly Gly Gly

1 5

<210> 133

<211> 4

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 133

Ala Ala Ala Leu

1

<210> 134

<211> 4

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 134

Ala Ala Ala Lys

1

<210> 135

<211> 4

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 135

Ala Ala Ala Arg

1

<210> 136

<211> 14

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 136

Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr

1 5 10

<210> 137

<211> 12

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 137

Gly Ser Ala Gly Ser Ala Ala Gly Ser Gly Glu Phe

1 5 10

<210> 138

<211> 12

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 138

Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala

1 5 10

<210> 139

<211> 18

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 139

Lys Glu Ser Gly Ser Val Ser Ser Glu Gln Leu Ala Gln Phe Arg Ser

1 5 10 15

Leu Asp

<210> 140

<211> 10

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 140

Gly Glu Asn Leu Tyr Phe Gln Ser Gly Gly

1 5 10

<210> 141

<211> 8

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 141

Ser Ala Cys Tyr Cys Glu Leu Ser

1 5

<210> 142

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 142

Arg Ser Ile Ala Thr

1 5

<210> 143

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 143

Arg Pro Ala Cys Lys Ile Pro Asn Asp Leu Lys Gln Lys Val Met Asn

1 5 10 15

His

<210> 144

<211> 36

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 144

Gly Gly Ser Ala Gly Gly Ser Gly Ser Gly Ser Ser Gly Gly Ser Ser

1 5 10 15

Gly Ala Ser Gly Thr Gly Thr Ala Gly Gly Thr Gly Ser Gly Ser Gly

20 25 30

Thr Gly Ser Gly

35

<210> 145

<211> 17

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 145

Ala Ala Ala Asn Ser Ser Ile Asp Leu Ile Ser Val Pro Val Asp Ser

1 5 10 15

Arg

<210> 146

<211> 36

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 146

Gly Gly Ser Gly Gly Gly Ser Glu Gly Gly Gly Ser Glu Gly Gly Gly

1 5 10 15

Ser Glu Gly Gly Gly Ser Glu Gly Gly Gly Ser Glu Gly Gly Gly Ser

20 25 30

Gly Gly Gly Ser

35

<210> 147

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 147

Glu Ala Ala Ala Lys

1 5

<210> 148

<211> 5

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 148

Pro Ala Pro Ala Pro

1 5

<210> 149

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 149

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Ala Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 150

<211> 227

<212> PRT

<213> Homo sapiens (Homo sapiens)

<400> 150

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

Pro Gly Lys

225

<210> 151

<211> 11

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 151

Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp

1 5 10

<210> 152

<211> 93

<212> PRT

<213> Homo sapiens (Homo sapiens)

<400> 152

Gly Pro Val Glu Val Phe Ile Thr Glu Thr Pro Ser Gln Pro Asn Ser

1 5 10 15

His Pro Ile Gln Trp Asn Ala Pro Gln Pro Ser His Ile Ser Lys Tyr

20 25 30

Ile Leu Arg Trp Arg Pro Lys Asn Ser Val Gly Arg Trp Lys Glu Ala

35 40 45

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

50 55 60

Gly Val Val Tyr Glu Gly Gln Leu Ile Ser Ile Gln Gln Tyr Gly His

65 70 75 80

Gln Glu Val Thr Arg Phe Asp Phe Thr Thr Thr Ser Thr

85 90

<210> 153

<211> 609

<212> PRT

<213> Homo sapiens (Homo sapiens)

<400> 153

Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala

1 5 10 15

Tyr Ser Arg Gly Val Phe Arg Arg Asp Ala His Lys Ser Glu Val Ala

20 25 30

His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu

35 40 45

Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val

50 55 60

Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp

65 70 75 80

Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp

85 90 95

Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala

100 105 110

Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln

115 120 125

His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val

130 135 140

Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys

145 150 155 160

Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro

165 170 175

Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys

180 185 190

Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu

195 200 205

Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys

210 215 220

Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val

225 230 235 240

Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser

245 250 255

Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly

260 265 270

Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile

275 280 285

Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu

290 295 300

Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp

305 310 315 320

Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser

325 330 335

Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly

340 345 350

Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val

355 360 365

Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys

370 375 380

Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu

385 390 395 400

Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys

405 410 415

Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu

420 425 430

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

435 440 445

Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His

450 455 460

Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val

465 470 475 480

Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg

485 490 495

Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe

500 505 510

Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala

515 520 525

Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu

530 535 540

Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys

545 550 555 560

Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala

565 570 575

Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe

580 585 590

Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly

595 600 605

Leu

<210> 154

<211> 6

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 154

Asn Pro Val Thr Pro Lys

1 5

<210> 155

<211> 226

<212> PRT

<213> Homo sapiens (Homo sapiens)

<400> 155

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

Pro Gly

225

<210> 156

<211> 338

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 156

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Val Glu Arg Cys

20 25 30

Glu Gly Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Thr Trp Arg Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

Pro Gly

<210> 157

<211> 115

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa is Ile or Leu

<220>

<221> MISC_FEATURE

<222> (12)..(12)

<223> Xaa is Phe or Tyr

<220>

<221> MISC_FEATURE

<222> (19)..(19)

<223> Xaa is Leu or Lys

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa is Asp or Glu

<220>

<221> MISC_FEATURE

<222> (25)..(25)

<223> Xaa is Thr or Ser

<220>

<221> MISC_FEATURE

<222> (27)..(27)

<223> Xaa is Leu or Val

<220>

<221> MISC_FEATURE

<222> (29)..(29)

<223> Xaa is Pro or Arg

<220>

<221> MISC_FEATURE

<222> (31)..(31)

<223> Xaa is Tyr or Glu

<220>

<221> MISC_FEATURE

<222> (33)..(33)

<223> Xaa is Asp or Glu

<220>

<221> MISC_FEATURE

<222> (34)..(34)

<223> Xaa is Lys or Gln

<220>

<221> MISC_FEATURE

<222> (38)..(38)

<223> Xaa is Arg or Leu

<220>

<221> MISC_FEATURE

<222> (41)..(41)

<223> Xaa is Tyr or Phe

<220>

<221> MISC_FEATURE

<222> (45)..(45)

<223> Xaa is Arg or Lys

<220>

<221> MISC_FEATURE

<222> (47)..(47)

<223> Xaa is Ser or Ile

<220>

<221> MISC_FEATURE

<222> (48)..(48)

<223> Xaa is Ser or Thr

<220>

<221> MISC_FEATURE

<222> (50)..(50)

<223> Xaa is Ser or Thr

<220>

<221> MISC_FEATURE

<222> (51)..(51)

<223> Xaa is Ile or Leu

<220>

<221> MISC_FEATURE

<222> (53)..(53)

<223> Xaa is Ile or Leu

<220>

<221> MISC_FEATURE

<222> (56)..(56)

<223> Xaa is Lys or Gln

<220>

<221> MISC_FEATURE

<222> (63)..(63)

<223> Xaa is Phe or Ile

<220>

<221> MISC_FEATURE

<222> (69)..(69)

<223> Xaa is Gln, thr or Asp

<220>

<221> MISC_FEATURE

<222> (70)..(70)

<223> Xaa is Glu, asp or Thr

<220>

<221> MISC_FEATURE

<222> (74)..(74)

<223> Xaa is Lys or Thr

<220>

<221> MISC_FEATURE

<222> (75)..(75)

<223> Xaa is Lys or Glu

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Asp or Glu

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Ser or Asn

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Glu or Gln

<220>

<221> MISC_FEATURE

<222> (89)..(89)

<223> Xaa is Phe or Met

<400> 157

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Xaa Xaa Tyr Asn Ala Asn

1 5 10 15

Trp Glu Xaa Xaa Arg Thr Asn Gln Xaa Gly Xaa Glu Xaa Cys Xaa Gly

20 25 30

Xaa Xaa Asp Lys Arg Xaa His Cys Xaa Ala Ser Trp Xaa Asn Xaa Xaa

35 40 45

Gly Xaa Xaa Glu Xaa Val Lys Xaa Gly Cys Trp Leu Asp Asp Xaa Asn

50 55 60

Cys Tyr Asp Arg Xaa Xaa Cys Val Ala Xaa Xaa Xaa Xaa Pro Xaa Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Xaa Cys Asn Glu Arg Phe Thr His

85 90 95

Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr

100 105 110

Ala Pro Thr

115

<210> 158

<211> 115

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 158

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Phe Tyr Asn Ala Asn

1 5 10 15

Trp Glu Lys Asp Arg Thr Asn Gln Ser Gly Leu Glu Pro Cys Tyr Gly

20 25 30

Asp Gln Asp Lys Arg Arg His Cys Phe Ala Ser Trp Lys Asn Ser Ser

35 40 45

Gly Thr Ile Glu Leu Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn

50 55 60

Cys Tyr Asp Arg Gln Glu Cys Val Ala Lys Lys Asp Ser Pro Glu Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His

85 90 95

Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr

100 105 110

Ala Pro Thr

115

<210> 159

<211> 115

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 159

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Asp Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Ile Asn

50 55 60

Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Lys Glu Asn Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His

85 90 95

Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr

100 105 110

Ala Pro Thr

115

<210> 160

<211> 115

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 160

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Gln Glu Cys Val Ala Lys Lys Asp Ser Pro Glu Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His

85 90 95

Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr

100 105 110

Ala Pro Thr

115

<210> 161

<211> 115

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 161

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ile Ser

35 40 45

Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Gln Glu Cys Val Ala Lys Lys Asp Ser Pro Glu Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His

85 90 95

Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr

100 105 110

Ala Pro Thr

115

<210> 162

<211> 115

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 162

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Thr Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ile Thr

35 40 45

Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Gln Glu Cys Val Ala Lys Lys Asp Ser Pro Glu Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His

85 90 95

Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr

100 105 110

Ala Pro Thr

115

<210> 163

<211> 115

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 163

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Pro Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Gln Glu Cys Val Ala Lys Lys Asp Ser Pro Glu Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His

85 90 95

Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr

100 105 110

Ala Pro Thr

115

<210> 164

<211> 115

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 164

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Tyr Gly

20 25 30

Asp Lys Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Gln Glu Cys Val Ala Lys Lys Asp Ser Pro Glu Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His

85 90 95

Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr

100 105 110

Ala Pro Thr

115

<210> 165

<211> 115

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 165

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Phe Ala Ser Trp Lys Asn Ser Ser

35 40 45

Gly Thr Ile Glu Leu Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Gln Glu Cys Val Ala Lys Lys Asp Ser Pro Glu Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His

85 90 95

Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr

100 105 110

Ala Pro Thr

115

<210> 166

<211> 115

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 166

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Phe Tyr Asn Ala Asn

1 5 10 15

Trp Glu Lys Asp Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Gln Glu Cys Val Ala Lys Lys Asp Ser Pro Glu Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His

85 90 95

Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr

100 105 110

Ala Pro Thr

115

<210> 167

<211> 115

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 167

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Tyr Gly

20 25 30

Asp Gln Asp Lys Arg Arg His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Gln Glu Cys Val Ala Lys Lys Asp Ser Pro Glu Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His

85 90 95

Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr

100 105 110

Ala Pro Thr

115

<210> 168

<211> 115

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 168

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Leu Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Val Glu Arg Cys Glu Gly

20 25 30

Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Ser Leu Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Ala Thr Glu Glu Asn Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Arg Phe Thr His

85 90 95

Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr

100 105 110

Ala Pro Thr

115

<210> 169

<211> 115

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 169

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Leu Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Val Glu Arg Cys Glu Gly

20 25 30

Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Ser Leu Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Asp Thr Cys Val Ala Thr Glu Glu Asn Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Arg Phe Thr His

85 90 95

Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr

100 105 110

Ala Pro Thr

115

<210> 170

<211> 115

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 170

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Leu Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Val Glu Arg Cys Glu Gly

20 25 30

Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Ser Leu Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Ala Thr Lys Glu Asn Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Arg Phe Thr His

85 90 95

Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr

100 105 110

Ala Pro Thr

115

<210> 171

<211> 115

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 171

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Leu Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Val Glu Arg Cys Glu Gly

20 25 30

Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Ser Leu Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Asp Thr Cys Val Ala Thr Lys Glu Asn Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Arg Phe Thr His

85 90 95

Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr

100 105 110

Ala Pro Thr

115

<210> 172

<211> 345

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 172

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Leu Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Val Glu Arg Cys Glu Gly

20 25 30

Glu Lys Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Ser Leu Glu Ile Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Asp Thr Cys Val Ala Thr Lys Glu Asn Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Arg Phe Thr His

85 90 95

Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr

100 105 110

Ala Pro Thr Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu

180 185 190

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His

195 200 205

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys

210 215 220

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

225 230 235 240

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

245 250 255

Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro

260 265 270

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

275 280 285

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

290 295 300

Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val

305 310 315 320

Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln

325 330 335

Lys Ser Leu Ser Leu Ser Pro Gly Lys

340 345

<210> 173

<211> 512

<212> PRT

<213> Homo sapiens (Homo sapiens)

<400> 173

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

1 5 10 15

Ala Gly Ser Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr

20 25 30

Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg

35 40 45

Cys Glu Gly Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg

50 55 60

Asn Ser Ser Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp

65 70 75 80

Asp Phe Asn Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn

85 90 95

Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg

100 105 110

Phe Thr His Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro

115 120 125

Pro Pro Thr Ala Pro Thr Leu Leu Thr Val Leu Ala Tyr Ser Leu Leu

130 135 140

Pro Ile Gly Gly Leu Ser Leu Ile Val Leu Leu Ala Phe Trp Met Tyr

145 150 155 160

Arg His Arg Lys Pro Pro Tyr Gly His Val Asp Ile His Glu Asp Pro

165 170 175

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

180 185 190

Leu Glu Ile Lys Ala Arg Gly Arg Phe Gly Cys Val Trp Lys Ala Gln

195 200 205

Leu Met Asn Asp Phe Val Ala Val Lys Ile Phe Pro Leu Gln Asp Lys

210 215 220

Gln Ser Trp Gln Ser Glu Arg Glu Ile Phe Ser Thr Pro Gly Met Lys

225 230 235 240

His Glu Asn Leu Leu Gln Phe Ile Ala Ala Glu Lys Arg Gly Ser Asn

245 250 255

Leu Glu Val Glu Leu Trp Leu Ile Thr Ala Phe His Asp Lys Gly Ser

260 265 270

Leu Thr Asp Tyr Leu Lys Gly Asn Ile Ile Thr Trp Asn Glu Leu Cys

275 280 285

His Val Ala Glu Thr Met Ser Arg Gly Leu Ser Tyr Leu His Glu Asp

290 295 300

Val Pro Trp Cys Arg Gly Glu Gly His Lys Pro Ser Ile Ala His Arg

305 310 315 320

Asp Phe Lys Ser Lys Asn Val Leu Leu Lys Ser Asp Leu Thr Ala Val

325 330 335

Leu Ala Asp Phe Gly Leu Ala Val Arg Phe Glu Pro Gly Lys Pro Pro

340 345 350

Gly Asp Thr His Gly Gln Val Gly Thr Arg Arg Tyr Met Ala Pro Glu

355 360 365

Val Leu Glu Gly Ala Ile Asn Phe Gln Arg Asp Ala Phe Leu Arg Ile

370 375 380

Asp Met Tyr Ala Met Gly Leu Val Leu Trp Glu Leu Val Ser Arg Cys

385 390 395 400

Lys Ala Ala Asp Gly Pro Val Asp Glu Tyr Met Leu Pro Phe Glu Glu

405 410 415

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

420 425 430

His Lys Lys Met Arg Pro Thr Ile Lys Asp His Trp Leu Lys His Pro

435 440 445

Gly Leu Ala Gln Leu Cys Val Thr Ile Glu Glu Cys Trp Asp His Asp

450 455 460

Ala Glu Ala Arg Leu Ser Ala Gly Cys Val Glu Glu Arg Val Ser Leu

465 470 475 480

Ile Arg Arg Ser Val Asn Gly Thr Thr Ser Asp Cys Leu Val Ser Leu

485 490 495

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

500 505 510

<210> 174

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<220>

<221> MISC_FEATURE

<222> (37)..(37)

<223> Xaa is Asp or Arg

<220>

<221> MISC_FEATURE

<222> (65)..(65)

<223> Xaa is Ile, phe, glu, asp, tyr, ser, asn, gln or Thr

<220>

<221> MISC_FEATURE

<222> (66)..(66)

<223> Xaa is Asn or Thr

<220>

<221> MISC_FEATURE

<222> (75)..(75)

<223> Xaa is Ala or Glu

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Thr or Lys

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Glu or Lys

<220>

<221> MISC_FEATURE

<222> (78)..(78)

<223> Xaa is Glu or Asp

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Asn or Ser

<220>

<221> MISC_FEATURE

<222> (81)..(81)

<223> Xaa is Gln, glu, lys, arg, asp or Asn

<400> 174

Gly Ala Ile Leu Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys

20 25 30

Glu Gly Glu Gln Xaa Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Xaa Xaa Cys Tyr Asp Arg Thr Asp Cys Val Xaa Xaa Xaa Xaa Xaa Pro

65 70 75 80

Xaa Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 175

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<220>

<221> MISC_FEATURE

<222> (37)..(37)

<223> Xaa is Asp or Arg

<220>

<221> MISC_FEATURE

<222> (65)..(65)

<223> Xaa is Ile, phe, glu, asp, tyr, ser, asn, gln or Thr

<220>

<221> MISC_FEATURE

<222> (66)..(66)

<223> Xaa is Asn or Thr

<220>

<221> MISC_FEATURE

<222> (75)..(75)

<223> Xaa is Ala or Glu

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Thr or Lys

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Glu or Lys

<220>

<221> MISC_FEATURE

<222> (78)..(78)

<223> Xaa is Glu or Asp

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Asn or Ser

<220>

<221> MISC_FEATURE

<222> (81)..(81)

<223> Xaa is Gln, glu, lys, arg, asp or Asn

<400> 175

Gly Ala Ile Leu Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys

20 25 30

Glu Gly Glu Gln Xaa Lys Arg Leu His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Xaa Xaa Cys Tyr Asp Arg Thr Asp Cys Val Xaa Xaa Xaa Xaa Xaa Pro

65 70 75 80

Xaa Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 176

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<220>

<221> MISC_FEATURE

<222> (37)..(37)

<223> Xaa is Asp or Arg

<220>

<221> MISC_FEATURE

<222> (65)..(65)

<223> Xaa is Ile, phe, glu, asp, tyr, ser, asn, gln or Thr

<220>

<221> MISC_FEATURE

<222> (66)..(66)

<223> Xaa is Asn or Thr

<220>

<221> MISC_FEATURE

<222> (75)..(75)

<223> Xaa is Ala or Glu

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Thr or Lys

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Glu or Lys

<220>

<221> MISC_FEATURE

<222> (78)..(78)

<223> Xaa is Glu or Asp

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Asn or Ser

<220>

<221> MISC_FEATURE

<222> (81)..(81)

<223> Xaa is Gln, glu, lys, arg, asp or Asn

<400> 176

Gly Ala Ile Leu Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys

20 25 30

Glu Gly Glu Gln Xaa Lys Arg Leu His Cys Tyr Ala Ser Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Xaa Xaa Cys Tyr Asp Arg Thr Asp Cys Val Xaa Xaa Xaa Xaa Xaa Pro

65 70 75 80

Xaa Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 177

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<220>

<221> MISC_FEATURE

<222> (37)..(37)

<223> Xaa is Asp or Arg

<220>

<221> MISC_FEATURE

<222> (65)..(65)

<223> Xaa is Ile, phe, glu, asp, tyr, ser, asn, gln or Thr

<220>

<221> MISC_FEATURE

<222> (66)..(66)

<223> Xaa is Asn or Thr

<220>

<221> MISC_FEATURE

<222> (75)..(75)

<223> Xaa is Ala or Glu

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Thr or Lys

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Glu or Lys

<220>

<221> MISC_FEATURE

<222> (78)..(78)

<223> Xaa is Glu or Asp

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Asn or Ser

<220>

<221> MISC_FEATURE

<222> (81)..(81)

<223> Xaa is Gln, glu, lys, arg, asp or Asn

<400> 177

Gly Ala Ile Leu Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys

20 25 30

Glu Gly Glu Gln Xaa Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn

35 40 45

Ser Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Xaa Xaa Cys Tyr Asp Arg Thr Asp Cys Val Xaa Xaa Xaa Xaa Xaa Pro

65 70 75 80

Xaa Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 178

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<220>

<221> MISC_FEATURE

<222> (37)..(37)

<223> Xaa is Asp or Arg

<220>

<221> MISC_FEATURE

<222> (65)..(65)

<223> Xaa is Ile, phe, glu, asp, tyr, ser, asn, gln or Thr

<220>

<221> MISC_FEATURE

<222> (66)..(66)

<223> Xaa is Asn or Thr

<220>

<221> MISC_FEATURE

<222> (75)..(75)

<223> Xaa is Ala or Glu

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Thr or Lys

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Glu or Lys

<220>

<221> MISC_FEATURE

<222> (78)..(78)

<223> Xaa is Glu or Asp

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Asn or Ser

<220>

<221> MISC_FEATURE

<222> (81)..(81)

<223> Xaa is Gln, glu, lys, arg, asp or Asn

<400> 178

Gly Ala Ile Leu Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys

20 25 30

Glu Gly Glu Gln Xaa Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn

35 40 45

Ser Ser Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Xaa Xaa Cys Tyr Asp Arg Thr Asp Cys Val Xaa Xaa Xaa Xaa Xaa Pro

65 70 75 80

Xaa Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 179

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<220>

<221> MISC_FEATURE

<222> (37)..(37)

<223> Xaa is Asp or Arg

<220>

<221> MISC_FEATURE

<222> (65)..(65)

<223> Xaa is Ile, phe, glu, asp, tyr, ser, asn, gln or Thr

<220>

<221> MISC_FEATURE

<222> (66)..(66)

<223> Xaa is Asn or Thr

<220>

<221> MISC_FEATURE

<222> (75)..(75)

<223> Xaa is Ala or Glu

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Thr or Lys

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Glu or Lys

<220>

<221> MISC_FEATURE

<222> (78)..(78)

<223> Xaa is Glu or Asp

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Asn or Ser

<220>

<221> MISC_FEATURE

<222> (81)..(81)

<223> Xaa is Gln, glu, lys, arg, asp or Asn

<400> 179

Gly Ala Ile Leu Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys

20 25 30

Glu Gly Glu Gln Xaa Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn

35 40 45

Ser Ser Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Xaa Xaa Cys Tyr Asp Arg Thr Asp Cys Val Xaa Xaa Xaa Xaa Xaa Pro

65 70 75 80

Xaa Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 180

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<220>

<221> MISC_FEATURE

<222> (37)..(37)

<223> Xaa is Asp or Arg

<220>

<221> MISC_FEATURE

<222> (65)..(65)

<223> Xaa is Ile, phe, glu, asp, tyr, ser, asn, gln or Thr

<220>

<221> MISC_FEATURE

<222> (66)..(66)

<223> Xaa is Asn or Thr

<220>

<221> MISC_FEATURE

<222> (75)..(75)

<223> Xaa is Ala or Glu

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Thr or Lys

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Glu or Lys

<220>

<221> MISC_FEATURE

<222> (78)..(78)

<223> Xaa is Glu or Asp

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Asn or Ser

<220>

<221> MISC_FEATURE

<222> (81)..(81)

<223> Xaa is Gln, glu, lys, arg, asp or Asn

<400> 180

Gly Ala Ile Leu Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys

20 25 30

Glu Gly Glu Gln Xaa Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn

35 40 45

Ser Ser Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Xaa Xaa Cys Tyr Asp Arg Gln Glu Cys Val Xaa Xaa Xaa Xaa Xaa Pro

65 70 75 80

Xaa Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 181

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<220>

<221> MISC_FEATURE

<222> (35)..(35)

<223> Xaa is Asp or Arg

<220>

<221> MISC_FEATURE

<222> (63)..(63)

<223> Xaa is Ile, phe, glu, asp, tyr, ser, asn, gln or Thr

<220>

<221> MISC_FEATURE

<222> (64)..(64)

<223> Xaa is Asn or Thr

<220>

<221> MISC_FEATURE

<222> (73)..(73)

<223> Xaa is Ala or Glu

<220>

<221> MISC_FEATURE

<222> (74)..(74)

<223> Xaa is Thr or Lys

<220>

<221> MISC_FEATURE

<222> (75)..(75)

<223> Xaa is Glu or Lys

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Glu or Asp

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Asn or Ser

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Gln, glu, lys, arg, asp or Asn

<400> 181

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Xaa Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn Ile Ser

35 40 45

Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Xaa Xaa

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Xaa Xaa Xaa Xaa Xaa Pro Xaa Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 182

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<220>

<221> MISC_FEATURE

<222> (35)..(35)

<223> Xaa is Asp or Arg

<220>

<221> MISC_FEATURE

<222> (63)..(63)

<223> Xaa is Ile, phe, glu, asp, tyr, ser, asn, gln or Thr

<220>

<221> MISC_FEATURE

<222> (64)..(64)

<223> Xaa is Asn or Thr

<220>

<221> MISC_FEATURE

<222> (73)..(73)

<223> Xaa is Ala or Glu

<220>

<221> MISC_FEATURE

<222> (74)..(74)

<223> Xaa is Thr or Lys

<220>

<221> MISC_FEATURE

<222> (75)..(75)

<223> Xaa is Glu or Lys

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Glu or Asp

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Asn or Ser

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Gln, glu, lys, arg, asp or Asn

<400> 182

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Xaa Lys Arg Leu His Cys Phe Ala Thr Trp Lys Asn Ile Ser

35 40 45

Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Xaa Xaa

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Xaa Xaa Xaa Xaa Xaa Pro Xaa Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 183

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<220>

<221> MISC_FEATURE

<222> (35)..(35)

<223> Xaa is Asp or Arg

<220>

<221> MISC_FEATURE

<222> (63)..(63)

<223> Xaa is Ile, phe, glu, asp, tyr, ser, asn, gln or Thr

<220>

<221> MISC_FEATURE

<222> (64)..(64)

<223> Xaa is Asn or Thr

<220>

<221> MISC_FEATURE

<222> (73)..(73)

<223> Xaa is Ala or Glu

<220>

<221> MISC_FEATURE

<222> (74)..(74)

<223> Xaa is Thr or Lys

<220>

<221> MISC_FEATURE

<222> (75)..(75)

<223> Xaa is Glu or Lys

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Glu or Asp

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Asn or Ser

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Gln, glu, lys, arg, asp or Asn

<400> 183

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Xaa Lys Arg Leu His Cys Tyr Ala Ser Trp Lys Asn Ile Ser

35 40 45

Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Xaa Xaa

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Xaa Xaa Xaa Xaa Xaa Pro Xaa Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 184

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<220>

<221> MISC_FEATURE

<222> (35)..(35)

<223> Xaa is Asp or Arg

<220>

<221> MISC_FEATURE

<222> (63)..(63)

<223> Xaa is Ile, phe, glu, asp, tyr, ser, asn, gln or Thr

<220>

<221> MISC_FEATURE

<222> (64)..(64)

<223> Xaa is Asn or Thr

<220>

<221> MISC_FEATURE

<222> (73)..(73)

<223> Xaa is Ala or Glu

<220>

<221> MISC_FEATURE

<222> (74)..(74)

<223> Xaa is Thr or Lys

<220>

<221> MISC_FEATURE

<222> (75)..(75)

<223> Xaa is Glu or Lys

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Glu or Asp

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Asn or Ser

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Gln, glu, lys, arg, asp or Asn

<400> 184

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Xaa Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Xaa Xaa

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Xaa Xaa Xaa Xaa Xaa Pro Xaa Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 185

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<220>

<221> MISC_FEATURE

<222> (35)..(35)

<223> Xaa is Asp or Arg

<220>

<221> MISC_FEATURE

<222> (63)..(63)

<223> Xaa is Ile, phe, glu, asp, tyr, ser, asn, gln or Thr

<220>

<221> MISC_FEATURE

<222> (64)..(64)

<223> Xaa is Asn or Thr

<220>

<221> MISC_FEATURE

<222> (73)..(73)

<223> Xaa is Ala or Glu

<220>

<221> MISC_FEATURE

<222> (74)..(74)

<223> Xaa is Thr or Lys

<220>

<221> MISC_FEATURE

<222> (75)..(75)

<223> Xaa is Glu or Lys

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Glu or Asp

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Asn or Ser

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Gln, glu, lys, arg, asp or Asn

<400> 185

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Xaa Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Xaa Xaa

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Xaa Xaa Xaa Xaa Xaa Pro Xaa Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 186

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<220>

<221> MISC_FEATURE

<222> (35)..(35)

<223> Xaa is Asp or Arg

<220>

<221> MISC_FEATURE

<222> (63)..(63)

<223> Xaa is Ile, phe, glu, asp, tyr, ser, asn, gln or Thr

<220>

<221> MISC_FEATURE

<222> (64)..(64)

<223> Xaa is Asn or Thr

<220>

<221> MISC_FEATURE

<222> (73)..(73)

<223> Xaa is Ala or Glu

<220>

<221> MISC_FEATURE

<222> (74)..(74)

<223> Xaa is Thr or Lys

<220>

<221> MISC_FEATURE

<222> (75)..(75)

<223> Xaa is Glu or Lys

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Glu or Asp

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Asn or Ser

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Gln, glu, lys, arg, asp or Asn

<400> 186

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Xaa Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Xaa Xaa

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Xaa Xaa Xaa Xaa Xaa Pro Xaa Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 187

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<220>

<221> MISC_FEATURE

<222> (35)..(35)

<223> Xaa is Asp or Arg

<220>

<221> MISC_FEATURE

<222> (63)..(63)

<223> Xaa is Ile, phe, glu, asp, tyr, ser, asn, gln or Thr

<220>

<221> MISC_FEATURE

<222> (64)..(64)

<223> Xaa is Asn or Thr

<220>

<221> MISC_FEATURE

<222> (73)..(73)

<223> Xaa is Ala or Glu

<220>

<221> MISC_FEATURE

<222> (74)..(74)

<223> Xaa is Thr or Lys

<220>

<221> MISC_FEATURE

<222> (75)..(75)

<223> Xaa is Glu or Lys

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Glu or Asp

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Asn or Ser

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Gln, glu, lys, arg, asp or Asn

<400> 187

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Xaa Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Xaa Xaa

50 55 60

Cys Tyr Asp Arg Gln Glu Cys Val Xaa Xaa Xaa Xaa Xaa Pro Xaa Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 188

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<220>

<221> MISC_FEATURE

<222> (37)..(37)

<223> Xaa is Asp or Arg

<220>

<221> MISC_FEATURE

<222> (65)..(65)

<223> Xaa is Ile, phe, glu, asp, tyr, ser, asn, gln or Thr

<220>

<221> MISC_FEATURE

<222> (66)..(66)

<223> Xaa is Asn or Thr

<220>

<221> MISC_FEATURE

<222> (75)..(75)

<223> Xaa is Ala or Glu

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Thr or Lys

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Glu or Lys

<220>

<221> MISC_FEATURE

<222> (78)..(78)

<223> Xaa is Glu or Asp

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Asn or Ser

<220>

<221> MISC_FEATURE

<222> (81)..(81)

<223> Xaa is Gln, glu, lys, arg, asp or Asn

<400> 188

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Ile Tyr Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys

20 25 30

Glu Gly Glu Gln Xaa Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Xaa Xaa Cys Tyr Asp Arg Thr Asp Cys Val Xaa Xaa Xaa Xaa Xaa Pro

65 70 75 80

Xaa Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 189

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<220>

<221> MISC_FEATURE

<222> (37)..(37)

<223> Xaa is Asp or Arg

<220>

<221> MISC_FEATURE

<222> (65)..(65)

<223> Xaa is Ile, phe, glu, asp, tyr, ser, asn, gln or Thr

<220>

<221> MISC_FEATURE

<222> (66)..(66)

<223> Xaa is Asn or Thr

<220>

<221> MISC_FEATURE

<222> (75)..(75)

<223> Xaa is Ala or Glu

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Thr or Lys

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Glu or Lys

<220>

<221> MISC_FEATURE

<222> (78)..(78)

<223> Xaa is Glu or Asp

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Asn or Ser

<220>

<221> MISC_FEATURE

<222> (81)..(81)

<223> Xaa is Gln, glu, lys, arg, asp or Asn

<400> 189

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Ile Tyr Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys

20 25 30

Glu Gly Glu Gln Xaa Lys Arg Leu His Cys Phe Ala Thr Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Xaa Xaa Cys Tyr Asp Arg Thr Asp Cys Val Xaa Xaa Xaa Xaa Xaa Pro

65 70 75 80

Xaa Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 190

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<220>

<221> MISC_FEATURE

<222> (37)..(37)

<223> Xaa is Asp or Arg

<220>

<221> MISC_FEATURE

<222> (65)..(65)

<223> Xaa is Ile, phe, glu, asp, tyr, ser, asn, gln or Thr

<220>

<221> MISC_FEATURE

<222> (66)..(66)

<223> Xaa is Asn or Thr

<220>

<221> MISC_FEATURE

<222> (75)..(75)

<223> Xaa is Ala or Glu

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Thr or Lys

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Glu or Lys

<220>

<221> MISC_FEATURE

<222> (78)..(78)

<223> Xaa is Glu or Asp

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Asn or Ser

<220>

<221> MISC_FEATURE

<222> (81)..(81)

<223> Xaa is Gln, glu, lys, arg, asp or Asn

<400> 190

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Ile Tyr Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys

20 25 30

Glu Gly Glu Gln Xaa Lys Arg Leu His Cys Tyr Ala Ser Trp Lys Asn

35 40 45

Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Xaa Xaa Cys Tyr Asp Arg Thr Asp Cys Val Xaa Xaa Xaa Xaa Xaa Pro

65 70 75 80

Xaa Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 191

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<220>

<221> MISC_FEATURE

<222> (37)..(37)

<223> Xaa is Asp or Arg

<220>

<221> MISC_FEATURE

<222> (65)..(65)

<223> Xaa is Ile, phe, glu, asp, tyr, ser, asn, gln or Thr

<220>

<221> MISC_FEATURE

<222> (66)..(66)

<223> Xaa is Asn or Thr

<220>

<221> MISC_FEATURE

<222> (75)..(75)

<223> Xaa is Ala or Glu

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Thr or Lys

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Glu or Lys

<220>

<221> MISC_FEATURE

<222> (78)..(78)

<223> Xaa is Glu or Asp

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Asn or Ser

<220>

<221> MISC_FEATURE

<222> (81)..(81)

<223> Xaa is Gln, glu, lys, arg, asp or Asn

<400> 191

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Ile Tyr Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys

20 25 30

Glu Gly Glu Gln Xaa Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn

35 40 45

Ser Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Xaa Xaa Cys Tyr Asp Arg Thr Asp Cys Val Xaa Xaa Xaa Xaa Xaa Pro

65 70 75 80

Xaa Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 192

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<220>

<221> MISC_FEATURE

<222> (37)..(37)

<223> Xaa is Asp or Arg

<220>

<221> MISC_FEATURE

<222> (65)..(65)

<223> Xaa is Ile, phe, glu, asp, tyr, ser, asn, gln or Thr

<220>

<221> MISC_FEATURE

<222> (66)..(66)

<223> Xaa is Asn or Thr

<220>

<221> MISC_FEATURE

<222> (75)..(75)

<223> Xaa is Ala or Glu

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Thr or Lys

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Glu or Lys

<220>

<221> MISC_FEATURE

<222> (78)..(78)

<223> Xaa is Glu or Asp

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Asn or Ser

<220>

<221> MISC_FEATURE

<222> (81)..(81)

<223> Xaa is Gln, glu, lys, arg, asp or Asn

<400> 192

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Ile Tyr Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys

20 25 30

Glu Gly Glu Gln Xaa Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn

35 40 45

Ser Ser Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Xaa Xaa Cys Tyr Asp Arg Thr Asp Cys Val Xaa Xaa Xaa Xaa Xaa Pro

65 70 75 80

Xaa Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 193

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<220>

<221> MISC_FEATURE

<222> (37)..(37)

<223> Xaa is Asp or Arg

<220>

<221> MISC_FEATURE

<222> (65)..(65)

<223> Xaa is Ile, phe, glu, asp, tyr, ser, asn, gln or Thr

<220>

<221> MISC_FEATURE

<222> (66)..(66)

<223> Xaa is Asn or Thr

<220>

<221> MISC_FEATURE

<222> (75)..(75)

<223> Xaa is Ala or Glu

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Thr or Lys

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Glu or Lys

<220>

<221> MISC_FEATURE

<222> (78)..(78)

<223> Xaa is Glu or Asp

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Asn or Ser

<220>

<221> MISC_FEATURE

<222> (81)..(81)

<223> Xaa is Gln, glu, lys, arg, asp or Asn

<400> 193

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Ile Tyr Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys

20 25 30

Glu Gly Glu Gln Xaa Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn

35 40 45

Ser Ser Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Xaa Xaa Cys Tyr Asp Arg Thr Asp Cys Val Xaa Xaa Xaa Xaa Xaa Pro

65 70 75 80

Xaa Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 194

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<220>

<221> MISC_FEATURE

<222> (37)..(37)

<223> Xaa is Asp or Arg

<220>

<221> MISC_FEATURE

<222> (65)..(65)

<223> Xaa is Ile, phe, glu, asp, tyr, ser, asn, gln or Thr

<220>

<221> MISC_FEATURE

<222> (66)..(66)

<223> Xaa is Asn or Thr

<220>

<221> MISC_FEATURE

<222> (75)..(75)

<223> Xaa is Ala or Glu

<220>

<221> MISC_FEATURE

<222> (76)..(76)

<223> Xaa is Thr or Lys

<220>

<221> MISC_FEATURE

<222> (77)..(77)

<223> Xaa is Glu or Lys

<220>

<221> MISC_FEATURE

<222> (78)..(78)

<223> Xaa is Glu or Asp

<220>

<221> MISC_FEATURE

<222> (79)..(79)

<223> Xaa is Asn or Ser

<220>

<221> MISC_FEATURE

<222> (81)..(81)

<223> Xaa is Gln, glu, lys, arg, asp or Asn

<400> 194

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Ile Tyr Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys

20 25 30

Glu Gly Glu Gln Xaa Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn

35 40 45

Ser Ser Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp

50 55 60

Xaa Xaa Cys Tyr Asp Arg Gln Glu Cys Val Xaa Xaa Xaa Xaa Xaa Pro

65 70 75 80

Xaa Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 195

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 195

Gly Ala Ile Leu Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys

20 25 30

Glu Gly Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn

35 40 45

Ser Ser Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Ala Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 196

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 196

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Glu Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 197

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 197

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 198

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 198

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 199

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 199

Gly Ala Ile Leu Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys

20 25 30

Glu Gly Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn

35 40 45

Ser Ser Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Ala Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 200

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 200

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Glu Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 201

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 201

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn Ile Ser

35 40 45

Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 202

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 202

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Phe Ala Thr Trp Lys Asn Ile Ser

35 40 45

Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 203

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 203

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Lys Asn Ile Ser

35 40 45

Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 204

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 204

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 205

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 205

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 206

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 206

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Lys Asp Ser Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 207

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 207

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 208

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 208

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Asn Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 209

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 209

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Thr Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 210

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 210

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Glu Thr

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 211

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 211

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Arg Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 212

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 212

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Thr Lys Asp Ser Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 213

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 213

Gly Ala Ile Leu Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys

20 25 30

Glu Gly Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn

35 40 45

Ser Ser Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 214

<211> 109

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 214

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Ile Tyr Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys

20 25 30

Glu Gly Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn

35 40 45

Ser Ser Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 215

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 215

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Lys Asp Ser Pro Glu Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 216

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 216

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Lys Glu Asn Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 217

<211> 339

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 217

Gly Ala Ile Leu Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys

20 25 30

Glu Gly Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn

35 40 45

Ser Ser Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Ala Thr Glu Glu Asn Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

Pro Gly Lys

<210> 218

<211> 337

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 218

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Glu Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

Lys

<210> 219

<211> 337

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 219

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

Lys

<210> 220

<211> 337

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 220

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

Lys

<210> 221

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 221

Ile Leu Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Ala Thr Glu Glu Asn Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 222

<211> 106

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 222

Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp

1 5 10 15

Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu

20 25 30

Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly

35 40 45

Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys

50 55 60

Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Glu Val Tyr

65 70 75 80

Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe

85 90 95

Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 223

<211> 106

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 223

Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp

1 5 10 15

Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu

20 25 30

Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly

35 40 45

Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys

50 55 60

Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr

65 70 75 80

Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe

85 90 95

Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 224

<211> 106

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 224

Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp

1 5 10 15

Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu

20 25 30

Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly

35 40 45

Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys

50 55 60

Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr

65 70 75 80

Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe

85 90 95

Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 225

<211> 106

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 225

Leu Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp

1 5 10 15

Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu

20 25 30

Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly

35 40 45

Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys

50 55 60

Tyr Asp Arg Thr Asp Cys Val Ala Thr Glu Glu Asn Pro Gln Val Tyr

65 70 75 80

Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe

85 90 95

Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 226

<211> 105

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 226

Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu

1 5 10 15

Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln

20 25 30

Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr

35 40 45

Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr

50 55 60

Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Glu Val Tyr Phe

65 70 75 80

Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro

85 90 95

Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 227

<211> 105

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 227

Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu

1 5 10 15

Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln

20 25 30

Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr

35 40 45

Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr

50 55 60

Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe

65 70 75 80

Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro

85 90 95

Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 228

<211> 105

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 228

Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu

1 5 10 15

Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln

20 25 30

Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr

35 40 45

Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr

50 55 60

Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe

65 70 75 80

Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro

85 90 95

Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 229

<211> 105

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 229

Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu

1 5 10 15

Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln

20 25 30

Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr

35 40 45

Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr

50 55 60

Asp Arg Thr Asp Cys Val Ala Thr Glu Glu Asn Pro Gln Val Tyr Phe

65 70 75 80

Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro

85 90 95

Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 230

<211> 104

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 230

Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu

1 5 10 15

Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp

20 25 30

Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile

35 40 45

Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp

50 55 60

Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Glu Val Tyr Phe Cys

65 70 75 80

Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu

85 90 95

Met Glu Val Thr Gln Pro Thr Ser

100

<210> 231

<211> 104

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 231

Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu

1 5 10 15

Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp

20 25 30

Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile

35 40 45

Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp

50 55 60

Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys

65 70 75 80

Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu

85 90 95

Met Glu Val Thr Gln Pro Thr Ser

100

<210> 232

<211> 104

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 232

Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu

1 5 10 15

Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp

20 25 30

Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile

35 40 45

Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp

50 55 60

Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys

65 70 75 80

Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu

85 90 95

Met Glu Val Thr Gln Pro Thr Ser

100

<210> 233

<211> 104

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 233

Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu

1 5 10 15

Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp

20 25 30

Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile

35 40 45

Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp

50 55 60

Arg Thr Asp Cys Val Ala Thr Glu Glu Asn Pro Gln Val Tyr Phe Cys

65 70 75 80

Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu

85 90 95

Met Glu Val Thr Gln Pro Thr Ser

100

<210> 234

<211> 103

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 234

Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu

1 5 10 15

Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys

20 25 30

Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu

35 40 45

Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg

50 55 60

Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Glu Val Tyr Phe Cys Cys

65 70 75 80

Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met

85 90 95

Glu Val Thr Gln Pro Thr Ser

100

<210> 235

<211> 103

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 235

Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu

1 5 10 15

Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys

20 25 30

Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu

35 40 45

Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg

50 55 60

Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys

65 70 75 80

Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met

85 90 95

Glu Val Thr Gln Pro Thr Ser

100

<210> 236

<211> 103

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 236

Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu

1 5 10 15

Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys

20 25 30

Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu

35 40 45

Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg

50 55 60

Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys

65 70 75 80

Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met

85 90 95

Glu Val Thr Gln Pro Thr Ser

100

<210> 237

<211> 103

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 237

Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu

1 5 10 15

Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys

20 25 30

Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu

35 40 45

Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg

50 55 60

Thr Asp Cys Val Ala Thr Glu Glu Asn Pro Gln Val Tyr Phe Cys Cys

65 70 75 80

Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met

85 90 95

Glu Val Thr Gln Pro Thr Ser

100

<210> 238

<211> 102

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 238

Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg

1 5 10 15

Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg

20 25 30

Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile

35 40 45

Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg Thr

50 55 60

Asp Cys Val Glu Lys Lys Asp Ser Pro Glu Val Tyr Phe Cys Cys Cys

65 70 75 80

Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu

85 90 95

Val Thr Gln Pro Thr Ser

100

<210> 239

<211> 102

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 239

Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg

1 5 10 15

Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg

20 25 30

Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile

35 40 45

Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg Thr

50 55 60

Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys

65 70 75 80

Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu

85 90 95

Val Thr Gln Pro Thr Ser

100

<210> 240

<211> 102

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 240

Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg

1 5 10 15

Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg

20 25 30

Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile

35 40 45

Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr

50 55 60

Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys

65 70 75 80

Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu

85 90 95

Val Thr Gln Pro Thr Ser

100

<210> 241

<211> 102

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 241

Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg

1 5 10 15

Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg

20 25 30

Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile

35 40 45

Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg Thr

50 55 60

Asp Cys Val Ala Thr Glu Glu Asn Pro Gln Val Tyr Phe Cys Cys Cys

65 70 75 80

Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu

85 90 95

Val Thr Gln Pro Thr Ser

100

<210> 242

<211> 101

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 242

Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr

1 5 10 15

Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu

20 25 30

His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val

35 40 45

Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg Thr Asp

50 55 60

Cys Val Glu Lys Lys Asp Ser Pro Glu Val Tyr Phe Cys Cys Cys Glu

65 70 75 80

Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val

85 90 95

Thr Gln Pro Thr Ser

100

<210> 243

<211> 101

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 243

Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr

1 5 10 15

Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu

20 25 30

His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val

35 40 45

Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg Thr Asp

50 55 60

Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu

65 70 75 80

Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val

85 90 95

Thr Gln Pro Thr Ser

100

<210> 244

<211> 101

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 244

Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr

1 5 10 15

Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu

20 25 30

His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val

35 40 45

Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr Asp

50 55 60

Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu

65 70 75 80

Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val

85 90 95

Thr Gln Pro Thr Ser

100

<210> 245

<211> 101

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 245

Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr

1 5 10 15

Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu

20 25 30

His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val

35 40 45

Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg Thr Asp

50 55 60

Cys Val Ala Thr Glu Glu Asn Pro Gln Val Tyr Phe Cys Cys Cys Glu

65 70 75 80

Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val

85 90 95

Thr Gln Pro Thr Ser

100

<210> 246

<211> 100

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 246

Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn

1 5 10 15

Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu His

20 25 30

Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val Lys

35 40 45

Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg Thr Asp Cys

50 55 60

Val Glu Lys Lys Asp Ser Pro Glu Val Tyr Phe Cys Cys Cys Glu Gly

65 70 75 80

Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr

85 90 95

Gln Pro Thr Ser

100

<210> 247

<211> 100

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 247

Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn

1 5 10 15

Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu His

20 25 30

Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val Lys

35 40 45

Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg Thr Asp Cys

50 55 60

Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly

65 70 75 80

Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr

85 90 95

Gln Pro Thr Ser

100

<210> 248

<211> 100

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 248

Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn

1 5 10 15

Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu His

20 25 30

Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val Lys

35 40 45

Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr Asp Cys

50 55 60

Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly

65 70 75 80

Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr

85 90 95

Gln Pro Thr Ser

100

<210> 249

<211> 100

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 249

Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn

1 5 10 15

Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu His

20 25 30

Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val Lys

35 40 45

Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg Thr Asp Cys

50 55 60

Val Ala Thr Glu Glu Asn Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly

65 70 75 80

Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr

85 90 95

Gln Pro Thr Ser

100

<210> 250

<211> 106

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 250

Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp

1 5 10 15

Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu

20 25 30

Gln Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn Ile Ser Gly

35 40 45

Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys

50 55 60

Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr

65 70 75 80

Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe

85 90 95

Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 251

<211> 106

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 251

Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp

1 5 10 15

Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu

20 25 30

Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly

35 40 45

Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Glu Thr Cys

50 55 60

Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr

65 70 75 80

Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe

85 90 95

Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 252

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 252

Ile Leu Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 253

<211> 107

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 253

Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 254

<211> 106

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 254

Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp

1 5 10 15

Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu

20 25 30

Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly

35 40 45

Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys

50 55 60

Tyr Asp Arg Gln Glu Cys Val Ala Thr Lys Asp Ser Pro Glu Val Tyr

65 70 75 80

Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe

85 90 95

Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 255

<211> 106

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 255

Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp

1 5 10 15

Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu

20 25 30

Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly

35 40 45

Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys

50 55 60

Tyr Asp Arg Gln Glu Cys Val Ala Thr Lys Glu Asn Pro Gln Val Tyr

65 70 75 80

Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe

85 90 95

Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 256

<211> 105

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 256

Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu

1 5 10 15

Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln

20 25 30

Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn Ile Ser Gly Ser

35 40 45

Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr

50 55 60

Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe

65 70 75 80

Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro

85 90 95

Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 257

<211> 105

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 257

Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu

1 5 10 15

Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln

20 25 30

Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr

35 40 45

Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Glu Thr Cys Tyr

50 55 60

Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe

65 70 75 80

Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro

85 90 95

Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 258

<211> 106

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 258

Leu Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp

1 5 10 15

Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu

20 25 30

Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly

35 40 45

Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys

50 55 60

Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr

65 70 75 80

Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe

85 90 95

Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 259

<211> 106

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 259

Leu Gly Arg Ser Glu Thr Gln Glu Cys Ile Tyr Tyr Asn Ala Asn Trp

1 5 10 15

Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu

20 25 30

Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly

35 40 45

Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys

50 55 60

Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr

65 70 75 80

Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe

85 90 95

Pro Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 260

<211> 105

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 260

Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu

1 5 10 15

Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln

20 25 30

Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr

35 40 45

Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr

50 55 60

Asp Arg Gln Glu Cys Val Ala Thr Lys Asp Ser Pro Glu Val Tyr Phe

65 70 75 80

Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro

85 90 95

Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 261

<211> 105

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 261

Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu

1 5 10 15

Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln

20 25 30

Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr

35 40 45

Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr

50 55 60

Asp Arg Gln Glu Cys Val Ala Thr Lys Glu Asn Pro Gln Val Tyr Phe

65 70 75 80

Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro

85 90 95

Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 262

<211> 104

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 262

Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu

1 5 10 15

Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp

20 25 30

Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn Ile Ser Gly Ser Ile

35 40 45

Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp

50 55 60

Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys

65 70 75 80

Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu

85 90 95

Met Glu Val Thr Gln Pro Thr Ser

100

<210> 263

<211> 104

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 263

Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu

1 5 10 15

Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp

20 25 30

Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile

35 40 45

Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Glu Thr Cys Tyr Asp

50 55 60

Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys

65 70 75 80

Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu

85 90 95

Met Glu Val Thr Gln Pro Thr Ser

100

<210> 264

<211> 105

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 264

Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu

1 5 10 15

Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln

20 25 30

Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr

35 40 45

Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr

50 55 60

Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe

65 70 75 80

Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro

85 90 95

Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 265

<211> 105

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 265

Gly Arg Ser Glu Thr Gln Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu

1 5 10 15

Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln

20 25 30

Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr

35 40 45

Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr

50 55 60

Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe

65 70 75 80

Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro

85 90 95

Glu Met Glu Val Thr Gln Pro Thr Ser

100 105

<210> 266

<211> 104

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 266

Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu

1 5 10 15

Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp

20 25 30

Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile

35 40 45

Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp

50 55 60

Arg Gln Glu Cys Val Ala Thr Lys Asp Ser Pro Glu Val Tyr Phe Cys

65 70 75 80

Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu

85 90 95

Met Glu Val Thr Gln Pro Thr Ser

100

<210> 267

<211> 104

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 267

Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu

1 5 10 15

Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp

20 25 30

Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile

35 40 45

Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp

50 55 60

Arg Gln Glu Cys Val Ala Thr Lys Glu Asn Pro Gln Val Tyr Phe Cys

65 70 75 80

Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu

85 90 95

Met Glu Val Thr Gln Pro Thr Ser

100

<210> 268

<211> 103

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 268

Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu

1 5 10 15

Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys

20 25 30

Arg Arg His Cys Phe Ala Thr Trp Lys Asn Ile Ser Gly Ser Ile Glu

35 40 45

Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg

50 55 60

Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys

65 70 75 80

Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met

85 90 95

Glu Val Thr Gln Pro Thr Ser

100

<210> 269

<211> 103

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 269

Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu

1 5 10 15

Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys

20 25 30

Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu

35 40 45

Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Glu Thr Cys Tyr Asp Arg

50 55 60

Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys

65 70 75 80

Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met

85 90 95

Glu Val Thr Gln Pro Thr Ser

100

<210> 270

<211> 104

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 270

Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu

1 5 10 15

Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp

20 25 30

Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile

35 40 45

Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp

50 55 60

Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys

65 70 75 80

Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu

85 90 95

Met Glu Val Thr Gln Pro Thr Ser

100

<210> 271

<211> 104

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 271

Arg Ser Glu Thr Gln Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu

1 5 10 15

Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp

20 25 30

Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile

35 40 45

Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp

50 55 60

Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys

65 70 75 80

Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu

85 90 95

Met Glu Val Thr Gln Pro Thr Ser

100

<210> 272

<211> 103

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 272

Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu

1 5 10 15

Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys

20 25 30

Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu

35 40 45

Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg

50 55 60

Gln Glu Cys Val Ala Thr Lys Asp Ser Pro Glu Val Tyr Phe Cys Cys

65 70 75 80

Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met

85 90 95

Glu Val Thr Gln Pro Thr Ser

100

<210> 273

<211> 103

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 273

Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu

1 5 10 15

Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys

20 25 30

Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu

35 40 45

Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg

50 55 60

Gln Glu Cys Val Ala Thr Lys Glu Asn Pro Gln Val Tyr Phe Cys Cys

65 70 75 80

Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met

85 90 95

Glu Val Thr Gln Pro Thr Ser

100

<210> 274

<211> 102

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 274

Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg

1 5 10 15

Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg

20 25 30

Arg His Cys Phe Ala Thr Trp Lys Asn Ile Ser Gly Ser Ile Glu Ile

35 40 45

Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr

50 55 60

Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys

65 70 75 80

Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu

85 90 95

Val Thr Gln Pro Thr Ser

100

<210> 275

<211> 102

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 275

Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg

1 5 10 15

Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg

20 25 30

Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile

35 40 45

Val Lys Gln Gly Cys Trp Leu Asp Asp Glu Thr Cys Tyr Asp Arg Thr

50 55 60

Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys

65 70 75 80

Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu

85 90 95

Val Thr Gln Pro Thr Ser

100

<210> 276

<211> 103

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 276

Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu

1 5 10 15

Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys

20 25 30

Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu

35 40 45

Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg

50 55 60

Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys

65 70 75 80

Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met

85 90 95

Glu Val Thr Gln Pro Thr Ser

100

<210> 277

<211> 103

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 277

Ser Glu Thr Gln Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu

1 5 10 15

Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys

20 25 30

Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu

35 40 45

Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg

50 55 60

Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys

65 70 75 80

Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met

85 90 95

Glu Val Thr Gln Pro Thr Ser

100

<210> 278

<211> 102

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 278

Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg

1 5 10 15

Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg

20 25 30

Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Leu

35 40 45

Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Gln

50 55 60

Glu Cys Val Ala Thr Lys Asp Ser Pro Glu Val Tyr Phe Cys Cys Cys

65 70 75 80

Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu

85 90 95

Val Thr Gln Pro Thr Ser

100

<210> 279

<211> 102

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 279

Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg

1 5 10 15

Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg

20 25 30

Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Leu

35 40 45

Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Gln

50 55 60

Glu Cys Val Ala Thr Lys Glu Asn Pro Gln Val Tyr Phe Cys Cys Cys

65 70 75 80

Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu

85 90 95

Val Thr Gln Pro Thr Ser

100

<210> 280

<211> 101

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 280

Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr

1 5 10 15

Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Arg

20 25 30

His Cys Phe Ala Thr Trp Lys Asn Ile Ser Gly Ser Ile Glu Ile Val

35 40 45

Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr Asp

50 55 60

Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu

65 70 75 80

Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val

85 90 95

Thr Gln Pro Thr Ser

100

<210> 281

<211> 101

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 281

Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr

1 5 10 15

Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu

20 25 30

His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val

35 40 45

Lys Gln Gly Cys Trp Leu Asp Asp Glu Thr Cys Tyr Asp Arg Thr Asp

50 55 60

Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu

65 70 75 80

Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val

85 90 95

Thr Gln Pro Thr Ser

100

<210> 282

<211> 102

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 282

Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg

1 5 10 15

Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg

20 25 30

Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile

35 40 45

Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr

50 55 60

Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys

65 70 75 80

Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu

85 90 95

Val Thr Gln Pro Thr Ser

100

<210> 283

<211> 102

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 283

Glu Thr Gln Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg

1 5 10 15

Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg

20 25 30

Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile

35 40 45

Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr

50 55 60

Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys

65 70 75 80

Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu

85 90 95

Val Thr Gln Pro Thr Ser

100

<210> 284

<211> 101

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 284

Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr

1 5 10 15

Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu

20 25 30

His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Leu Val

35 40 45

Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Gln Glu

50 55 60

Cys Val Ala Thr Lys Asp Ser Pro Glu Val Tyr Phe Cys Cys Cys Glu

65 70 75 80

Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val

85 90 95

Thr Gln Pro Thr Ser

100

<210> 285

<211> 101

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 285

Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr

1 5 10 15

Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu

20 25 30

His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Leu Val

35 40 45

Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Gln Glu

50 55 60

Cys Val Ala Thr Lys Glu Asn Pro Gln Val Tyr Phe Cys Cys Cys Glu

65 70 75 80

Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val

85 90 95

Thr Gln Pro Thr Ser

100

<210> 286

<211> 100

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 286

Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn

1 5 10 15

Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Arg His

20 25 30

Cys Phe Ala Thr Trp Lys Asn Ile Ser Gly Ser Ile Glu Ile Val Lys

35 40 45

Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr Asp Cys

50 55 60

Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly

65 70 75 80

Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr

85 90 95

Gln Pro Thr Ser

100

<210> 287

<211> 100

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 287

Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn

1 5 10 15

Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu His

20 25 30

Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val Lys

35 40 45

Gln Gly Cys Trp Leu Asp Asp Glu Thr Cys Tyr Asp Arg Thr Asp Cys

50 55 60

Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly

65 70 75 80

Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr

85 90 95

Gln Pro Thr Ser

100

<210> 288

<211> 101

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 288

Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr

1 5 10 15

Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu

20 25 30

His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val

35 40 45

Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr Asp

50 55 60

Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu

65 70 75 80

Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val

85 90 95

Thr Gln Pro Thr Ser

100

<210> 289

<211> 101

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 289

Thr Gln Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr

1 5 10 15

Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu

20 25 30

His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val

35 40 45

Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr Asp

50 55 60

Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu

65 70 75 80

Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val

85 90 95

Thr Gln Pro Thr Ser

100

<210> 290

<211> 100

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 290

Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn

1 5 10 15

Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu His

20 25 30

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

35 40 45

Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Gln Glu Cys

50 55 60

Val Ala Thr Lys Asp Ser Pro Glu Val Tyr Phe Cys Cys Cys Glu Gly

65 70 75 80

Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr

85 90 95

Gln Pro Thr Ser

100

<210> 291

<211> 100

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 291

Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn

1 5 10 15

Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu His

20 25 30

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

35 40 45

Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Gln Glu Cys

50 55 60

Val Ala Thr Lys Glu Asn Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly

65 70 75 80

Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr

85 90 95

Gln Pro Thr Ser

100

<210> 292

<211> 100

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 292

Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn

1 5 10 15

Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu His

20 25 30

Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val Lys

35 40 45

Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr Asp Cys

50 55 60

Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly

65 70 75 80

Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr

85 90 95

Gln Pro Thr Ser

100

<210> 293

<211> 100

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 293

Gln Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn

1 5 10 15

Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu His

20 25 30

Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val Lys

35 40 45

Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr Asp Cys

50 55 60

Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly

65 70 75 80

Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr

85 90 95

Gln Pro Thr Ser

100

<210> 294

<211> 337

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 294

Ile Leu Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Ala Thr Glu Glu Asn Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

Lys

<210> 295

<211> 336

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 295

Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp

1 5 10 15

Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu

20 25 30

Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly

35 40 45

Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys

50 55 60

Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Glu Val Tyr

65 70 75 80

Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe

85 90 95

Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

<210> 296

<211> 336

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 296

Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp

1 5 10 15

Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu

20 25 30

Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly

35 40 45

Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys

50 55 60

Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr

65 70 75 80

Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe

85 90 95

Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

<210> 297

<211> 336

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 297

Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp

1 5 10 15

Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu

20 25 30

Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly

35 40 45

Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys

50 55 60

Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr

65 70 75 80

Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe

85 90 95

Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

<210> 298

<211> 336

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 298

Leu Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp

1 5 10 15

Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu

20 25 30

Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly

35 40 45

Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys

50 55 60

Tyr Asp Arg Thr Asp Cys Val Ala Thr Glu Glu Asn Pro Gln Val Tyr

65 70 75 80

Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe

85 90 95

Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

<210> 299

<211> 335

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 299

Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu

1 5 10 15

Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln

20 25 30

Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr

35 40 45

Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr

50 55 60

Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Glu Val Tyr Phe

65 70 75 80

Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro

85 90 95

Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His

100 105 110

Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

<210> 300

<211> 335

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 300

Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu

1 5 10 15

Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln

20 25 30

Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr

35 40 45

Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr

50 55 60

Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe

65 70 75 80

Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro

85 90 95

Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His

100 105 110

Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

<210> 301

<211> 335

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 301

Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu

1 5 10 15

Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln

20 25 30

Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr

35 40 45

Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr

50 55 60

Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe

65 70 75 80

Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro

85 90 95

Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His

100 105 110

Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

<210> 302

<211> 335

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 302

Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu

1 5 10 15

Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln

20 25 30

Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr

35 40 45

Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr

50 55 60

Asp Arg Thr Asp Cys Val Ala Thr Glu Glu Asn Pro Gln Val Tyr Phe

65 70 75 80

Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro

85 90 95

Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His

100 105 110

Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

<210> 303

<211> 334

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 303

Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu

1 5 10 15

Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp

20 25 30

Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile

35 40 45

Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp

50 55 60

Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Glu Val Tyr Phe Cys

65 70 75 80

Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu

85 90 95

Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330

<210> 304

<211> 334

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 304

Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu

1 5 10 15

Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp

20 25 30

Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile

35 40 45

Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp

50 55 60

Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys

65 70 75 80

Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu

85 90 95

Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330

<210> 305

<211> 334

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 305

Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu

1 5 10 15

Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp

20 25 30

Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile

35 40 45

Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp

50 55 60

Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys

65 70 75 80

Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu

85 90 95

Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330

<210> 306

<211> 334

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 306

Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu

1 5 10 15

Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp

20 25 30

Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile

35 40 45

Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp

50 55 60

Arg Thr Asp Cys Val Ala Thr Glu Glu Asn Pro Gln Val Tyr Phe Cys

65 70 75 80

Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu

85 90 95

Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330

<210> 307

<211> 333

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 307

Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu

1 5 10 15

Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys

20 25 30

Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu

35 40 45

Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg

50 55 60

Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Glu Val Tyr Phe Cys Cys

65 70 75 80

Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met

85 90 95

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

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330

<210> 308

<211> 333

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 308

Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu

1 5 10 15

Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys

20 25 30

Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu

35 40 45

Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg

50 55 60

Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys

65 70 75 80

Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met

85 90 95

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

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330

<210> 309

<211> 333

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 309

Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu

1 5 10 15

Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys

20 25 30

Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu

35 40 45

Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg

50 55 60

Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys

65 70 75 80

Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met

85 90 95

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

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330

<210> 310

<211> 333

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 310

Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu

1 5 10 15

Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys

20 25 30

Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu

35 40 45

Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg

50 55 60

Thr Asp Cys Val Ala Thr Glu Glu Asn Pro Gln Val Tyr Phe Cys Cys

65 70 75 80

Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met

85 90 95

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

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330

<210> 311

<211> 332

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 311

Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg

1 5 10 15

Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg

20 25 30

Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile

35 40 45

Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg Thr

50 55 60

Asp Cys Val Glu Lys Lys Asp Ser Pro Glu Val Tyr Phe Cys Cys Cys

65 70 75 80

Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu

85 90 95

Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 312

<211> 332

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 312

Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg

1 5 10 15

Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg

20 25 30

Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile

35 40 45

Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg Thr

50 55 60

Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys

65 70 75 80

Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu

85 90 95

Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 313

<211> 332

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 313

Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg

1 5 10 15

Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg

20 25 30

Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile

35 40 45

Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr

50 55 60

Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys

65 70 75 80

Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu

85 90 95

Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 314

<211> 332

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 314

Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg

1 5 10 15

Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg

20 25 30

Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile

35 40 45

Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg Thr

50 55 60

Asp Cys Val Ala Thr Glu Glu Asn Pro Gln Val Tyr Phe Cys Cys Cys

65 70 75 80

Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu

85 90 95

Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 315

<211> 331

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 315

Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr

1 5 10 15

Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu

20 25 30

His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val

35 40 45

Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg Thr Asp

50 55 60

Cys Val Glu Lys Lys Asp Ser Pro Glu Val Tyr Phe Cys Cys Cys Glu

65 70 75 80

Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val

85 90 95

Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro

100 105 110

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

115 120 125

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

130 135 140

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

145 150 155 160

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

165 170 175

Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 316

<211> 331

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 316

Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr

1 5 10 15

Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu

20 25 30

His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val

35 40 45

Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg Thr Asp

50 55 60

Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu

65 70 75 80

Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val

85 90 95

Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro

100 105 110

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

115 120 125

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

130 135 140

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

145 150 155 160

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

165 170 175

Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 317

<211> 331

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 317

Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr

1 5 10 15

Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu

20 25 30

His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val

35 40 45

Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr Asp

50 55 60

Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu

65 70 75 80

Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val

85 90 95

Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro

100 105 110

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

115 120 125

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

130 135 140

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

145 150 155 160

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

165 170 175

Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 318

<211> 331

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 318

Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr

1 5 10 15

Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu

20 25 30

His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val

35 40 45

Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg Thr Asp

50 55 60

Cys Val Ala Thr Glu Glu Asn Pro Gln Val Tyr Phe Cys Cys Cys Glu

65 70 75 80

Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val

85 90 95

Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro

100 105 110

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

115 120 125

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

130 135 140

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

145 150 155 160

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

165 170 175

Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 319

<211> 330

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 319

Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn

1 5 10 15

Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu His

20 25 30

Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val Lys

35 40 45

Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg Thr Asp Cys

50 55 60

Val Glu Lys Lys Asp Ser Pro Glu Val Tyr Phe Cys Cys Cys Glu Gly

65 70 75 80

Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr

85 90 95

Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

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

260 265 270

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

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 320

<211> 330

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 320

Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn

1 5 10 15

Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu His

20 25 30

Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val Lys

35 40 45

Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg Thr Asp Cys

50 55 60

Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly

65 70 75 80

Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr

85 90 95

Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

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

260 265 270

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

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 321

<211> 330

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 321

Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn

1 5 10 15

Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu His

20 25 30

Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val Lys

35 40 45

Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr Asp Cys

50 55 60

Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly

65 70 75 80

Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr

85 90 95

Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

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

260 265 270

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

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 322

<211> 330

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 322

Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn

1 5 10 15

Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu His

20 25 30

Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val Lys

35 40 45

Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg Thr Asp Cys

50 55 60

Val Ala Thr Glu Glu Asn Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly

65 70 75 80

Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr

85 90 95

Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

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

260 265 270

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

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 323

<211> 337

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 323

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn Ile Ser

35 40 45

Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

Lys

<210> 324

<211> 337

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 324

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Glu Thr

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

Lys

<210> 325

<211> 339

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 325

Gly Ala Ile Leu Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys

20 25 30

Glu Gly Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn

35 40 45

Ser Ser Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

Pro Gly Lys

<210> 326

<211> 339

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 326

Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Ile Tyr Tyr Asn

1 5 10 15

Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys

20 25 30

Glu Gly Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn

35 40 45

Ser Ser Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp

50 55 60

Phe Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro

65 70 75 80

Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe

85 90 95

Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

Pro Gly Lys

<210> 327

<211> 337

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 327

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Lys Asp Ser Pro Glu Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

Lys

<210> 328

<211> 337

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 328

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Lys Glu Asn Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

Lys

<210> 329

<211> 336

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 329

Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp

1 5 10 15

Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu

20 25 30

Gln Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn Ile Ser Gly

35 40 45

Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys

50 55 60

Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr

65 70 75 80

Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe

85 90 95

Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

<210> 330

<211> 336

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 330

Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp

1 5 10 15

Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu

20 25 30

Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly

35 40 45

Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Glu Thr Cys

50 55 60

Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr

65 70 75 80

Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe

85 90 95

Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

<210> 331

<211> 337

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 331

Ile Leu Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

Lys

<210> 332

<211> 337

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 332

Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

Lys

<210> 333

<211> 336

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 333

Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp

1 5 10 15

Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu

20 25 30

Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly

35 40 45

Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys

50 55 60

Tyr Asp Arg Gln Glu Cys Val Ala Thr Lys Asp Ser Pro Glu Val Tyr

65 70 75 80

Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe

85 90 95

Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

<210> 334

<211> 336

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 334

Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp

1 5 10 15

Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu

20 25 30

Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly

35 40 45

Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys

50 55 60

Tyr Asp Arg Gln Glu Cys Val Ala Thr Lys Glu Asn Pro Gln Val Tyr

65 70 75 80

Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe

85 90 95

Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

<210> 335

<211> 335

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 335

Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu

1 5 10 15

Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln

20 25 30

Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn Ile Ser Gly Ser

35 40 45

Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr

50 55 60

Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe

65 70 75 80

Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro

85 90 95

Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His

100 105 110

Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

<210> 336

<211> 335

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 336

Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu

1 5 10 15

Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln

20 25 30

Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr

35 40 45

Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Glu Thr Cys Tyr

50 55 60

Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe

65 70 75 80

Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro

85 90 95

Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His

100 105 110

Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

<210> 337

<211> 336

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 337

Leu Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp

1 5 10 15

Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu

20 25 30

Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly

35 40 45

Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys

50 55 60

Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr

65 70 75 80

Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe

85 90 95

Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

<210> 338

<211> 336

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 338

Leu Gly Arg Ser Glu Thr Gln Glu Cys Ile Tyr Tyr Asn Ala Asn Trp

1 5 10 15

Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu

20 25 30

Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly

35 40 45

Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys

50 55 60

Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr

65 70 75 80

Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe

85 90 95

Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

<210> 339

<211> 335

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 339

Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu

1 5 10 15

Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln

20 25 30

Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr

35 40 45

Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr

50 55 60

Asp Arg Gln Glu Cys Val Ala Thr Lys Asp Ser Pro Glu Val Tyr Phe

65 70 75 80

Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro

85 90 95

Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His

100 105 110

Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

<210> 340

<211> 335

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 340

Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu

1 5 10 15

Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln

20 25 30

Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr

35 40 45

Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr

50 55 60

Asp Arg Gln Glu Cys Val Ala Thr Lys Glu Asn Pro Gln Val Tyr Phe

65 70 75 80

Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro

85 90 95

Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His

100 105 110

Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

<210> 341

<211> 334

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 341

Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu

1 5 10 15

Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp

20 25 30

Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn Ile Ser Gly Ser Ile

35 40 45

Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp

50 55 60

Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys

65 70 75 80

Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu

85 90 95

Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330

<210> 342

<211> 334

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 342

Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu

1 5 10 15

Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp

20 25 30

Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile

35 40 45

Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Glu Thr Cys Tyr Asp

50 55 60

Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys

65 70 75 80

Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu

85 90 95

Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330

<210> 343

<211> 335

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 343

Gly Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu

1 5 10 15

Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln

20 25 30

Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr

35 40 45

Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr

50 55 60

Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe

65 70 75 80

Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro

85 90 95

Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His

100 105 110

Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

<210> 344

<211> 335

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 344

Gly Arg Ser Glu Thr Gln Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu

1 5 10 15

Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln

20 25 30

Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr

35 40 45

Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr

50 55 60

Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe

65 70 75 80

Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro

85 90 95

Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His

100 105 110

Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

<210> 345

<211> 334

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 345

Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu

1 5 10 15

Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp

20 25 30

Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile

35 40 45

Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp

50 55 60

Arg Gln Glu Cys Val Ala Thr Lys Asp Ser Pro Glu Val Tyr Phe Cys

65 70 75 80

Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu

85 90 95

Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330

<210> 346

<211> 334

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 346

Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu

1 5 10 15

Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp

20 25 30

Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile

35 40 45

Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp

50 55 60

Arg Gln Glu Cys Val Ala Thr Lys Glu Asn Pro Gln Val Tyr Phe Cys

65 70 75 80

Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu

85 90 95

Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

180 185 190

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

195 200 205

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

210 215 220

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

225 230 235 240

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

245 250 255

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

260 265 270

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

275 280 285

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

290 295 300

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

305 310 315 320

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 347

<211> 333

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 347

Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu

1 5 10 15

Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys

20 25 30

Arg Arg His Cys Phe Ala Thr Trp Lys Asn Ile Ser Gly Ser Ile Glu

35 40 45

Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg

50 55 60

Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys

65 70 75 80

Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met

85 90 95

Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys

100 105 110

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu

115 120 125

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

130 135 140

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

145 150 155 160

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

165 170 175

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

180 185 190

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

195 200 205

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys

210 215 220

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

225 230 235 240

Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

245 250 255

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

260 265 270

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

275 280 285

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

290 295 300

Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

305 310 315 320

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 348

<211> 333

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 348

Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu

1 5 10 15

Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys

20 25 30

Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu

35 40 45

Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Glu Thr Cys Tyr Asp Arg

50 55 60

Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys

65 70 75 80

Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met

85 90 95

Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys

100 105 110

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu

115 120 125

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

130 135 140

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

145 150 155 160

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

165 170 175

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

180 185 190

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

195 200 205

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys

210 215 220

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

225 230 235 240

Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

245 250 255

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

260 265 270

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

275 280 285

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

290 295 300

Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

305 310 315 320

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 349

<211> 334

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 349

Arg Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu

1 5 10 15

Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp

20 25 30

Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile

35 40 45

Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp

50 55 60

Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys

65 70 75 80

Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu

85 90 95

Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr

100 105 110

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

115 120 125

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

130 135 140

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

145 150 155 160

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

165 170 175

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

180 185 190

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

195 200 205

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

210 215 220

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

225 230 235 240

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

245 250 255

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

260 265 270

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

275 280 285

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

290 295 300

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

305 310 315 320

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 350

<211> 334

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 350

Arg Ser Glu Thr Gln Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu

1 5 10 15

Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp

20 25 30

Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile

35 40 45

Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp

50 55 60

Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys

65 70 75 80

Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu

85 90 95

Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr

100 105 110

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

115 120 125

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

130 135 140

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

145 150 155 160

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

165 170 175

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

180 185 190

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

195 200 205

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

210 215 220

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

225 230 235 240

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

245 250 255

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

260 265 270

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

275 280 285

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

290 295 300

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

305 310 315 320

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 351

<211> 333

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 351

Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu

1 5 10 15

Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys

20 25 30

Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu

35 40 45

Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg

50 55 60

Gln Glu Cys Val Ala Thr Lys Asp Ser Pro Glu Val Tyr Phe Cys Cys

65 70 75 80

Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met

85 90 95

Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys

100 105 110

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu

115 120 125

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

130 135 140

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

145 150 155 160

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

165 170 175

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

180 185 190

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

195 200 205

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys

210 215 220

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

225 230 235 240

Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

245 250 255

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

260 265 270

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

275 280 285

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

290 295 300

Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

305 310 315 320

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 352

<211> 333

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 352

Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu

1 5 10 15

Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys

20 25 30

Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu

35 40 45

Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg

50 55 60

Gln Glu Cys Val Ala Thr Lys Glu Asn Pro Gln Val Tyr Phe Cys Cys

65 70 75 80

Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met

85 90 95

Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys

100 105 110

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu

115 120 125

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

130 135 140

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

145 150 155 160

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

165 170 175

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

180 185 190

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

195 200 205

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys

210 215 220

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

225 230 235 240

Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

245 250 255

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

260 265 270

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

275 280 285

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

290 295 300

Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

305 310 315 320

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 353

<211> 332

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 353

Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg

1 5 10 15

Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg

20 25 30

Arg His Cys Phe Ala Thr Trp Lys Asn Ile Ser Gly Ser Ile Glu Ile

35 40 45

Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr

50 55 60

Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys

65 70 75 80

Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu

85 90 95

Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro

100 105 110

Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe

115 120 125

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val

130 135 140

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe

145 150 155 160

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

165 170 175

Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

180 185 190

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

195 200 205

Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala

210 215 220

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg

225 230 235 240

Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

245 250 255

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

260 265 270

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

275 280 285

Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln

290 295 300

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

305 310 315 320

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 354

<211> 332

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 354

Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg

1 5 10 15

Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg

20 25 30

Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile

35 40 45

Val Lys Gln Gly Cys Trp Leu Asp Asp Glu Thr Cys Tyr Asp Arg Thr

50 55 60

Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys

65 70 75 80

Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu

85 90 95

Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro

100 105 110

Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe

115 120 125

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val

130 135 140

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe

145 150 155 160

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

165 170 175

Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

180 185 190

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

195 200 205

Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala

210 215 220

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg

225 230 235 240

Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

245 250 255

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

260 265 270

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

275 280 285

Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln

290 295 300

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

305 310 315 320

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 355

<211> 333

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 355

Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu

1 5 10 15

Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys

20 25 30

Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu

35 40 45

Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg

50 55 60

Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys

65 70 75 80

Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met

85 90 95

Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys

100 105 110

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu

115 120 125

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

130 135 140

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

145 150 155 160

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

165 170 175

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

180 185 190

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

195 200 205

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys

210 215 220

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

225 230 235 240

Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

245 250 255

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

260 265 270

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

275 280 285

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

290 295 300

Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

305 310 315 320

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 356

<211> 333

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 356

Ser Glu Thr Gln Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu

1 5 10 15

Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys

20 25 30

Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu

35 40 45

Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg

50 55 60

Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys

65 70 75 80

Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met

85 90 95

Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys

100 105 110

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu

115 120 125

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

130 135 140

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

145 150 155 160

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

165 170 175

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

180 185 190

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

195 200 205

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys

210 215 220

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

225 230 235 240

Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

245 250 255

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

260 265 270

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

275 280 285

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

290 295 300

Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

305 310 315 320

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 357

<211> 332

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 357

Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg

1 5 10 15

Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg

20 25 30

Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Leu

35 40 45

Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Gln

50 55 60

Glu Cys Val Ala Thr Lys Asp Ser Pro Glu Val Tyr Phe Cys Cys Cys

65 70 75 80

Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu

85 90 95

Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro

100 105 110

Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe

115 120 125

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val

130 135 140

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe

145 150 155 160

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

165 170 175

Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

180 185 190

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

195 200 205

Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala

210 215 220

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg

225 230 235 240

Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

245 250 255

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

260 265 270

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

275 280 285

Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln

290 295 300

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

305 310 315 320

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 358

<211> 332

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 358

Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg

1 5 10 15

Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg

20 25 30

Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Leu

35 40 45

Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Gln

50 55 60

Glu Cys Val Ala Thr Lys Glu Asn Pro Gln Val Tyr Phe Cys Cys Cys

65 70 75 80

Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu

85 90 95

Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro

100 105 110

Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe

115 120 125

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val

130 135 140

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe

145 150 155 160

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

165 170 175

Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

180 185 190

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

195 200 205

Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala

210 215 220

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg

225 230 235 240

Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

245 250 255

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

260 265 270

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

275 280 285

Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln

290 295 300

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

305 310 315 320

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 359

<211> 331

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 359

Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr

1 5 10 15

Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Arg

20 25 30

His Cys Phe Ala Thr Trp Lys Asn Ile Ser Gly Ser Ile Glu Ile Val

35 40 45

Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr Asp

50 55 60

Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu

65 70 75 80

Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val

85 90 95

Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro

100 105 110

Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

115 120 125

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

130 135 140

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

145 150 155 160

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

165 170 175

Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

180 185 190

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

195 200 205

Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys

210 215 220

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp

225 230 235 240

Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

245 250 255

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

260 265 270

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

275 280 285

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

290 295 300

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

305 310 315 320

Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 360

<211> 331

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 360

Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr

1 5 10 15

Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu

20 25 30

His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val

35 40 45

Lys Gln Gly Cys Trp Leu Asp Asp Glu Thr Cys Tyr Asp Arg Thr Asp

50 55 60

Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu

65 70 75 80

Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val

85 90 95

Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro

100 105 110

Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

115 120 125

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

130 135 140

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

145 150 155 160

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

165 170 175

Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

180 185 190

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

195 200 205

Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys

210 215 220

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp

225 230 235 240

Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

245 250 255

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

260 265 270

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

275 280 285

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

290 295 300

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

305 310 315 320

Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 361

<211> 330

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 361

Gln Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn

1 5 10 15

Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu His

20 25 30

Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val Lys

35 40 45

Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr Asp Cys

50 55 60

Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly

65 70 75 80

Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr

85 90 95

Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

225 230 235 240

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 362

<211> 332

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 362

Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg

1 5 10 15

Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg

20 25 30

Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile

35 40 45

Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr

50 55 60

Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys

65 70 75 80

Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu

85 90 95

Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro

100 105 110

Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe

115 120 125

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val

130 135 140

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe

145 150 155 160

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

165 170 175

Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

180 185 190

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

195 200 205

Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala

210 215 220

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg

225 230 235 240

Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

245 250 255

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

260 265 270

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

275 280 285

Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln

290 295 300

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

305 310 315 320

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 363

<211> 332

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 363

Glu Thr Gln Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg

1 5 10 15

Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg

20 25 30

Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile

35 40 45

Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr

50 55 60

Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys

65 70 75 80

Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu

85 90 95

Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro

100 105 110

Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe

115 120 125

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val

130 135 140

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe

145 150 155 160

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

165 170 175

Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

180 185 190

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

195 200 205

Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala

210 215 220

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg

225 230 235 240

Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

245 250 255

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

260 265 270

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

275 280 285

Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln

290 295 300

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

305 310 315 320

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 364

<211> 331

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 364

Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr

1 5 10 15

Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu

20 25 30

His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Leu Val

35 40 45

Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Gln Glu

50 55 60

Cys Val Ala Thr Lys Asp Ser Pro Glu Val Tyr Phe Cys Cys Cys Glu

65 70 75 80

Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val

85 90 95

Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro

100 105 110

Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

115 120 125

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

130 135 140

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

145 150 155 160

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

165 170 175

Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

180 185 190

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

195 200 205

Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys

210 215 220

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp

225 230 235 240

Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

245 250 255

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

260 265 270

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

275 280 285

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

290 295 300

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

305 310 315 320

Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 365

<211> 331

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 365

Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr

1 5 10 15

Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu

20 25 30

His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Leu Val

35 40 45

Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Gln Glu

50 55 60

Cys Val Ala Thr Lys Glu Asn Pro Gln Val Tyr Phe Cys Cys Cys Glu

65 70 75 80

Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val

85 90 95

Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro

100 105 110

Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

115 120 125

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

130 135 140

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

145 150 155 160

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

165 170 175

Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

180 185 190

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

195 200 205

Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys

210 215 220

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp

225 230 235 240

Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

245 250 255

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

260 265 270

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

275 280 285

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

290 295 300

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

305 310 315 320

Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 366

<211> 330

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 366

Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn

1 5 10 15

Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Arg His

20 25 30

Cys Phe Ala Thr Trp Lys Asn Ile Ser Gly Ser Ile Glu Ile Val Lys

35 40 45

Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr Asp Cys

50 55 60

Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly

65 70 75 80

Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr

85 90 95

Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

225 230 235 240

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 367

<211> 330

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 367

Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn

1 5 10 15

Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu His

20 25 30

Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val Lys

35 40 45

Gln Gly Cys Trp Leu Asp Asp Glu Thr Cys Tyr Asp Arg Thr Asp Cys

50 55 60

Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly

65 70 75 80

Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr

85 90 95

Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

225 230 235 240

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 368

<211> 331

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 368

Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr

1 5 10 15

Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu

20 25 30

His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val

35 40 45

Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr Asp

50 55 60

Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu

65 70 75 80

Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val

85 90 95

Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro

100 105 110

Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

115 120 125

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

130 135 140

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

145 150 155 160

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

165 170 175

Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

180 185 190

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

195 200 205

Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys

210 215 220

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp

225 230 235 240

Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

245 250 255

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

260 265 270

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

275 280 285

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

290 295 300

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

305 310 315 320

Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 369

<211> 331

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 369

Thr Gln Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr

1 5 10 15

Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu

20 25 30

His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val

35 40 45

Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr Asp

50 55 60

Cys Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu

65 70 75 80

Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val

85 90 95

Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro

100 105 110

Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

115 120 125

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

130 135 140

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

145 150 155 160

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

165 170 175

Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

180 185 190

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

195 200 205

Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys

210 215 220

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp

225 230 235 240

Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

245 250 255

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

260 265 270

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

275 280 285

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

290 295 300

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

305 310 315 320

Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 370

<211> 330

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 370

Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn

1 5 10 15

Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu His

20 25 30

Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Leu Val Lys

35 40 45

Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Gln Glu Cys

50 55 60

Val Ala Thr Lys Asp Ser Pro Glu Val Tyr Phe Cys Cys Cys Glu Gly

65 70 75 80

Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr

85 90 95

Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

225 230 235 240

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 371

<211> 330

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 371

Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn

1 5 10 15

Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu His

20 25 30

Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Leu Val Lys

35 40 45

Lys Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Gln Glu Cys

50 55 60

Val Ala Thr Lys Glu Asn Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly

65 70 75 80

Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr

85 90 95

Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

225 230 235 240

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 372

<211> 330

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 372

Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn

1 5 10 15

Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu His

20 25 30

Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Ile Val Lys

35 40 45

Gln Gly Cys Trp Leu Asp Asp Phe Asn Cys Tyr Asp Arg Thr Asp Cys

50 55 60

Val Glu Lys Lys Asp Ser Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly

65 70 75 80

Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr

85 90 95

Gln Pro Thr Ser Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

225 230 235 240

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 373

<211> 337

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 373

Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn

1 5 10 15

Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly

20 25 30

Glu Gln Arg Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser

35 40 45

Gly Thr Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Phe Asn

50 55 60

Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Gln Val

65 70 75 80

Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr

85 90 95

Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Gly Gly Gly Asp Lys

100 105 110

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

115 120 125

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

130 135 140

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

145 150 155 160

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

165 170 175

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

180 185 190

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

195 200 205

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

210 215 220

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

225 230 235 240

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

245 250 255

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

260 265 270

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

275 280 285

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

290 295 300

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

305 310 315 320

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

325 330 335

Lys

<210> 374

<211> 4

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 374

Thr Glu Glu Asn

1

<210> 375

<211> 4

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 375

Thr Lys Glu Asn

1

<210> 376

<211> 22

<212> DNA

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 376

ttcagcggat tctggagtgc ct 22

<210> 377

<211> 22

<212> DNA

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 377

agcaacagcg agatgaggac ca 22

<210> 378

<211> 17

<212> DNA

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 378

catcgtgggc cgcccta 17

<210> 379

<211> 22

<212> DNA

<213> Artificial sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 379

cacccacata ggagtccttc tg 22

Claims (34)

1. A method of treating a subject having a disease or condition treatable with erythropoietin or an erythropoiesis stimulating agent, the method comprising administering to the subject a therapeutically effective amount of a composition of table 10, a composition of table 11, or a composition of table 12.

2. A method of increasing erythropoietin levels in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition of table 10, a composition of table 11, or a composition of table 12.

3. A method of increasing the level of an erythropoietin receptor in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition of table 10, a composition of table 11, or a composition of table 12.

4. The method of any one of claims 1-3, wherein the subject has or is at risk of developing anemia due to dialysis or anemia of premature infants.

5. The method of any one of claims 1-3, wherein the subject has or is at risk of developing: end stage renal disease, renal insufficiency, polycythemia, hemochromatosis, diseases or conditions associated with endothelial progenitor cell dysfunction, diseases or conditions having an autoimmune or inflammatory component, neurological or inflammatory encephalopathy, gastrointestinal motility disorders, endocrinological disorders, reproductive system diseases, aging, pregnancy, menstrual disorders, ischemic or ischemic disorders or conditions, anoxic or anoxic disorders or conditions, ulcers, burns, wounds, ischemia-reperfusion injury, asthma, hypertension, viral diseases or infections, systemic microbial infections, gastrointestinal diseases, arteriosclerosis, cancer, psychosis, genetic diseases, inflammatory diseases, graft versus host diseases, cardiovascular diseases, allergic reactions or arthritis.

6. The method of claim 5, wherein the ischemia is central nervous system ischemia, liver ischemia, kidney ischemia, or cardiac ischemia.

7. The method of claim 5, wherein the ischemic condition or disorder is an obstructive arterial disease, chronic venous insufficiency, circulatory shock, pulmonary embolism, myocardial infarction, ischemic stroke, acute respiratory failure, chronic heart failure, atherosclerosis, cardiac cirrhosis, macular degeneration, sleep apnea, raynaud's disease, systemic sclerosis, non-bacterial thrombotic endocarditis, transient ischemic attacks, or ischemia caused by general anesthesia.

8. The method of claim 5, wherein the hypoxic condition or disorder is a pulmonary condition, severe pneumonia, pulmonary edema, hyaline membrane disease, liver disease, kidney disease, cancer, or altitude disease.

9. The method of claim 5, wherein the viral disease or infection is a hepatitis C virus infection or an HIV infection.

10. The method of claim 5, wherein the disease or disorder associated with endothelial progenitor cell dysfunction is heart failure, angina, endothelial proliferation, reticuloendotheliosis, age-related cardiovascular disorder, coronary heart disease, atherosclerosis, myocardial ischemia, hypercholesterolemia, limb ischemic disorder, raynaud's disease, preeclampsia, pregnancy induced hypertension, endothelial-mediated chronic inflammatory disorder, wound healing, chronic renal failure, or acute renal failure.

11. The method of claim 10, wherein the disease or disorder associated with endothelial progenitor cell dysfunction is chronic renal failure.

12. The method of claim 5, wherein the autoimmune or inflammatory disease or disorder is acute cerebrovascular injury, acute brain injury, acute cardiovascular injury, arthritis, autoimmune disease, stroke, nerve injury, or immune-mediated inflammation.

13. The method of claim 5, wherein the neurological disorder or inflammatory brain disease is a demyelinating disease, epilepsy, spinal cord injury, post traumatic brain injury complications, chronic inflammatory brain disease, or a neurological disorder associated with surgery.

14. The method of claim 13, wherein the chronic inflammatory brain disease is a neurodegenerative disease.

15. The method of claim 14, wherein the neurodegenerative disease is alzheimer's disease, parkinson's disease, huntington's disease, amyotrophic Lateral Sclerosis (ALS), or age-related macular degeneration (AMD).

16. The method of claim 13, wherein the demyelinating disease is multiple sclerosis, neuromyelitis optica, acute disseminated encephalomyelitis, or transverse myelitis.

17. The method of claim 5, wherein the gastrointestinal motility disorder is associated with: intestinal injury, abdominal trauma, inflammatory disorders of the intestinal tract, intestinal infection, chronic constipation, postoperative ileus, neurodegenerative injury, neurotraumatic injury, congenital problems or malnutrition-malabsorption problems.

18. The method of claim 17, wherein the intestinal infection is a bacterial infection, peritonitis, or ascites.

19. The method of claim 17, wherein the intestinal inflammatory disorder is inflammatory bowel disease, crohn's disease, or ulcerative colitis.

20. The method of claim 17, wherein the chronic-transmission constipation is chronic constipation, idiopathic constipation, constipation due to post-operative ileus, or constipation caused by opiate use.

21. The method of claim 17, wherein the congenital condition is abdominal fissure, umbilical hernia, ganglionic megacolon, helschlerian disease, chronic intestinal pseudo-obstruction, left small colon syndrome, anorectal abnormalities, esophageal dysplasia and closure, anal closure, congenital hernia, or internal anal sphincter relaxant.

22. The method of claim 17, wherein the malnutrition-malabsorption problem is associated with: intestinal injury, abdominal trauma, intestinal inflammatory disorders, intestinal infection, constipation, post-operative ileus, neurodegenerative injury, neurotraumatic injury, congenital problems, gaucher's disease, refeeding syndrome, very low birth weight, cancer cachexia, infection, cancer, spinal cord dysfunction, spinal cord insufficiency, spinal fissures, tumors, central nervous system dysfunction, peripheral neuropathy, removal of a portion of the gastrointestinal tract, bleeding, liver dysfunction, celiac disease, cystic fibrosis, muscular dystrophy, or cerebral palsy.

23. The method of claim 5, wherein the subject has or is at risk of developing end stage renal disease.

24. The method of claim 5, wherein the subject has or is at risk of developing polycythemia.

25. The method of any one of claims 1-24, wherein the composition of table 10, table 11, or table 12 is administered to the subject prior to surgery, after stem cell transplantation, prior to or during space flight, during or after tissue or organ transplantation to promote neovascular growth, form granulation tissue, perform wound therapy, or perform post-vascular transplantation therapy.

26. The method of any one of claims 1-25, wherein the subject is undergoing kidney dialysis.

27. The method of any one of claims 1-3 and 5-26, wherein the subject does not have anemia.

28. The method of any one of claims 1-3 and 5-27, wherein the subject has normal hematopoiesis.

29. The method of any one of claims 1-28, wherein the subject has low serum erythropoietin.

30. A method of preparing a tissue or organ for transplantation, the method comprising contacting the tissue or organ with a therapeutically effective amount of a composition of table 10, a composition of table 11, or a composition of table 12.

31. The method of any one of claims 1-30, wherein the method comprises administering to the subject a therapeutically effective amount of a composition of table 10.

32. The method of any one of claims 1-30, wherein the method comprises administering to the subject a therapeutically effective amount of the composition of table 11.

33. The method of any one of claims 1-30, wherein the method comprises administering to the subject a therapeutically effective amount of a composition of table 12.

34. The method of any one of claims 1-33, wherein the composition is administered in an amount sufficient to increase EPO levels, increase EPO receptor levels, promote neovascular growth and/or replace damaged vascular areas, promote granulation tissue formation, reduce infiltration of monocytes into the brain of the subject, improve neurological deficit, reduce axonal damage, reduce neuronal cell death, reduce glial cell death, affect myostatin, activin a, activin B, and/or BMP9 signaling or reduce or inhibit activin a, activin B, and/or myostatin binding to its receptor in the subject.